Details of the Researcher

PHOTO

Juro Sakai
Section
Graduate School of Medicine
Job title
Professor
Degree

  • 博士（医学）（東北大学）

e-Rad No.
80323020

Research History 8

  • 2023/04 - Present
    東京大学先端科学技術研究センター　代謝医学分野　客員教授

  • 2020/04 - Present
    東北大学 大学院医学系研究科 細胞生物学講座 分子代謝生理学分野 (分野名改称)　教授

  • 2009/07 - 2023/03
    The University of Tokyo　Research Center for Advanced Science and Technology

  • 2017/04 - 2020/03
    Tohoku University　Graduate School of Medicine

  • 2003/01 - 2009/06
    The University of Tokyo　Research Center for Advanced Science and Technology

  • 2001/12 - 2006/03
    科学技術振興事業団 創造科学技術推進事業　柳沢オーファン受容体プロジェクト　グループリーダー

  • 2000/04 - 2001/12
    Tohoku University

  • 1994/09 - 1998/10
    米国テキサス州立テキサス大学サウスウェスタンメディカルセンター　分子遺伝学講座　博士研究員

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Education 2

  • 東北大学大学院　医学研究科内科学系

    1990/04 - 1994/03

  • Tohoku University　Faculty of Medicine

    1982/04 - 1988/03

Committee Memberships 2

  • Chonnam National University, the Host Directed Antiviral Research Center　International advisory committee member

    2023/11 - Present

  • 日本内分泌学会　理事

    2023/04 - Present

Professional Memberships 12

  • 日本生理学会

  • 日本心血管内分泌学会

  • 日本臨床分子医学会

  • 日本血管生物医学会

  • 日本高血圧学会

  • The Japan Endocrine Society

  • THE JAPAN DIABETES SOCIETY

  • JAPAN SOCIETY FOR THE STUDY OF OBESITY

  • THE MOLECULAR BIOLOGY SOCIETY OF JAPAN

  • THE JAPANESE SOCIETY OF INTERNAL MEDICINE

  • THE JAPANESE BIOCHEMICAL SOCIETY

  • JAPAN ATHEROSCLEROSIS SOCIETY

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Research Areas 2

  • Life sciences / Clinical pharmacy /

  • Life sciences / Physiology /

Awards 4

  1. 第16回柿内三郎記念賞

    2021/11　公益社団法人 日本生化学会　エピゲノム因子によるシグナル感知とエピゲノム制御による環境への適応機構の解明

  2. 第6回 五島雄一郎賞

    2011/07　日本動脈硬化学会

  3. 第39回最優秀理事長賞

    2008/10　財団法人 病態代謝研究会

  4. 岡本研究奨励賞

    2001　財団法人成人血管病研究振興財団

Papers 134

  1. Glucose-activated JMJD1A drives visceral adipogenesis via α-ketoglutarate-dependent chromatin remodeling

    Chenxu Yang, Makoto Arai, Eko Fuji Ariyanto, Ji Zhang, Debby Mirani Lubis, Ryo Ito, Shiyu Xie, Mio Nitta, Fuka Kawashima, Tomofumi Ishitsuka, Chaoran Yang, Tomohiro Suzuki, Tetsuro Komatsu, Hina Sagae, Hitomi Jin, Hiroki Takahashi, Eri Kobayashi, Yuchen Wei, Bohao Liu, Hyunmi Choi, Youichiro Wada, Toshiya Tanaka, Tsuyoshi Osawa, Hiroshi Kimura, Tatsuhiko Kodama, Hiroyuki Aburatani, Makoto Tachibana, Yoichi Shinkai, Takeshi Inagaki, Tomoyoshi Soga, Timothy F. Osborne, Takeshi Yoneshiro, Yoshihiro Matsumura, Juro Sakai

    Cell Reports　44　(8)　116060-116060　2025/08

    Publisher: Elsevier BV

    DOI： 10.1016/j.celrep.2025.116060 　

    ISSN： 2211-1247

  2. Brown fat thermogenesis and cold adaptation in humans. International-journal

    Takeshi Yoneshiro, Mami Matsushita, Juro Sakai, Masayuki Saito

    Journal of physiological anthropology　44　(1)　11-11　2025/04/21

    DOI： 10.1186/s40101-025-00391-w 　

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    Brown adipose tissue (BAT) is a site of non-shivering thermogenesis (NST) in mammals. Since the rediscovery of BAT in adult humans, there has been a remarkable advance in human BAT researches, revealing the significant roles of this thermogenic tissue in cold-induced NST and cold adaptation. Cold stress influences BAT in various time spans: acute cold exposure promptly activates BAT to induce NST, which contributes to immediate maintenance of body temperature. Prolonged cold exposure recruits BAT, resulting in increased capacity of NST and improved cold tolerance. Such BAT adaptation not only occurs in the exposed individual but also is passed on to the next generation, probably via the paternal lineage. As such, BAT plays a role in acute, chronic, and transgenerational adaptation to cold environment in humans.

  3. Pre-fertilization-origin preservation of brown fat-mediated energy expenditure in humans

    Takeshi Yoneshiro, Mami Matsushita, Sayuri Fuse-Hamaoka, Miyuki Kuroiwa, Yuko Kurosawa, Yosuke Yamada, Makoto Arai, Yuchen Wei, Makoto Iida, Kenichi Kuma, Toshimitsu Kameya, Tomoya Harada, Yoshihiro Matsumura, Tsuyoshi Osawa, Yoshiko Aoki, Hisashi Nakamura, Takafumi Hamaoka, Juro Sakai, Masayuki Saito

    Nature Metabolism　7　(4)　778-791　2025/04/07

    Publisher: Springer Science and Business Media LLC

    DOI： 10.1038/s42255-025-01249-2 　

    eISSN： 2522-5812

  4. Acetate derived from the intestinal tract has a critical role in maintaining skeletal muscle mass and strength in mice. International-journal Peer-reviewed

    Saki Kobayashi, Katsutaro Morino, Takuya Okamoto, Mitsumi Tanaka, Shogo Ida, Natsuko Ohashi, Koichiro Murata, Tsuyoshi Yanagimachi, Juro Sakai, Hiroshi Maegawa, Yukihiro Fujita, Shinji Kume

    Physiological reports　12　(11)　e16047　2024/06

    DOI： 10.14814/phy2.16047 　

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    Acetate is a short-chain fatty acid (SCFA) that is produced by microbiota in the intestinal tract. It is an important nutrient for the intestinal epithelium, but also has a high plasma concentration and is used in the various tissues. Acetate is involved in endurance exercise, but its role in resistance exercise remains unclear. To investigate this, mice were administered either multiple antibiotics with and without oral acetate supplementation or fed a low-fiber diet. Antibiotic treatment for 2 weeks significantly reduced grip strength and the cross-sectional area (CSA) of muscle fiber compared with the control group. Intestinal concentrations of SCFAs were reduced in the antibiotic-treated group. Oral administration of acetate with antibiotics prevented antibiotic-induced weakness of skeletal muscle and reduced CSA of muscle fiber. Similarly, a low-fiber diet for 1 year significantly reduced the CSA of muscle fiber and fecal and plasma acetate concentrations. To investigate the role of acetate as an energy source, acetyl-CoA synthase 2 knockout mice were used. These mice had a shorter lifespan, reduced skeletal muscle mass and smaller CSA of muscle fiber than their wild type littermates. In conclusion, acetate derived from the intestinal microbiome can contribute to maintaining skeletal muscle performance.

  5. Mitochondrial biogenesis in white adipose tissue mediated by JMJD1A-PGC-1 axis limits age-related metabolic disease. International-journal Peer-reviewed

    Ryo Ito, Shiyu Xie, Myagmar Tumenjargal, Yuto Sugahara, Chaoran Yang, Hiroki Takahashi, Makoto Arai, Shin-Ichi Inoue, Aoi Uchida, Kenji Nakano, Hyunmi Choi, Ge Yang, Yanan Zhao, Rei Yamaguchi, Hitomi Jin, Hina Sagae, Youichiro Wada, Toshiya Tanaka, Hiroshi Kimura, Tatsuhiko Kodama, Hiroyuki Aburatani, Kazuhisa Takeda, Takeshi Inagaki, Timothy F Osborne, Takeshi Yoneshiro, Yoshihiro Matsumura, Juro Sakai

    iScience　27　(4)　109398-109398　2024/04/19

    DOI： 10.1016/j.isci.2024.109398 　

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    Mitochondria play a vital role in non-shivering thermogenesis in both brown and subcutaneous white adipose tissues (BAT and scWAT, respectively). However, specific regulatory mechanisms driving mitochondrial function in these tissues have been unclear. Here we demonstrate that prolonged activation of β-adrenergic signaling induces epigenetic modifications in scWAT, specifically targeting the enhancers for the mitochondria master regulator genes Pgc1a/b. This is mediated at least partially through JMJD1A, a histone demethylase that in response to β-adrenergic signals, facilitates H3K9 demethylation of the Pgc1a/b enhancers, promoting mitochondrial biogenesis and the formation of beige adipocytes. Disruption of demethylation activity of JMJD1A in mice impairs activation of Pgc1a/b driven mitochondrial biogenesis and limits scWAT beiging, contributing to reduced energy expenditure, obesity, insulin resistance, and metabolic disorders. Notably, JMJD1A demethylase activity is not required for Pgc1a/b dependent thermogenic capacity of BAT especially during acute cold stress, emphasizing the importance of scWAT thermogenesis in overall energy metabolism.

  6. A TLR4/TRAF6-dependent signaling pathway mediates NCoR coactivator complex formation for inflammatory gene activation. International-journal Peer-reviewed

    Yohei Abe, Eric R Kofman, Zhengyu Ouyang, Grisel Cruz-Becerra, Nathanael J Spann, Jason S Seidman, Ty D Troutman, Joshua D Stender, Havilah Taylor, Weiwei Fan, Verena M Link, Zeyang Shen, Juro Sakai, Michael Downes, Ronald M Evans, James T Kadonaga, Michael G Rosenfeld, Christopher K Glass

    Proceedings of the National Academy of Sciences of the United States of America　121　(2)　e2316104121　2024/01/09

    DOI： 10.1073/pnas.2316104121 　

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    The nuclear receptor corepressor (NCoR) forms a complex with histone deacetylase 3 (HDAC3) that mediates repressive functions of unliganded nuclear receptors and other transcriptional repressors by deacetylation of histone substrates. Recent studies provide evidence that NCoR/HDAC3 complexes can also exert coactivator functions in brown adipocytes by deacetylating and activating PPARγ coactivator 1α (PGC1α) and that signaling via receptor activator of nuclear factor kappa-B (RANK) promotes the formation of a stable NCoR/HDAC3/PGC1β complex that coactivates nuclear factor kappa-B (NFκB)- and activator protein 1 (AP-1)-dependent genes required for osteoclast differentiation. Here, we demonstrate that activation of Toll-like receptor (TLR) 4, but not TLR3, the interleukin 4 (IL4) receptor nor the Type I interferon receptor, also promotes assembly of an NCoR/HDAC3/PGC1β coactivator complex. Receptor-specific utilization of TNF receptor-associated factor 6 (TRAF6) and downstream activation of extracellular signal-regulated kinase 1 (ERK1) and TANK-binding kinase 1 (TBK1) accounts for the common ability of RANK and TLR4 to drive assembly of an NCoR/HDAC3/PGC1β complex in macrophages. ERK1, the p65 component of NFκB, and the p300 histone acetyltransferase (HAT) are also components of the induced complex and are associated with local histone acetylation and transcriptional activation of TLR4-dependent enhancers and promoters. These observations identify a TLR4/TRAF6-dependent signaling pathway that converts NCoR from a corepressor of nuclear receptors to a coactivator of NFκB and AP-1 that may be relevant to functions of NCoR in other developmental and homeostatic processes.

  7. Environmental factor reversibly determines cellular identity through opposing Integrators that unify epigenetic and transcriptional pathways. International-journal Peer-reviewed

    Hiroki Takahashi, Ryo Ito, Yoshihiro Matsumura, Juro Sakai

    BioEssays : news and reviews in molecular, cellular and developmental biology　e2300084　2023/11/27

    DOI： 10.1002/bies.202300084 　

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    Organisms must adapt to environmental stresses to ensure their survival and prosperity. Different types of stresses, including thermal, mechanical, and hypoxic stresses, can alter the cellular state that accompanies changes in gene expression but not the cellular identity determined by a chromatin state that remains stable throughout life. Some tissues, such as adipose tissue, demonstrate remarkable plasticity and adaptability in response to environmental cues, enabling reversible cellular identity changes; however, the mechanisms underlying these changes are not well understood. We hypothesized that positive and/or negative "Integrators" sense environmental cues and coordinate the epigenetic and transcriptional pathways required for changes in cellular identity. Adverse environmental factors such as pollution disrupt the coordinated control contributing to disease development. Further research based on this hypothesis will reveal how organisms adapt to fluctuating environmental conditions, such as temperature, extracellular matrix stiffness, oxygen, cytokines, and hormonal cues by changing their cellular identities.

  8. Hypoxia activates SREBP2 through Golgi disassembly in bone marrow-derived monocytes for enhanced tumor growth. International-journal Peer-reviewed

    Ryuichi Nakahara, Sho Aki, Maki Sugaya, Haruka Hirose, Miki Kato, Keisuke Maeda, Daichi M Sakamoto, Yasuhiro Kojima, Miyuki Nishida, Ritsuko Ando, Masashi Muramatsu, Melvin Pan, Rika Tsuchida, Yoshihiro Matsumura, Hideyuki Yanai, Hiroshi Takano, Ryoji Yao, Shinsuke Sando, Masabumi Shibuya, Juro Sakai, Tatsuhiko Kodama, Hiroyasu Kidoya, Teppei Shimamura, Tsuyoshi Osawa

    The EMBO journal　e114032　2023/10/02

    DOI： 10.15252/embj.2023114032 　

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    Bone marrow-derived cells (BMDCs) infiltrate hypoxic tumors at a pre-angiogenic state and differentiate into mature macrophages, thereby inducing pro-tumorigenic immunity. A critical factor regulating this differentiation is activation of SREBP2-a well-known transcription factor participating in tumorigenesis progression-through unknown cellular mechanisms. Here, we show that hypoxia-induced Golgi disassembly and Golgi-ER fusion in monocytic myeloid cells result in nuclear translocation and activation of SREBP2 in a SCAP-independent manner. Notably, hypoxia-induced SREBP2 activation was only observed in an immature lineage of bone marrow-derived cells. Single-cell RNA-seq analysis revealed that SREBP2-mediated cholesterol biosynthesis was upregulated in HSCs and monocytes but not in macrophages in the hypoxic bone marrow niche. Moreover, inhibition of cholesterol biosynthesis impaired tumor growth through suppression of pro-tumorigenic immunity and angiogenesis. Thus, our findings indicate that Golgi-ER fusion regulates SREBP2-mediated metabolic alteration in lineage-specific BMDCs under hypoxia for tumor progression.

  9. RANK ligand converts the NCoR/HDAC3 co-repressor to a PGC1β- and RNA-dependent co-activator of osteoclast gene expression. International-journal Peer-reviewed

    Yohei Abe, Eric R Kofman, Maria Almeida, Zhengyu Ouyang, Filipa Ponte, Jasmine R Mueller, Grisel Cruz-Becerra, Mashito Sakai, Thomas A Prohaska, Nathanael J Spann, Ana Resende-Coelho, Jason S Seidman, Joshua D Stender, Havilah Taylor, Weiwei Fan, Verena M Link, Isidoro Cobo, Johannes C M Schlachetzki, Takao Hamakubo, Kristen Jepsen, Juro Sakai, Michael Downes, Ronald M Evans, Gene W Yeo, James T Kadonaga, Stavros C Manolagas, Michael G Rosenfeld, Christopher K Glass

    Molecular cell　83　3421-3437　2023/09/14

    DOI： 10.1016/j.molcel.2023.08.029 　

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    The nuclear receptor co-repressor (NCoR) complex mediates transcriptional repression dependent on histone deacetylation by histone deacetylase 3 (HDAC3) as a component of the complex. Unexpectedly, we found that signaling by the receptor activator of nuclear factor κB (RANK) converts the NCoR/HDAC3 co-repressor complex to a co-activator of AP-1 and NF-κB target genes that are required for mouse osteoclast differentiation. Accordingly, the dominant function of NCoR/HDAC3 complexes in response to RANK signaling is to activate, rather than repress, gene expression. Mechanistically, RANK signaling promotes RNA-dependent interaction of the transcriptional co-activator PGC1β with the NCoR/HDAC3 complex, resulting in the activation of PGC1β and inhibition of HDAC3 activity for acetylated histone H3. Non-coding RNAs Dancr and Rnu12, which are associated with altered human bone homeostasis, promote NCoR/HDAC3 complex assembly and are necessary for RANKL-induced osteoclast differentiation in vitro. These findings may be prototypic for signal-dependent functions of NCoR in other biological contexts.

  10. Chemogenetic activation of G12 signaling enhances adipose tissue browning. International-journal Peer-reviewed

    Yuki Ono, Ryo Ito, Kaito Arai, Gurdeep Singh, Tsuyoshi Saitoh, Robert B Russell, Francesco Raimondi, Junken Aoki, Juro Sakai, Asuka Inoue

    Signal transduction and targeted therapy　8　(1)　307-307　2023/08/21

    DOI： 10.1038/s41392-023-01524-2 　

  11. Crucial role of iron in epigenetic rewriting during adipocyte differentiation mediated by JMJD1A and TET2 activity Peer-reviewed

    Tomohiro Suzuki, Tetsuro Komatsu, Hiroshi Shibata, Akiko Tanioka, Diana Vargas, Reika Kawabata-Iwakawa, Fumihito Miura, Shinnosuke Masuda, Mayuko Hayashi, Kyoko Tanimura-Inagaki, Sumiyo Morita, Junki Kohmaru, Koji Adachi, Masayuki Tobo, Hideru Obinata, Tasuku Hirayama, Hiroshi Kimura, Juro Sakai, Hideko Nagasawa, Hideyuki Itabashi, Izuho Hatada, Takashi Ito, Takeshi Inagaki

    Nucleic Acids Research　51　(12)　6120-6142　2023/05/09

    Publisher: Oxford University Press (OUP)

    DOI： 10.1093/nar/gkad342 　

    ISSN： 0305-1048

    eISSN： 1362-4962

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    Abstract Iron metabolism is closely associated with the pathogenesis of obesity. However, the mechanism of the iron-dependent regulation of adipocyte differentiation remains unclear. Here, we show that iron is essential for rewriting of epigenetic marks during adipocyte differentiation. Iron supply through lysosome-mediated ferritinophagy was found to be crucial during the early stage of adipocyte differentiation, and iron deficiency during this period suppressed subsequent terminal differentiation. This was associated with demethylation of both repressive histone marks and DNA in the genomic regions of adipocyte differentiation-associated genes, including Pparg, which encodes PPARγ, the master regulator of adipocyte differentiation. In addition, we identified several epigenetic demethylases to be responsible for iron-dependent adipocyte differentiation, with the histone demethylase jumonji domain-containing 1A and the DNA demethylase ten-eleven translocation 2 as the major enzymes. The interrelationship between repressive histone marks and DNA methylation was indicated by an integrated genome-wide association analysis, and was also supported by the findings that both histone and DNA demethylation were suppressed by either the inhibition of lysosomal ferritin flux or the knockdown of iron chaperone poly(rC)-binding protein 2. In summary, epigenetic regulations through iron-dependent control of epigenetic enzyme activities play an important role in the organized gene expression mechanisms of adipogenesis.

  12. Epitranscriptomics in metabolic disease. International-journal Peer-reviewed

    Yoshihiro Matsumura, Fan-Yan Wei, Juro Sakai

    Nature metabolism　5　(3)　370-384　2023/03

    DOI： 10.1038/s42255-023-00764-4 　

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    While epigenetic modifications of DNA and histones play main roles in gene transcription regulation, recently discovered post-transcriptional RNA modifications, known as epitranscriptomic modifications, have been found to have a profound impact on gene expression by regulating RNA stability, localization and decoding efficiency. Importantly, genetic variations or environmental perturbations of epitranscriptome modifiers (that is, writers, erasers and readers) are associated with obesity and metabolic diseases, such as type 2 diabetes. The epitranscriptome is closely coupled to epigenetic signalling, adding complexity to our understanding of gene expression in both health and disease. Moreover, the epitranscriptome in the parental generation can affect organismal phenotypes in the next generation. In this Review, we discuss the relationship between epitranscriptomic modifications and metabolic diseases, their relationship with the epigenome and possible therapeutic strategies.

  13. MYPT1-PP1β phosphatase negatively regulates both chromatin landscape and co-activator recruitment for beige adipogenesis. International-journal Peer-reviewed

    Hiroki Takahashi, Ge Yang, Takeshi Yoneshiro, Yohei Abe, Ryo Ito, Chaoran Yang, Junna Nakazono, Mayumi Okamoto-Katsuyama, Aoi Uchida, Makoto Arai, Hitomi Jin, Hyunmi Choi, Myagmar Tumenjargal, Shiyu Xie, Ji Zhang, Hina Sagae, Yanan Zhao, Rei Yamaguchi, Yu Nomura, Yuichi Shimizu, Kaito Yamada, Satoshi Yasuda, Hiroshi Kimura, Toshiya Tanaka, Youichiro Wada, Tatsuhiko Kodama, Hiroyuki Aburatani, Min-Sheng Zhu, Takeshi Inagaki, Timothy F Osborne, Takeshi Kawamura, Yasushi Ishihama, Yoshihiro Matsumura, Juro Sakai

    Nature communications　13　(1)　5715-5715　2022/09/29

    DOI： 10.1038/s41467-022-33363-0 　

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    Protein kinase A promotes beige adipogenesis downstream from β-adrenergic receptor signaling by phosphorylating proteins, including histone H3 lysine 9 (H3K9) demethylase JMJD1A. To ensure homeostasis, this process needs to be reversible however, this step is not well understood. We show that myosin phosphatase target subunit 1- protein phosphatase 1β (MYPT1-PP1β) phosphatase activity is inhibited via PKA-dependent phosphorylation, which increases phosphorylated JMJD1A and beige adipogenesis. Mechanistically, MYPT1-PP1β depletion results in JMJD1A-mediated H3K9 demethylation and activation of the Ucp1 enhancer/promoter regions. Interestingly, MYPT1-PP1β also dephosphorylates myosin light chain which regulates actomyosin tension-mediated activation of YAP/TAZ which directly stimulates Ucp1 gene expression. Pre-adipocyte specific Mypt1 deficiency increases cold tolerance with higher Ucp1 levels in subcutaneous white adipose tissues compared to control mice, confirming this regulatory mechanism in vivo. Thus, we have uncovered regulatory cross-talk involved in beige adipogenesis that coordinates epigenetic regulation with direct activation of the mechano-sensitive YAP/TAZ transcriptional co-activators.

  14. Glutamine deficiency in solid tumor cells confers resistance to ribosomal RNA synthesis inhibitors. International-journal Peer-reviewed

    Melvin Pan, Christiane Zorbas, Maki Sugaya, Kensuke Ishiguro, Miki Kato, Miyuki Nishida, Hai-Feng Zhang, Marco M Candeias, Akimitsu Okamoto, Takamasa Ishikawa, Tomoyoshi Soga, Hiroyuki Aburatani, Juro Sakai, Yoshihiro Matsumura, Tsutomu Suzuki, Christopher G Proud, Denis L J Lafontaine, Tsuyoshi Osawa

    Nature communications　13　(1)　3706-3706　2022/06/28

    DOI： 10.1038/s41467-022-31418-w 　

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    Ribosome biogenesis is an energetically expensive program that is dictated by nutrient availability. Here we report that nutrient deprivation severely impairs precursor ribosomal RNA (pre-rRNA) processing and leads to the accumulation of unprocessed rRNAs. Upon nutrient restoration, pre-rRNAs stored under starvation are processed into mature rRNAs that are utilized for ribosome biogenesis. Failure to accumulate pre-rRNAs under nutrient stress leads to perturbed ribosome assembly upon nutrient restoration and subsequent apoptosis via uL5/uL18-mediated activation of p53. Restoration of glutamine alone activates p53 by triggering uL5/uL18 translation. Induction of uL5/uL18 protein synthesis by glutamine is dependent on the translation factor eukaryotic elongation factor 2 (eEF2), which is in turn dependent on Raf/MEK/ERK signaling. Depriving cells of glutamine prevents the activation of p53 by rRNA synthesis inhibitors. Our data reveals a mechanism that tumor cells can exploit to suppress p53-mediated apoptosis during fluctuations in environmental nutrient availability.

  15. Epigenetic and environmental regulation of adipocyte function. International-journal Peer-reviewed

    Yoshihiro Matsumura, Timothy F Osborne, Juro Sakai

    Journal of biochemistry　2022/04/27

    DOI： 10.1093/jb/mvac033 　

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    Adipocytes play an essential role in the maintenance of whole-body energy homeostasis. White adipocytes regulate energy storage, whereas brown and beige adipocytes regulate energy expenditure and heat production. De novo production of adipocytes (i.e., adipogenesis) and their functions are dynamically controlled by environmental cues. Environmental changes (e.g., temperature, nutrients, hormones, cytokines) are transmitted via intracellular signaling to facilitate short-term responses and long-term adaptation in adipocytes; however, the molecular mechanisms that link the environment and epigenome are poorly understood. Our recent studies have demonstrated that environmental cues dynamically regulate interactions between transcription factors and epigenomic chromatin regulators, which together trigger combinatorial changes in chromatin structure to influence gene expression in adipocytes. Thus, environmental sensing by the concerted action of multiple chromatin-associated protein complexes is a key determinant of the epigenetic regulation of adipocyte functions.

  16. Selective PPARα Modulator Pemafibrate and Sodium-Glucose Cotransporter 2 Inhibitor Tofogliflozin Combination Treatment Improved Histopathology in Experimental Mice Model of Non-Alcoholic Steatohepatitis. International-journal Peer-reviewed

    Kentaro Murakami, Yusuke Sasaki, Masato Asahiyama, Wataru Yano, Toshiaki Takizawa, Wakana Kamiya, Yoshihiro Matsumura, Motonobu Anai, Tsuyoshi Osawa, Jean-Charles Fruchart, Jamila Fruchart-Najib, Hiroyuki Aburatani, Juro Sakai, Tatsuhiko Kodama, Toshiya Tanaka

    Cells　11　(4)　2022/02/18

    DOI： 10.3390/cells11040720 　

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    Ballooning degeneration of hepatocytes is a major distinguishing histological feature of non-alcoholic steatosis (NASH) progression that can lead to cirrhosis and hepatocellular carcinoma (HCC). In this study, we evaluated the effect of the selective PPARα modulator (SPPARMα) pemafibrate (Pema) and sodium-glucose cotransporter 2 (SGLT2) inhibitor tofogliflozin (Tofo) combination treatment on pathological progression in the liver of a mouse model of NASH (STAM) at two time points (onset of NASH progression and HCC survival). At both time points, the Pema and Tofo combination treatment significantly alleviated hyperglycemia and hypertriglyceridemia. The combination treatment significantly reduced ballooning degeneration of hepatocytes. RNA-seq analysis suggested that Pema and Tofo combination treatment resulted in an increase in glyceroneogenesis, triglyceride (TG) uptake, lipolysis and liberated fatty acids re-esterification into TG, lipid droplet (LD) formation, and Cidea/Cidec ratio along with an increased number and reduced size and area of LDs. In addition, combination treatment reduced expression levels of endoplasmic reticulum stress-related genes (Ire1a, Grp78, Xbp1, and Phlda3). Pema and Tofo treatment significantly improved survival rates and reduced the number of tumors in the liver compared to the NASH control group. These results suggest that SPPARMα and SGLT2 inhibitor combination therapy has therapeutic potential to prevent NASH-HCC progression.

  17. Spatiotemporal dynamics of SETD5-containing NCoR-HDAC3 complex determines enhancer activation for adipogenesis International-journal Peer-reviewed

    Yoshihiro Matsumura, Ryo Ito, Ayumu Yajima, Rei Yamaguchi, Kenta Magoori, Toshiya Tanaka, Takeshi Kawamura, Hiroyuki Hirakawa, Hitomi Fujihashi, Yohei Abe, Ryo Nakaki, Aoi Uchida, Shogo Yamamoto, Satoshi Ota, Shuichi Tsutsumi, Shin-ichi Inoue, Hiroshi Kimura, Yoichiro Wada, Takeshi Inagaki, Tatsuhiko Kodama, Timothy Osborne, Hiroyuki Aburatani, Koichi Node, Juro Sakai

    Nature Communications　12　(1)　7045-7045　2021/12/02

    Publisher: Research Square Platform LLC

    DOI： 10.21203/rs.3.rs-250361/v1 　

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    <title>Abstract</title> Enhancer activation is essential for cell-type specific gene expression during cellular differentiation, however, how enhancers transition from a hypoacetylated “primed” state to a hyperacetylated-active state is incompletely understood. Here, we show SET domain-containing 5 (SETD5) forms a complex with NCoR-HDAC3 co-repressor that prevents histone acetylation of enhancers for two master adipogenic regulatory genes <italic>Cebpa</italic> and <italic>Pparg</italic> early during adipogenesis. The loss of SETD5 from the complex is followed by enhancer hyperacetylation. SETD5 protein levels were transiently increased and rapidly degraded prior to enhancer activation providing a mechanism for the loss of SETD5 during the transition. We show that induction of the CDC20 co-activator of the ubiquitin ligase leads to APC/C mediated degradation of SETD5 during the transition and this operates as a molecular switch that facilitates adipogenesis.

  18. Measurement of the nuclear concentration of α-ketoglutarate during adipocyte differentiation by using a fluorescence resonance energy transfer-based biosensor with nuclear localization signals. Peer-reviewed

    Tomohiro Suzuki, Mayuko Hayashi, Tetsuro Komatsu, Akiko Tanioka, Masahiro Nagasawa, Kyoko Tanimura-Inagaki, Mohammad Sharifur Rahman, Shinnosuke Masuda, Kosuke Yusa, Juro Sakai, Hiroshi Shibata, Takeshi Inagaki

    Endocrine journal　68　(12)　1429-1438　2021/07/15

    Publisher: Japan Endocrine Society

    DOI： 10.1507/endocrj.EJ21-0255 　

    ISSN： 0918-8959

    eISSN： 1348-4540

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    α-Ketoglutarate (α-KG) also known as 2-oxoglutarate (2-OG) is an intermediate metabolite in the tricarboxylic acid (TCA) cycle and is also produced by the deamination of glutamate. It is an indispensable cofactor for a series of 2-oxoglutarate-dependent oxygenases including epigenetic modifiers such as ten-eleven translocation DNA demethylases (TETs) and JmjC domain-containing histone demethylases (JMJDs). Since these epigenetic enzymes target genomic DNA and histone in the nucleus, the nuclear concentration of α-KG would affect the levels of transcription by modulating the activity of the epigenetic enzymes. Thus, it is of great interest to measure the nuclear concentration of α-KG to elucidate the regulatory mechanism of these enzymes. Here, we report a novel fluorescence resonance energy transfer (FRET)-based biosensor with multiple nuclear localization signals (NLSs) to measure the nuclear concentration of α-KG. The probe contains the α-KG-binding GAF domain of NifA protein from Azotobacter vinelandii fused with EYFP and ECFP. Treatment of 3T3-L1 preadipocytes expressing this probe with either dimethyl-2-oxoglutarate (dimethyl-2-OG), a cell-permeable 2-OG derivative, or citrate elicited time- and dose-dependent changes in the FRET ratio, proving that this probe functions as an α-KG sensor. Measurement of the nuclear α-KG levels in the 3T3-L1 cells stably expressing the probe during adipocyte differentiation revealed that the nuclear concentration of α-KG increased in the early stage of differentiation and remained high thereafter. Thus, this nuclear-localized α-KG probe is a powerful tool for real-time monitoring of α-KG concentrations with subcellular resolution in living cells and is useful for elucidating the regulatory mechanisms of epigenetic enzymes.

  19. ERAD components Derlin-1 and Derlin-2 are essential for postnatal brain development and motor function Peer-reviewed

    Takashi Sugiyama, Naoya Murao, Hisae Kadowaki, Keizo Takao, Tsuyoshi Miyakawa, Yosuke Matsushita, Toyomasa Katagiri, Akira Futatsugi, Yohei Shinmyo, Hiroshi Kawasaki, Juro Sakai, Kazutaka Shiomi, Masamitsu Nakazato, Kohsuke Takeda, Katsuhiko Mikoshiba, Hidde L. Ploegh, Hidenori Ichijo, Hideki Nishitoh

    iScience　24　(7)　102758-102758　2021/07

    Publisher: Elsevier BV

    DOI： 10.1016/j.isci.2021.102758 　

    ISSN： 2589-0042

  20. Ubiquitination dependent and independent repression of target genes by SETDB1 reveals a context dependent role for its methyltransferase activity during adipogenesis International-journal Peer-reviewed

    Ji Zhang, Yoshihiro Matsumura, Yuka Kano, Ayano Yoshida, Takeshi Kawamura, Hiroyuki Hirakawa, Takeshi Inagaki, Toshiya Tanaka, Hiroshi Kimura, Shigeru Yanagi, Kiyoko Fukami, Takefumi Doi, Timothy F. Osborne, Tatsuhiko Kodama, Hiroyuki Aburatani, Juro Sakai

    Genes to Cells　26　(7)　513-529　2021/05/10

    Publisher: Wiley

    DOI： 10.1111/gtc.12868 　

    ISSN： 1356-9597

    eISSN： 1365-2443

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    The lysine methyltransferase SETDB1, an enzyme responsible for methylation of histone H3 at lysine 9, plays a key role in H3K9 tri-methylation-dependent silencing of endogenous retroviruses and developmental genes. Recent studies have shown that ubiquitination of human SETDB1 complements its catalytic activity and the silencing of endogenous retroviruses in human embryonic stem cells. However, it is not known whether SETDB1 ubiquitination is essential for its other major role in epigenetic silencing of developmental gene programs. We previously showed that SETDB1 contributes to the formation of H3K4/H3K9me3 bivalent chromatin domains that keep adipogenic Cebpa and Pparg genes in a poised state for activation and restricts the differentiation potential of pre-adipocytes. Here, we show that ubiquitin-resistant K885A mutant of SETDB1 represses adipogenic genes and inhibits pre-adipocyte differentiation similar to wild-type SETDB1. We show this was due to a compensation mechanism for H3K9me3 chromatin modifications on the Cebpa locus by other H3K9 methyltransferases Suv39H1 and Suv39H2. In contrast, the K885A mutant did not repress other SETDB1 target genes such as Tril and Gas6 suggesting SETDB1 represses its target genes by two mechanisms; one that requires its ubiquitination and another that still requires SETDB1 but not its enzyme activity.

  21. Metabolic flexibility via mitochondrial BCAA carrier SLC25A44 is required for optimal fever Peer-reviewed

    Takeshi Yoneshiro, Naoya Kataoka, Jacquelyn M Walejko, Kenji Ikeda, Zachary Brown, Momoko Yoneshiro, Scott B Crown, Tsuyoshi Osawa, Juro Sakai, Robert W McGarrah, Phillip J White, Kazuhiro Nakamura, Shingo Kajimura

    eLife　10　e66865　2021/05/04

    Publisher: eLife Sciences Publications, Ltd

    DOI： 10.7554/elife.66865 　

    eISSN： 2050-084X

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    Importing necessary metabolites into the mitochondrial matrix is a crucial step of fuel choice during stress adaptation. Branched chain-amino acids (BCAA) are essential amino acids needed for anabolic processes, but they are also imported into the mitochondria for catabolic reactions. What controls the distinct subcellular BCAA utilization during stress adaptation is insufficiently understood. The present study reports the role of SLC25A44, a recently identified mitochondrial BCAA carrier (MBC), in the regulation of mitochondrial BCAA catabolism and adaptive response to fever in rodents. We found that mitochondrial BCAA oxidation in brown adipose tissue (BAT) is significantly enhanced during fever in response to the pyrogenic mediator prostaglandin E2 (PGE2) and psychological stress in mice and rats. Genetic deletion of MBC in a BAT-specific manner blunts mitochondrial BCAA oxidation and non-shivering thermogenesis following intracerebroventricular PGE2 administration. At a cellular level, MBC is required for mitochondrial BCAA deamination as well as the synthesis of mitochondrial amino acids and TCA intermediates. Together, these results illuminate the role of MBC as a determinant of metabolic flexibility to mitochondrial BCAA catabolism and optimal febrile responses. This study also offers an opportunity to control fever by rewiring the subcellular BCAA fate.

  22. Loss of Down syndrome critical region-1 leads to cholesterol metabolic dysfunction that exaggerates hypercholesterolemia in ApoE-null background. International-journal Peer-reviewed

    Muramatsu M, Osawa T, Miyamura Y, Nakagawa S, Tanaka T, Kodama T, Aburatani H, Sakai J, Ryeom S, Minami T

    J Biol Chem　296　100697-100697　2021/04

    DOI： 10.1016/j.jbc.2021.100697 　

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    Down syndrome critical region (DSCR)-1 functions as a feedback modulator for calcineurin-nuclear factor for activated T cell (NFAT) signals, which are crucial for cell proliferation and inflammation. Stable expression of DSCR-1 inhibits pathological angiogenesis and septic inflammation. DSCR-1 also plays a critical role in vascular wall remodeling associated with aneurysm development that occurs primarily in smooth muscle cells. Besides, Dscr-1 deficiency promotes the M1-to M2-like phenotypic switch in macrophages, which correlates to the reduction of denatured cholesterol uptakes. However, the distinct roles of DSCR-1 in cholesterol and lipid metabolism are not well understood. Here, we show that loss of apolipoprotein (Apo) E in mice with chronic hypercholesterolemia induced Dscr-1 expression in the liver and aortic atheroma. In Dscr-1-null mice fed a high-fat diet, oxidative- and endoplasmic reticulum (ER) stress was induced, and sterol regulatory element-binding protein (SREBP) 2 production in hepatocytes was stimulated. This exaggerated ApoE-/--mediated nonalcoholic fatty liver disease (NAFLD) and subsequent hypercholesterolemia. Genome-wide screening revealed that loss of both ApoE and Dscr-1 resulted in the induction of immune- and leukocyte activation-related genes in the liver compared with ApoE deficiency alone. However, expressions of inflammation-activated markers and levels of monocyte adhesion were suspended upon induction of the Dscr-1 null background in the aortic endothelium. Collectively, our study shows that the combined loss of Dscr-1 and ApoE causes metabolic dysfunction in the liver but reduces atherosclerotic plaques, thereby leading to a dramatic increase in serum cholesterol and the formation of sporadic vasculopathy.

  23. PPARα activation directly upregulates thrombomodulin in the diabetic retina. International-journal Peer-reviewed

    Akira Shiono, Hiroki Sasaki, Reio Sekine, Yohei Abe, Yoshihiro Matsumura, Takeshi Inagaki, Toshiya Tanaka, Tatsuhiko Kodama, Hiroyuki Aburatani, Juro Sakai, Hitoshi Takagi

    Scientific reports　10　(1)　10837-10837　2020/07/02

    DOI： 10.1038/s41598-020-67579-1 　

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    Two large clinical studies showed that fenofibrate, a commonly used peroxisome proliferator-activated receptor α (PPARα) agonist, has protective effects against diabetic retinopathy. However, the underlying mechanism has not been clarified. We performed genome-wide analyses of gene expression and PPARα binding sites in vascular endothelial cells treated with the selective PPARα modulator pemafibrate and identified 221 target genes of PPARα including THBD, which encodes thrombomodulin (TM). ChIP-qPCR and luciferase reporter analyses showed that PPARα directly regulated THBD expression via binding to the promoter. In the rat diabetic retina, treatment with pemafibrate inhibited the expression of inflammatory molecules such as VCAM-1 and MCP1, and these effects were attenuated by intravitreal injection of small interfering RNA targeted to THBD. Furthermore, pemafibrate treatment inhibited diabetes-induced vascular leukostasis and leakage through the upregulation of THBD. Our results indicate that PPARα activation inhibits inflammatory and vasopermeable responses in the diabetic retina through the upregulation of TM.

  24. Pemafibrate, a selective PPARα modulator, prevents non-alcoholic steatohepatitis development without reducing the hepatic triglyceride content. International-journal Peer-reviewed

    Yusuke Sasaki, Masato Asahiyama, Toshiya Tanaka, Shogo Yamamoto, Kentaro Murakami, Wakana Kamiya, Yoshihiro Matsumura, Tsuyoshi Osawa, Motonobu Anai, Jean-Charles Fruchart, Hiroyuki Aburatani, Juro Sakai, Tatsuhiko Kodama

    Scientific reports　10　(1)　7818-7818　2020/05/08

    DOI： 10.1038/s41598-020-64902-8 　

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    Non-alcoholic steatohepatitis (NASH) is characterized by macrovesicular steatosis with ballooning degeneration of hepatocytes, diffused lobular inflammation, and fibrosis. PPAR ligands are promising therapeutic agents in NASH; accordingly, we evaluated the effects of the first clinically available selective PPARα modulator, pemafibrate. We found that pemafibrate improves F4/80-positive macrophage accumulation, ballooning degeneration of hepatocytes, and the non-alcoholic fatty liver disease (NAFLD) activity score without affecting triglyceride (TG) accumulation in the liver of a mouse model of NASH (STAM). A global gene expression analysis indicated that pemafibrate enhances TG hydrolysis and fatty acid β-oxidation as well as re-esterification from dihydroxyacetone 3-phosphate and monoacylglycerol to TG. These changes are accompanied by the induction of genes involved in lipolysis and lipid droplet formation, along with an increased number and reduced size of lipid droplets in pemafibrate-treated livers. Pemafibrate reduced the expression of the cell adhesion molecule Vcam-1, myeloid cell markers, and inflammation- and fibrosis-related genes in STAM mice. Furthermore, pemafibrate significantly reduced VCAM-1 expression induced by high glucose in cultured human umbilical vein endothelial cells. These results suggest that pemafibrate prevents NASH development by reducing myeloid cell recruitment via interactions with liver sinusoidal endothelial cells, without altering hepatic TG accumulation.

  25. Gene Expression Profiles Induced by a Novel Selective Peroxisome Proliferator-Activated Receptor α Modulator (SPPARMα) Pemafibrate. International-journal Peer-reviewed

    Yusuke Sasaki, Sana Raza-Iqbal, Toshiya Tanaka, Kentaro Murakami, Motonobu Anai, Tsuyoshi Osawa, Yoshihiro Matsumura, Juro Sakai, Tatsuhiko Kodama

    International journal of molecular sciences　20　(22)　E5682　2019/11/13

    DOI： 10.3390/ijms20225682 　

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    Pemafibrate is the first clinically-available selective peroxisome proliferator-activated receptor α modulator (SPPARMα) that has been shown to effectively improve hypertriglyceridemia and low high-density lipoprotein cholesterol (HDL-C) levels. Global gene expression analysis reveals that the activation of PPARα by pemafibrate induces fatty acid (FA) uptake, binding, and mitochondrial or peroxisomal oxidation as well as ketogenesis in mouse liver. Pemafibrate most profoundly induces HMGCS2 and PDK4, which regulate the rate-limiting step of ketogenesis and glucose oxidation, respectively, compared to other fatty acid metabolic genes in human hepatocytes. This suggests that PPARα plays a crucial role in nutrient flux in the human liver. Additionally, pemafibrate induces clinically favorable genes, such as ABCA1, FGF21, and VLDLR. Furthermore, pemafibrate shows anti-inflammatory effects in vascular endothelial cells. Pemafibrate is predicted to exhibit beneficial effects in patients with atherogenic dyslipidemia and diabetic microvascular complications.

  26. Phosphoethanolamine Accumulation Protects Cancer Cells under Glutamine Starvation through Downregulation of PCYT2. International-journal Peer-reviewed

    Osawa T, Shimamura T, Saito K, Hasegawa Y, Ishii N, Nishida M, Ando R, Kondo A, Anwar M, Tsuchida R, Hino S, Sakamoto A, Igarashi K, Saitoh K, Kato K, Endo K, Yamano S, Kanki Y, Matsumura Y, Minami T, Tanaka T, Anai M, Wada Y, Wanibuchi H, Hayashi M, Hamada A, Yoshida M, Yachida S, Nakao M, Sakai J, Aburatani H, Shibuya M, Hanada K, Miyano S, Soga T, Kodama T

    Cell Reports　29　(1)　89-103.e7　2019/10

    DOI： 10.1016/j.celrep.2019.08.087. 　

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    Tolerance to severe tumor microenvironments, including hypoxia and nutrient starvation, is a common feature of aggressive cancer cells and can be targeted. However, metabolic alterations that support cancer cells upon nutrient starvation are not well understood. Here, by comprehensive metabolome analyses, we show that glutamine deprivation leads to phosphoethanolamine (PEtn) accumulation in cancer cells via the downregulation of PEtn cytidylyltransferase (PCYT2), a rate-limiting enzyme of phosphatidylethanolamine biosynthesis. PEtn accumulation correlated with tumor growth under nutrient starvation. PCYT2 suppression was partially mediated by downregulation of the transcription factor ELF3. Furthermore, PCYT2 overexpression reduced PEtn levels and tumor growth. In addition, PEtn accumulation and PCYT2 downregulation in human breast tumors correlated with poor prognosis. Thus, we show that glutamine deprivation leads to tumor progression by regulating PE biosynthesis via the ELF3-PCYT2 axis. Furthermore, manipulating glutamine-responsive genes could be a therapeutic approach to limit cancer progression.

  27. 脂肪細胞でのスーパーエンハンサーループの形成を介したPPARγによるC/EBPα遺伝子の転写制御

    青山 倫久, 脇 裕典, 井上 剛, 岡部 篤史, 堤 修一, 中村 正裕, 于 静, 平池 勇雄, 和田 洋一郎, 酒井 寿郎, 山内 敏正, 門脇 孝

    糖尿病　62　(Suppl.1)　S-179　2019/04

    Publisher: (一社)日本糖尿病学会

    ISSN： 0021-437X

    eISSN： 1881-588X

  28. Development of a Ligand Screening Tool Using Full-Length Human Peroxisome Proliferator-Activated Receptor-Expressing Cell Lines to Ameliorate Metabolic Syndrome. Peer-reviewed

    Tachibana K, Ishimoto K, Takahashi R, Kadono H, Awaji T, Yuzuriha T, Tanaka T, Hamakubo T, Sakai J, Kodama T, Aoki S, Doi T

    Chemical & pharmaceutical bulletin　67　(3)　199-202　2019

    DOI： 10.1248/cpb.c18-00627 　

    ISSN： 0009-2363

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    Peroxisome proliferator-activated receptors (PPARs) belong to the nuclear hormone receptor superfamily and include three subtypes (PPARα, PPARδ, and PPARγ). They regulate gene expression in a ligand-dependent manner. PPARα plays an important role in lipid metabolism. PPARγ is involved in glucose metabolism and is a potential therapeutic target in Type 2 diabetes. PPARδ ligands are candidates for the treatment of metabolic disorders. Thus, the detection of PPAR ligands may facilitate the treatment of various diseases. In this study, to identify PPAR ligands, we engineered reporter cell lines that can be used to quantify PPARγ and PPARδ activity. We evaluated several known ligands using these reporter cell lines and confirmed that they are useful for PPAR ligand detection. Furthermore, we evaluated extracts of approximately 200 natural resources and found various extracts that enhance reporter gene activity. Finally, we identified a main alkaloid of the Evodia fruit, evodiamine, as a PPARγ activator using this screening tool. These results suggest that the established reporter cell lines may serve as a useful cell-based screening tool for finding PPAR ligands to ameliorate metabolic syndromes.

  29. Histone demethylase JMJD1A coordinates acute and chronic adaptation to cold stress via thermogenic phospho-switch Peer-reviewed

    Yohei Abe, Yosuke Fujiwara, Hiroki Takahashi, Yoshihiro Matsumura, Tomonobu Sawada, Shuying Jiang, Ryo Nakaki, Aoi Uchida, Noriko Nagao, Makoto Naito, Shingo Kajimura, Hiroshi Kimura, Timothy F. Osborne, Hiroyuki Aburatani, Tatsuhiko Kodama, Takeshi Inagaki, Juro Sakai

    Nature Communications　9　(1)　1566　2018/12/01

    Publisher: Nature Publishing Group

    DOI： 10.1038/s41467-018-03868-8 　

    ISSN： 2041-1723

  30. Downregulation of ERG and FLI1 expression in endothelial cells triggers endothelial-to-mesenchymal transition. International-journal Peer-reviewed

    Nagai N, Ohguchi H, Nakaki R, Matsumura Y, Kanki Y, Sakai J, Aburatani H, Minami T

    PLoS genetics　14　(11)　e1007826　2018/11

    DOI： 10.1371/journal.pgen.1007826 　

    ISSN： 1553-7390

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    Endothelial cell (EC) plasticity in pathological settings has recently been recognized as a driver of disease progression. Endothelial-to-mesenchymal transition (EndMT), in which ECs acquire mesenchymal properties, has been described for a wide range of pathologies, including cancer. However, the mechanism regulating EndMT in the tumor microenvironment and the contribution of EndMT in tumor progression are not fully understood. Here, we found that combined knockdown of two ETS family transcription factors, ERG and FLI1, induces EndMT coupled with dynamic epigenetic changes in ECs. Genome-wide analyses revealed that ERG and FLI1 are critical transcriptional activators for EC-specific genes, among which microRNA-126 partially contributes to blocking the induction of EndMT. Moreover, we demonstrated that ERG and FLI1 expression is downregulated in ECs within tumors by soluble factors enriched in the tumor microenvironment. These data provide new insight into the mechanism of EndMT, functions of ERG and FLI1 in ECs, and EC behavior in pathological conditions.

  31. Discovery of peroxisome proliferator-activated receptor α (PPARα) activators with a ligand-screening system using a human PPARα-expressing cell line. International-journal Peer-reviewed

    Tachibana K, Yuzuriha T, Tabata R, Fukuda S, Maegawa T, Takahashi R, Tanimoto K, Tsujino H, Nunomura K, Lin B, Matsuura Y, Tanaka T, Hamakubo T, Sakai J, Kodama T, Kobayashi T, Ishimoto K, Miyachi H, Doi T

    The Journal of biological chemistry　293　(26)　10333-10343　2018/06

    DOI： 10.1074/jbc.RA118.002077 　

    ISSN： 0021-9258

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    Peroxisome proliferator-activated receptor α (PPARα) is a ligand-activated transcription factor that belongs to the superfamily of nuclear hormone receptors. PPARα is mainly expressed in the liver, where it activates fatty acid oxidation and lipoprotein metabolism and improves plasma lipid profiles. Therefore, PPARα activators are often used to treat patients with dyslipidemia. To discover additional PPARα activators as potential compounds for use in hypolipidemic drugs, here we established human hepatoblastoma cell lines with luciferase reporter expression from the promoters containing peroxisome proliferator-responsive elements (PPREs) and tetracycline-regulated expression of full-length human PPARα to quantify the effects of chemical ligands on PPARα activity. Using the established cell-based PPARα-activator screening system to screen a library of >12,000 chemical compounds, we identified several hit compounds with basic chemical skeletons different from those of known PPARα agonists. One of the hit compounds, a 1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid derivative we termed compound 3, selectively up-regulated PPARα transcriptional activity, leading to PPARα target gene expression both in vitro and in vivo Of note, the half-maximal effective concentrations of the hit compounds were lower than that of the known PPARα ligand fenofibrate. Finally, fenofibrate or compound 3 treatment of high fructose-fed rats having elevated plasma triglyceride levels for 14 days indicated that compound 3 reduces plasma triglyceride levels with similar efficiency as fenofibrate. These observations raise the possibility that 1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid derivatives might be effective drug candidates for selective targeting of PPARα to manage dyslipidemia.

  32. Overexpression of p54nrb/NONO induces differential EPHA6 splicing and contributes to castration-resistant prostate cancer growth Peer-reviewed

    Ryuji Yamamoto, Tsuyoshi Osawa, Yusuke Sasaki, Shogo Yamamoto, Motonobu Anai, Kouji Izumi, Yoshihiro Matsumura, Juro Sakai, Hiroyuki Aburatani, Atsushi Mizokami, Tatsuhiko Kodama, Toshiya Tanaka

    Oncotarget　9　(12)　10510-10524　2018

    Publisher: Impact Journals LLC

    DOI： 10.18632/oncotarget.24063 　

    ISSN： 1949-2553

  33. Impact of histone demethylase KDM3A-dependent AP-1 transactivity on hepatotumorigenesis induced by PI3K activation Peer-reviewed

    T. Nakatsuka, K. Tateishi, Y. Kudo, K. Yamamoto, H. Nakagawa, H. Fujiwara, R. Takahashi, K. Miyabayashi, Y. Asaoka, Y. Tanaka, H. Ijichi, Y. Hirata, M. Otsuka, M. Kato, J. Sakai, M. Tachibana, H. Aburatani, Y. Shinkai, K. Koike

    ONCOGENE　36　(45)　6262-6271　2017/11

    DOI： 10.1038/onc.2017.222 　

    ISSN： 0950-9232

    eISSN： 1476-5594

  34. Transcriptional and epigenetic control of brown and beige adipose cell fate and function (vol 17, pg 480, 2016) Peer-reviewed

    Takeshi Inagaki, Juro Sakai, Shingo Kajimura

    NATURE REVIEWS MOLECULAR CELL BIOLOGY　18　(8)　527　2017/08

    DOI： 10.1038/nrm.2017.72 　

    ISSN： 1471-0072

    eISSN： 1471-0080

  35. Degradation of human Lipin-1 by BTRC E3 ubiquitin ligase Peer-reviewed

    Kenji Ishimoto, Ayaka Hayase, Fumiko Kumagai, Megumi Kawai, Hiroko Okuno, Nobumasa Hino, Yoshiaki Okada, Takeshi Kawamura, Toshiya Tanaka, Takao Hamakubo, Juro Sakai, Tatsuhiko Kodama, Keisuke Tachibana, Takefumi Doi

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS　488　(1)　159-164　2017/06

    DOI： 10.1016/j.bbrc.2017.04.159 　

    ISSN： 0006-291X

    eISSN： 1090-2104

  36. KDM3A coordinates actin dynamics with intraflagellar transport to regulate cilia stability Peer-reviewed

    Patricia L. Yeyati, Rachel Schiller, Girish Mali, Ioannis Kasioulis, Akane Kawamura, Ian R. Adams, Christopher Playfoot, Nick Gilbert, Veronica van Heyningen, Jimi Wills, Alex von Kriegsheim, Andrew Finch, Juro Sakai, Christopher J. Schofield, Ian J. Jackson, Pleasantine Mill

    JOURNAL OF CELL BIOLOGY　216　(4)　999-1013　2017/04

    DOI： 10.1083/jcb.201607032 　

    ISSN： 0021-9525

    eISSN： 1540-8140

  37. Vitamin D Metabolite, 25-Hydroxyvitamin D, Regulates Lipid Metabolism by Inducing Degradation of SREBP/SCAP Peer-reviewed

    Lisa Asano, Mizuki Watanabe, Yuta Ryoden, Kousuke Usuda, Takuya Yamaguchi, Bilon Khambu, Megumi Takashima, Shin-ichi Sato, Juro Sakai, Kazuo Nagasawa, Motonari Uesugi

    Cell Chemical Biology　24　(2)　207-217　2017/02/16

    Publisher: Elsevier Ltd

    DOI： 10.1016/j.chembiol.2016.12.017 　

    ISSN： 2451-9448 2451-9456

  38. Extracellular Acidic pH Activates the Sterol Regulatory Element-Binding Protein 2 to Promote Tumor Progression Peer-reviewed

    Ayano Kondo, Shogo Yamamoto, Ryo Nakaki, Teppei Shimamura, Takao Hamakubo, Juro Sakai, Tatsuhiko Kodama, Tetsuo Yoshida, Hiroyuki Aburatani, Tsuyoshi Osawa

    CELL REPORTS　18　(9)　2228-2242　2017/02

    DOI： 10.1016/j.celrep.2017.02.006 　

    ISSN： 2211-1247

  39. QRFP-Deficient Mice Are Hypophagic, Lean, Hypoactive and Exhibit Increased Anxiety-Like Behavior Peer-reviewed

    Kitaro Okamoto, Miwako Yamasaki, Keizo Takao, Shingo Soya, Monica Iwasaki, Koh Sasaki, Kenta Magoori, Iori Sakakibara, Tsuyoshi Miyakawa, Michihiro Mieda, Masahiko Watanabe, Juro Sakai, Masashi Yanagisawa, Takeshi Sakurai

    PLOS ONE　11　(11)　e0164716　2016/11

    DOI： 10.1371/journal.pone.0164716 　

    ISSN： 1932-6203

  40. Ubiquitination of Lysine 867 of the Human SETDB1 Protein Upregulates Its Histone H3 Lysine 9 (H3K9) Methyltransferase Activity Peer-reviewed

    Kenji Ishimoto, Natsuko Kawamata, Yoshie Uchihara, Moeka Okubo, Reiko Fujimoto, Eiko Gotoh, Keisuke Kakinouchi, Eiichi Mizohata, Nobumasa Hino, Yoshiaki Okada, Yasuhiro Mochizuki, Toshiya Tanaka, Takao Hamakubo, Juro Sakai, Tatsuhiko Kodama, Tsuyoshi Inoue, Keisuke Tachibana, Takefumi Doi

    PLOS ONE　11　(10)　e0165766　2016/10

    DOI： 10.1371/journal.pone.0165766 　

    ISSN： 1932-6203

  41. Transcriptional and epigenetic control of brown and beige adipose cell fate and function Peer-reviewed

    Takeshi Inagaki, Juro Sakai, Shingo Kajimura

    NATURE REVIEWS MOLECULAR CELL BIOLOGY　17　(8)　480-495　2016/08

    DOI： 10.1038/nrm.2016.62 　

    ISSN： 1471-0072

    eISSN： 1471-0080

  42. The H3K9 methyltransferase Setdb1 regulates TLR4-mediated inflammatory responses in macrophages Peer-reviewed

    Rumi Hachiya, Takuya Shiihashi, Ibuki Shirakawa, Yorihiro Iwasaki, Yoshihiro Matsumura, Yumiko Oishi, Yukiteru Nakayama, Yoshihiro Miyamoto, Ichiro Manabe, Kozue Ochi, Miyako Tanaka, Nobuhito Goda, Juro Sakai, Takayoshi Suganami, Yoshihiro Ogawa

    SCIENTIFIC REPORTS　6　28845　2016/06

    DOI： 10.1038/srep28845 　

    ISSN： 2045-2322

  43. The KDM3A-KLF2-IRF4 axis maintains myeloma cell survival Peer-reviewed

    Hiroto Ohguchi, Teru Hideshima, Manoj K. Bhasin, Gullu T. Gorgun, Loredana Santo, Michele Cea, Mehmet K. Samur, Naoya Mimura, Rikio Suzuki, Yu-Tzu Tai, Ruben D. Carrasco, Noopur Raje, Paul G. Richardson, Nikhil C. Munshi, Hideo Harigae, Takaomi Sanda, Juro Sakai, Kenneth C. Anderson

    NATURE COMMUNICATIONS　7　10258　2016/01

    DOI： 10.1038/ncomms10258 　

    ISSN： 2041-1723

  44. H3K4/H3K9me3 Bivalent Chromatin Domains Targeted by Lineage-Specific DNA Methylation Pauses Adipocyte Differentiation Peer-reviewed

    Yoshihiro Matsumura, Ryo Nakaki, Takeshi Inagaki, Ayano Yoshida, Yuka Kano, Hiroshi Kimura, Toshiya Tanaka, Shuichi Tsutsumi, Mitsuyoshi Nakao, Takefumi Doi, Kiyoko Fukami, Timothy F. Osborne, Tatsuhiko Kodama, Hiroyuki Aburatani, Juro Sakai

    MOLECULAR CELL　60　(4)　584-596　2015/11

    DOI： 10.1016/j.molcel.2015.10.025 　

    ISSN： 1097-2765

    eISSN： 1097-4164

  45. Analysis of the subcellular localization of the human histone methyltransferase SETDB1. International-journal Peer-reviewed

    Keisuke Tachibana, Eiko Gotoh, Natsuko Kawamata, Kenji Ishimoto, Yoshie Uchihara, Hiroko Iwanari, Akira Sugiyama, Takeshi Kawamura, Yasuhiro Mochizuki, Toshiya Tanaka, Juro Sakai, Takao Hamakubo, Tatsuhiko Kodama, Takefumi Doi

    Biochemical and biophysical research communications　465　(4)　725-31　2015/10/02

    DOI： 10.1016/j.bbrc.2015.08.065 　

    ISSN： 0006-291X

    More details Close

    SET domain, bifurcated 1 (SETDB1) is a histone methyltransferase that methylates lysine 9 on histone H3. Although it is important to know the localization of proteins to elucidate their physiological function, little is known of the subcellular localization of human SETDB1. In the present study, to investigate the subcellular localization of hSETDB1, we established a human cell line constitutively expressing enhanced green fluorescent protein fused to hSETDB1. We then generated a monoclonal antibody against the hSETDB1 protein. Expression of both exogenous and endogenous hSETDB1 was observed mainly in the cytoplasm of various human cell lines. Combined treatment with the nuclear export inhibitor leptomycin B and the proteasome inhibitor MG132 led to the accumulation of hSETDB1 in the nucleus. These findings suggest that hSETDB1, localized in the nucleus, might undergo degradation by the proteasome and be exported to the cytosol, resulting in its detection mainly in the cytosol.

  46. JMJD1A is a signal-sensing scaffold that regulates acute chromatin dynamics via SWI/SNF association for thermogenesis Peer-reviewed

    Yohei Abe, Royhan Rozqie, Yoshihiro Matsumura, Takeshi Kawamura, Ryo Nakaki, Yuya Tsurutani, Kyoko Tanimura-Inagaki, Akira Shiono, Kenta Magoori, Kanako Nakamura, Shotaro Ogi, Shingo Kajimura, Hiroshi Kimura, Toshiya Tanaka, Kiyoko Fukami, Timothy F. Osborne, Tatsuhiko Kodama, Hiroyuki Aburatani, Takeshi Inagaki, Juro Sakai

    NATURE COMMUNICATIONS　6　7052　2015/05

    DOI： 10.1038/ncomms8052 　

    ISSN： 2041-1723

  47. 【動脈硬化症の最先端】ゲノム・エピゲノムからみた動脈硬化症

    稲垣 毅, 谷村 恭子, 酒井 寿郎

    臨床検査　59　(2)　110-118　2015/02

    Publisher: (株)医学書院

    ISSN： 0485-1420

    eISSN： 1882-1367

  48. The FBXL10/KDM2B Scaffolding Protein Associates with Novel Polycomb Repressive Complex-1 to Regulate Adipogenesis Peer-reviewed

    Takeshi Inagaki, Satoshi Iwasaki, Yoshihiro Matsumura, Takeshi Kawamura, Toshiya Tanaka, Yohei Abe, Ayumu Yamasaki, Yuya Tsurutani, Ayano Yoshida, Yoko Chikaoka, Kanako Nakamura, Kenta Magoori, Ryo Nakaki, Timothy F. Osborne, Kiyoko Fukami, Hiroyuki Aburatani, Tatsuhiko Kodama, Juro Sakai

    JOURNAL OF BIOLOGICAL CHEMISTRY　290　(7)　4163-4177　2015/02

    DOI： 10.1074/jbc.M114.626929 　

    ISSN： 0021-9258

    eISSN： 1083-351X

  49. Transcriptome Analysis of K-877 (a Novel Selective PPAR alpha Modulator (SPPARM alpha))-Regulated Genes in Primary Human Hepatocytes and the Mouse Liver Peer-reviewed

    Sana Raza-Iqbal, Toshiya Tanaka, Motonobu Anai, Takeshi Inagaki, Yoshihiro Matsumura, Kaori Ikeda, Akashi Taguchi, Frank J. Gonzalez, Juro Sakai, Tatsuhiko Kodama

    JOURNAL OF ATHEROSCLEROSIS AND THROMBOSIS　22　(8)　754-772　2015

    DOI： 10.5551/jat.28720 　

    ISSN： 1340-3478

    eISSN： 1880-3873

  50. PPAR beta/delta activation of CD300a controls intestinal immunity Peer-reviewed

    Toshiya Tanaka, Satoko Tahara-Hanaoka, Tsukasa Nabekura, Kaori Ikeda, Shuying Jiang, Shuichi Tsutsumi, Takeshi Inagaki, Kenta Magoori, Takuma Higurashi, Hirokazu Takahashi, Keisuke Tachibana, Yuya Tsurutani, Sana Raza, Motonobu Anai, Takashi Minami, Youichiro Wada, Koutaro Yokote, Takefumi Doi, Takao Hamakubo, Johan Auwerx, Frank J. Gonzalez, Atsushi Nakajima, Hiroyuki Aburatani, Makoto Naito, Akira Shibuya, Tatsuhiko Kodama, Juro Sakai

    SCIENTIFIC REPORTS　4　5412　2014/06

    DOI： 10.1038/srep05412 　

    ISSN： 2045-2322

  51. Direct Evidence for Pitavastatin Induced Chromatin Structure Change in the KLF4 Gene in Endothelial Cells Peer-reviewed

    Takashi Maejima, Tsuyoshi Inoue, Yasuharu Kanki, Takahide Kohro, Guoliang Li, Yoshihiro Ohta, Hiroshi Kimura, Mika Kobayashi, Akashi Taguchi, Shuichi Tsutsumi, Hiroko Iwanari, Shogo Yamamoto, Hirofumi Aruga, Shoulian Dong, Junko F. Stevens, Huay Mei Poh, Kazuki Yamamoto, Takeshi Kawamura, Imari Mimura, Jun-ichi Suehiro, Akira Sugiyama, Kiyomi Kaneki, Haruki Shibata, Yasunobu Yoshinaka, Takeshi Doi, Akimune Asanuma, Sohei Tanabe, Toshiya Tanaka, Takashi Minami, Takao Hamakubo, Juro Sakai, Naohito Nozaki, Hiroyuki Aburatani, Masaomi Nangaku, Xiaoan Ruan, Hideyuki Tanabe, Yijun Ruan, Sigeo Ihara, Akira Endo, Tatsuhiko Kodama, Youichiro Wada

    PLOS ONE　9　(5)　e96005　2014/05

    DOI： 10.1371/journal.pone.0096005 　

    ISSN： 1932-6203

  52. Endoplasmic Reticulum Protein Quality Control Is Determined by Cooperative Interactions between Hsp/c70 Protein and the CHIP E3 Ligase Peer-reviewed

    Yoshihiro Matsumura, Juro Sakai, William R. Skach

    JOURNAL OF BIOLOGICAL CHEMISTRY　288　(43)　31069-31079　2013/10

    DOI： 10.1074/jbc.M113.479345 　

    ISSN： 0021-9258

    eISSN： 1083-351X

  53. Human mannose-binding lectin 2 is directly regulated by peroxisome proliferator-activated receptors via a peroxisome proliferator responsive element Peer-reviewed

    Keisuke Tachibana, Kentaro Takeuchi, Hirohiko Inada, Ken Sugimoto, Kenji Ishimoto, Masanori Yamashita, Takashi Maegawa, Daisuke Yamasaki, Shigehiro Osada, Toshiya Tanaka, Hiromi Rakugi, Takao Hamakubo, Juro Sakai, Tatsuhiko Kodama, Takefumi Doi

    JOURNAL OF BIOCHEMISTRY　154　(3)　265-273　2013/09

    DOI： 10.1093/jb/mvt050 　

    ISSN： 0021-924X

  54. Metabolic Syndrome and Epigenomic Regulations

    Sakai Juro

    J.Jpn.Cosmet.Sci.Soc　37　(4)　292-298　2013

    Publisher: Japanese Cosmetic Science Society

    DOI： 10.11469/koshohin.37.292 　

    ISSN： 1880-2532

    More details Close

    All of our tissues contain the same 30,000 genes; however, in a given tissue and at a given stage, owing to an "epigenetic code," only a few of these genes are expressed, giving rise to the "phenotype." Disruption of the balance of epigenetic networks may cause several major diseases, including cancer, syndromes involving chromosomal instabilities, and mental retardation. However, the relevance of epigenetics to other physiopathological mechanisms in common diseases, such as metabolic syndrome, was less clear. Through genome wide identification of PPARγ targets by chromatin immunoprecipitation on Chip (ChIP-Chip) analysis, we identified several histone modification enzymes (HKMTs) and candidates genes as new PPARγ targets. We show that these HKMTs function either anti-, or pro-adipogenic factor and coordinately regulated their gene expressions by PPARγ to promote adipogenesis. We therefore propose the novel action of PPARγ: controlling epigenomic status in fat cell differentiation. In addition, we demonstrate that JHDM2a, a demehtylase of H3K9me2, regulates metabolic genes related to energy homeostasis. Mice deficient in JHDM2a (JHDM2a-/-) develop adult onset obesity, hypertriglyceridemia, hypercholesterolemia, hyperinsulinemia, and hyperleptinemia, which are hallmarks of metabolic syndrome. Thus, H3K9 demethylase JHDM2a is a crucial regulator of genes involved in energy expenditure and fat storage, which suggests it is a previously unrecognized key regulator of obesity and metabolic syndrome.

  55. Dynamic Change of Chromatin Conformation in Response to Hypoxia Enhances the Expression of GLUT3 (SLC2A3) by Cooperative Interaction of Hypoxia-Inducible Factor 1 and KDM3A Peer-reviewed

    Imari Mimura, Masaomi Nangaku, Yasuharu Kanki, Shuichi Tsutsumi, Tsuyoshi Inoue, Takahide Kohro, Shogo Yamamoto, Takanori Fujita, Teppei Shimamura, Jun-ichi Suehiro, Akashi Taguchi, Mika Kobayashi, Kyoko Tanimura, Takeshi Inagaki, Toshiya Tanaka, Takao Hamakubo, Juro Sakai, Hiroyuki Aburatani, Tatsuhiko Kodama, Youichiro Wada

    MOLECULAR AND CELLULAR BIOLOGY　32　(15)　3018-3032　2012/08

    DOI： 10.1128/MCB.06643-11 　

    ISSN： 0270-7306

  56. Novel repressor regulates insulin sensitivity through interaction with Foxo1 Peer-reviewed

    Jun Nakae, Yongheng Cao, Fumihiko Hakuno, Hiroshi Takemori, Yoshinaga Kawano, Risa Sekioka, Takaya Abe, Hiroshi Kiyonari, Toshiya Tanaka, Juro Sakai, Shin-Ichiro Takahashi, Hiroshi Itoh

    EMBO Journal　31　(10)　2275-2295　2012/05/16

    DOI： 10.1038/emboj.2012.97 　

    ISSN： 0261-4189 1460-2075

  57. [Epigenomic contribution in the onset of diabetes]. Peer-reviewed

    Sakai J, Inagaki T

    Nihon rinsho. Japanese journal of clinical medicine　70 Suppl 3　196-201　2012/05

    ISSN： 0047-1852

  58. Novel repressor regulates insulin sensitivity through interaction with Foxo1 Peer-reviewed

    Jun Nakae, Yongheng Cao, Fumihiko Hakuno, Hiroshi Takemori, Yoshinaga Kawano, Risa Sekioka, Takaya Abe, Hiroshi Kiyonari, Toshiya Tanaka, Juro Sakai, Shin-Ichiro Takahashi, Hiroshi Itoh

    EMBO JOURNAL　31　(10)　2275-2295　2012/05

    DOI： 10.1038/emboj.2012.97 　

    ISSN： 0261-4189

    eISSN： 1460-2075

  59. Global Mapping of Cell Type-Specific Open Chromatin by FAIRE-seq Reveals the Regulatory Role of the NFI Family in Adipocyte Differentiation Peer-reviewed

    Hironori Waki, Masahiro Nakamura, Toshimasa Yamauchi, Ken-ichi Wakabayashi, Jing Yu, Lisa Hirose-Yotsuya, Kazumi Take, Wei Sun, Masato Iwabu, Miki Okada-Iwabu, Takanori Fujita, Tomohisa Aoyama, Shuichi Tsutsumi, Kohjiro Ueki, Tatsuhiko Kodama, Juro Sakai, Hiroyuki Aburatani, Takashi Kadowaki

    PLOS GENETICS　7　(10)　e1002311　2011/10

    DOI： 10.1371/journal.pgen.1002311 　

    ISSN： 1553-7390

  60. Fenofibrate suppresses growth of the human hepatocellular carcinoma cell via PPAR alpha-independent mechanisms Peer-reviewed

    Daisuke Yamasaki, Natsuko Kawabe, Hitomi Nakamura, Keisuke Tachibana, Kenji Ishimoto, Toshiya Tanaka, Hiroyuki Aburatani, Juro Sakai, Takao Hamakubo, Tatsuhiko Kodama, Takefumi Doi

    EUROPEAN JOURNAL OF CELL BIOLOGY　90　(8)　657-664　2011/08

    DOI： 10.1016/j.ejcb.2011.02.005 　

    ISSN： 0171-9335

  61. Sterol-regulatory-element-binding protein 2 and nuclear factor Y control human farnesyl diphosphate synthase expression and affect cell proliferation in hepatoblastoma cells Peer-reviewed

    Kenji Ishimoto, Keisuke Tachibana, Ikuko Hanano, Daisuke Yamasaki, Hiroki Nakamura, Megumi Kawai, Yasuomi Urano, Toshiya Tanaka, Takao Hamakubo, Juro Sakai, Tatsuhiko Kodama, Takefumi Doi

    BIOCHEMICAL JOURNAL　429　(2)　347-357　2010/07

    DOI： 10.1042/BJ20091511 　

    ISSN： 0264-6021

  62. Wnt signaling and its downstream target N-myc regulate basal progenitors in the developing neocortex Peer-reviewed

    Atsushi Kuwahara, Yusuke Hirabayashi, Paul S. Knoepfler, Makoto M. Taketo, Juro Sakai, Tatsuhiko Kodama, Yukiko Gotoh

    DEVELOPMENT　137　(7)　1035-1044　2010/04

    DOI： 10.1242/dev.046417 　

    ISSN： 0950-1991

  63. Role of histone methylation and demethylation in adipogenesis and obesity Peer-reviewed

    Masashi Okamura, Takeshi Inagaki, Toshiya Tanaka, Juro Sakai

    ORGANOGENESIS　6　(1)　24-32　2010/01

    DOI： 10.4161/org.6.1.11121 　

    ISSN： 1547-6278

  64. Regulation of the human SLC25A20 expression by peroxisome proliferator-activated receptor alpha in human hepatoblastoma cells Peer-reviewed

    Keisuke Tachibana, Kentaro Takeuchi, Hirohiko Nada, Daisuke Yamasaki, Kenji Ishimoto, Toshiya Tanaka, Takao Hamakubo, Juro Sakai, Tatsuhiko Kodama, Takefumi Doi

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS　389　(3)　501-505　2009/11

    DOI： 10.1016/j.bbrc.2009.09.018 　

    ISSN： 0006-291X

  65. Sterol-mediated Regulation of Human Lipin 1 Gene Expression in Hepatoblastoma Cells Peer-reviewed

    Kenji Ishimoto, Hiroki Nakamura, Keisuke Tachibana, Daisuke Yamasaki, Akemi Ota, Ken-ichi Hirano, Toshiya Tanaka, Takao Hamakubo, Juro Sakai, Tatsuhiko Kodama, Takefumi Doi

    JOURNAL OF BIOLOGICAL CHEMISTRY　284　(33)　22195-22205　2009/08

    DOI： 10.1074/jbc.M109.028753 　

    ISSN： 0021-9258

    eISSN： 1083-351X

  66. Obesity and metabolic syndrome in histone demethylase JHDM2a-deficient mice Peer-reviewed

    Takeshi Inagaki, Makoto Tachibana, Kenta Magoori, Hiromi Kudo, Toshiya Tanaka, Masashi Okamura, Makoto Naito, Tatsuhiko Kodama, Yoichi Shinkai, Juro Sakai

    GENES TO CELLS　14　(8)　991-1001　2009/08

    DOI： 10.1111/j.1365-2443.2009.01326.x 　

    ISSN： 1356-9597

  67. A Small Molecule That Blocks Fat Synthesis By Inhibiting the Activation of SREBP Peer-reviewed

    Shinji Kamisuki, Qian Mao, Lutfi Abu-Elheiga, Ziwei Gu, Akira Kugimiya, Youngjoo Kwon, Tokuyuki Shinohara, Yoshinori Kawazoe, Shin-ichi Sato, Koko Asakura, Hea-Young Park Choo, Juro Sakai, Salih J. Wakil, Motonari Uesugi

    CHEMISTRY & BIOLOGY　16　(8)　882-892　2009/08

    DOI： 10.1016/j.chembiol.2009.07.007 　

    ISSN： 1074-5521

  68. The Peroxisome Proliferator-Activated Receptor gamma/Retinoid X Receptor alpha Heterodimer Targets the Histone Modification Enzyme PR-Set7/Setd8 Gene and Regulates Adipogenesis through a Positive Feedback Loop Peer-reviewed

    Ken-ichi Wakabayashi, Masashi Okamura, Shuichi Tsutsumi, Naoko S. Nishikawa, Toshiya Tanaka, Iori Sakakibara, Jun-ichi Kitakami, Sigeo Ihara, Yuichi Hashimoto, Takao Hamakubo, Tatsuhiko Kodama, Hiroyuki Aburatani, Juro Sakai

    MOLECULAR AND CELLULAR BIOLOGY　29　(13)　3544-3555　2009/07

    DOI： 10.1128/MCB.01856-08 　

    ISSN： 0270-7306

  69. COUP-TFII acts downstream of Wnt/beta-catenin signal to silence PPAR gamma gene expression and repress adipogenesis Peer-reviewed

    Masashi Okamura, Hiromi Kudo, Ken-ichi Wakabayashi, Toshiya Tanaka, Aya Nonaka, Aoi Uchida, Shuichi Tsutsumi, Iori Sakakibara, Makoto Naito, Timothy F. Osborne, Takao Hamakubo, Sadayoshi Ito, Hiroyuki Aburatani, Masashi Yanagisawa, Tatsuhiko Kodama, Juro Sakai

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA　106　(14)　5819-5824　2009/04

    DOI： 10.1073/pnas.0901676106 　

    ISSN： 0027-8424

  70. Expression of liver X receptor alpha and lipid metabolism in granulocyte-macrophage colony-stimulating factor-induced human monocyte-derived macrophage Peer-reviewed

    Toshihiro Kazawa, Takashi Kawasaki, Azusa Sakamoto, Masaru Imamura, Riuko Ohashi, Shuying Jiang, Toshiya Tanaka, Hiroko Iwanari, Takao Hamakubo, Juro Sakai, Tatsuhiko Kodama, Makoto Naito

    PATHOLOGY INTERNATIONAL　59　(3)　152-160　2009/03

    DOI： 10.1111/j.1440-1827.2009.02343.x 　

    ISSN： 1320-5463

  71. Fasting-induced Hypothermia and Reduced Energy Production in Mice Lacking Acetyl-CoA Synthetase 2 Peer-reviewed

    Iori Sakakibara, Takahiro Fujino, Makoto Ishii, Toshiya Tanaka, Tatsuo Shimosawa, Shinji Miura, Wei Zhang, Yuka Tokutake, Joji Yamamoto, Mutsumi Awano, Satoshi Iwasaki, Toshiyuki Motoike, Masashi Okamura, Takeshi Inagaki, Kiyoshi Kita, Osamu Ezaki, Makoto Naito, Tomoyuki Kuwaki, Shigeru Chohnan, Tokuo T. Yamamoto, Robert E. Hammer, Tatsuhiko Kodama, Masashi Yanagisawa, Juro Sakai

    CELL METABOLISM　9　(2)　191-202　2009/02

    DOI： 10.1016/j.cmet.2008.12.008 　

    ISSN： 1550-4131

  72. Regulation of the human PDZK1 expression by peroxisome proliferator-activated receptor alpha Peer-reviewed

    Keisuke Tachibana, Naohiko Anzai, Chihiro Ueda, Tatsuya Katayama, Daisuke Yamasaki, Takayoshi Kirino, Rika Takahashi, Kenji Ishimoto, Hidenori Komori, Toshiya Tanaka, Takao Hamakubo, Yukihiko Ueda, Hiroyuki Arai, Juro Sakai, Tatsuhiko Kodama, Takefumi Doi

    FEBS LETTERS　582　(28)　3884-3888　2008/11

    DOI： 10.1016/j.febslet.2008.10.027 　

    ISSN： 0014-5793

  73. Hepatocyte nuclear factor 4 alpha contributes to thyroid hormone homeostasis by cooperatively regulating the type 1 iodothyronine deiodinase gene with GATA4 and Kruppel-like transcription factor 9 Peer-reviewed

    Hiroto Ohguchi, Toshiya Tanaka, Aoi Uchida, Kenta Magoori, Hiromi Kudo, Insook Kim, Kenji Daigo, Iori Sakakibara, Masashi Okamura, Hideo Harigae, Takeshi Sasaki, Timothy F. Osborne, Frank J. Gonzalez, Takao Hamakubo, Tatsuhiko Kodama, Juro Sakai

    MOLECULAR AND CELLULAR BIOLOGY　28　(12)　3917-3931　2008/06

    DOI： 10.1128/MCB.02154-07 　

    ISSN： 0270-7306

  74. [Bile acids and control of lipid metabolism]. Peer-reviewed

    Tanaka T, Sakai J, Kodama T

    Nihon rinsho. Japanese journal of clinical medicine　65 Suppl 7　557-563　2007/07

    ISSN： 0047-1852

  75. Expression of liver X receptor alpha in rat fetal tissues at different developmental stages Peer-reviewed

    Azusa Sakamoto, Takashi Kawasaki, Toshihiro Kazawa, Riuko Ohashi, Shuying Jiang, Takashi Maejima, Toshiya Tanaka, Hiroko Iwanari, Takao Hamakubo, Juro Sakai, Tatsuhiko Kodama, Makoto Naito

    JOURNAL OF HISTOCHEMISTRY & CYTOCHEMISTRY　55　(6)　641-649　2007/06

    DOI： 10.1369/jhc.6A7120.2007 　

    ISSN： 0022-1554

  76. Cooperative interaction between hepatocyte nuclear factor 4 alpha and GATA transcription factors regulates ATP-binding cassette sterol transporters ABCG5 and ABCG8 Peer-reviewed

    Koichi Sumi, Toshiya Tanaka, Aoi Uchida, Kenta Magoori, Yasuyo Urashima, Riuko Ohashi, Hiroto Ohguchi, Masashi Okamura, Hiromi Kudo, Kenji Daigo, Takashi Maejima, Noriaki Kojima, Iori Sakakibara, Shuying Jiang, Go Hasegawa, Insook Kim, Timothy F. Osborne, Makoto Naito, Frank J. Gonzalez, Takao Hamakubo, Tatsuhiko Kodama, Juro Sakai

    MOLECULAR AND CELLULAR BIOLOGY　27　(12)　4248-4260　2007/06

    DOI： 10.1128/MCB.01894-06 　

    ISSN： 0270-7306

  77. New therapeutic target for metabolic syndrome: PPAR delta Peer-reviewed

    Sadao Takahashi, Toshiya Tanaka, Juro Sakai

    ENDOCRINE JOURNAL　54　(3)　347-357　2007/06

    DOI： 10.1507/endocrj.KR-99 　

    ISSN： 0918-8959

  78. SOX6 suppresses cyclin D1 promoter activity by interacting with beta-catenin and histone deacetylase 1, and its down-regulation induces pancreatic beta-cell proliferation Peer-reviewed

    Haruhisa Iguchi, Yasuyo Urashima, Yosuke Inagaki, Yukio Ikeda, Masashi Okamura, Toshiya Tanaka, Aoi Uchida, Tokuo T. Yamamoto, Tatsuhiko Kodama, Juro Sakai

    JOURNAL OF BIOLOGICAL CHEMISTRY　282　(26)　19052-19061　2007/06

    DOI： 10.1074/jbc.M700460200 　

    ISSN： 0021-9258

  79. Antisense activity of 2',4'-BNA targeted to PPAR gamma in THP-1 and HCT116 cells. Peer-reviewed

    Tachibana K, Katayama T, Ueda C, Sumitomo M, Tagami M, Ishimoto K, Yamasaki D, Tanaka T, Hamakubo T, Sakai J, Kodama T, Obika S, Imanishi T, Doi T

    Nucleic acids symposium series (2004)　(51)　441-442　2007

    DOI： 10.1093/nass/nrm221 　

  80. A neuropeptide ligand of the g proteincoupled receptor GPR103 regulates feeding, behavioral arousal, and blood pressure, and is implicated in metabolic syndrome Peer-reviewed

    Shinobu Takayasu, Takashi Ohuchi, Takeshi Sakurai, Satoshi Iwasaki, Haruhisa Iguchi, Akihiro Yamanaka, Hitoshi Teranishi, S. Clay Williams, Yuka Kawasawa, Yukio Ikeda, Naoshi Dohmaes, Toshihiro Suda, Toshiyuki Motoike, Masashi Yanagisawa, Juro Sakai

    JOURNAL OF HYPERTENSION　24　(Suppl. 6)　155-155　2006/12

    ISSN： 0263-6352

  81. SOX6 attenuates glucose-stimulated insulin secretion by repressing PDX1 transcriptional activity

    IGUCHI Haruhisa, SAKAI Juro

    Folia Pharmacologica Japonica　128　(4)　219-224　2006/10/01

    Publisher: The Japanese Pharmacological Society

    DOI： 10.1254/fpj.128.219 　

    ISSN： 0015-5691

  82. GPR103の内因性リガンドの構造決定と中枢における薬理学機能解析

    岩崎 聡, 高安 忍, 桜井 武, 山中 章弘, 井口 晴久, 寺西 仁志, 榊原 伊織, 須田 俊宏, 柳沢 正史, 酒井 寿郎

    日本内分泌学会雑誌　82　(2)　509-509　2006/09

    Publisher: (一社)日本内分泌学会

    ISSN： 0029-0661

    eISSN： 2186-506X

  83. Identification of human low-density lipoprotein receptor as a novel target gene regulated by liver X receptor alpha Peer-reviewed

    Kenji Ishimoto, Keisuke Tachibana, Mikako Sumitomo, Shiho Omote, Ikuko Hanano, Daisuke Yamasaki, Yuichiro Watanabe, Toshiya Tanaka, Takao Hamakubo, Juro Sakai, Tatsuhiko Kodama, Takefumi Doi

    FEBS LETTERS　580　(20)　4929-4933　2006/09

    DOI： 10.1016/j.febslet.2006.08.010 　

    ISSN： 0014-5793

  84. Peroxisome proliferator-activated receptor delta (PPAR delta), a novel target site for drug discovery in metabolic syndrome Peer-reviewed

    Sadao Takahashi, Toshiya Tanaka, Tatsuhiko Kodama, Juro Sakai

    PHARMACOLOGICAL RESEARCH　53　(6)　501-507　2006/06

    DOI： 10.1016/j.phrs.2006.03.019 　

    ISSN： 1043-6618

  85. A neuropeptide ligand of the G protein-coupled receptor GPR103 regulates feeding, behavioral arousal, and blood pressure in mice Peer-reviewed

    S Takayasu, T Sakurai, S Iwasaki, H Teranishi, A Yamanaka, SC Williams, H Iguchi, YI Kawasawa, Y Ikeda, L Sakakibara, K Ohno, RX Ioka, S Murakami, N Dohmae, J Xie, T Suda, T Motoike, T Ohuchi, M Yanagisawa, J Sakai

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA　103　(19)　7438-7443　2006/05

    DOI： 10.1073/pnas.060231103 　

    ISSN： 0027-8424

  86. GPR103の内因性リガンドの構造決定と中枢におけるその生理機能

    岩崎 聡, 高安 忍, 桜井 武, 井口 晴久, 山中 章弘, 井岡 亮一, 川澤 百可, 池田 勧夫, 寺西 仁志, 榊原 伊織, 大野 耕作, 村上 紗織, 堂前 直, 須田 俊宏, 本池 俊行, 大内 崇史, 柳沢 正史, 酒井 寿郎

    糖尿病　49　(Suppl.1)　S160-S160　2006/04

    Publisher: (一社)日本糖尿病学会

    ISSN： 0021-437X

    eISSN： 1881-588X

  87. GPR103の内因性リガンドの構造決定と中枢におけるその生理機能

    高安 忍, 桜井 武, 岩崎 聡, 井口 晴久, 山中 章弘, 井岡 亮一, 川澤 百可, Williams S.Clay, 池田 勧夫, 寺西 仁志, 榊原 伊織, 大野 耕作, 村上 紗織, 堂前 直, Xie Jian, 須田 俊宏, 本池 俊行, 大内 崇史, 柳沢 正史, 酒井 寿郎

    日本内分泌学会雑誌　82　(1)　121-121　2006/04

    Publisher: (一社)日本内分泌学会

    ISSN： 0029-0661

    eISSN： 2186-506X

  88. Dysregulated expression of P1 and P2 promoter-driven hepatocyte nuclear factor-4 alpha in the pathogenesis of human cancer Peer-reviewed

    T Tanaka, S Jiang, H Hotta, K Takano, H Iwanari, K Sumi, K Daigo, R Ohashi, M Sugai, C Ikegame, H Umezu, Y Hirayama, Y Midorikawa, Y Hippo, A Watanabe, Y Uchiyama, G Hasegawa, PC Reid, H Aburatani, T Hamakubo, J Sakai, M Naito, T Kodama

    JOURNAL OF PATHOLOGY　208　(5)　662-672　2006/04

    DOI： 10.1002/path.1928 　

    ISSN： 0022-3417

    eISSN： 1096-9896

  89. Analysis of PPAR alpha function in human kidney cell line using siRNA. Peer-reviewed

    Tachibana K, Anzai N, Ueda C, Katayama T, Kirino T, Takahashi R, Yamasaki D, Ishimoto K, Tanaka T, Hamakubo T, Ueda Y, Arai H, Sakai J, Kodama T, Doi T

    Nucleic acids symposium series (2004)　50　(50)　257-258　2006

    DOI： 10.1093/nass/nrl128 　

  90. SOX6 attenuates glucose-stimulated insulin secretion by repressing PDX1 transcriptional actvity and is down-regulated in hyperinsulinemic obese mice Peer-reviewed

    H Iguchi, Y Ikeda, M Okamura, T Tanaka, Y Urashima, H Ohguchi, S Takayasu, N Kojima, S Iwasaki, R Ohashi, SY Jiang, G Hasegawa, RX Ioca, K Magoori, K Sumi, T Maejima, A Uchida, M Naito, TF Osborne, M Yanagisawa, TT Yamamoto, T Kodama, J Sakai

    JOURNAL OF BIOLOGICAL CHEMISTRY　280　(45)　37669-37680　2005/11

    DOI： 10.1074/jbc.M505392200 　

    ISSN： 0021-9258

  91. Gene expression profiling of potential peroxisome proliferator-activated receptor (PPAR) target genes in human hepatoblastoma cell lines inducibly expressing different PPAR isoforms. International-journal Peer-reviewed

    Keisuke Tachibana, Yumi Kobayashi, Toshiya Tanaka, Masayuki Tagami, Akira Sugiyama, Tatsuya Katayama, Chihiro Ueda, Daisuke Yamasaki, Kenji Ishimoto, Mikako Sumitomo, Yasutoshi Uchiyama, Takahide Kohro, Juro Sakai, Takao Hamakubo, Tatsuhiko Kodama, Takefumi Doi

    Nuclear receptor　3　3-3　2005/10/03

    DOI： 10.1186/1478-1336-3-3 　

    eISSN： 1478-1336

    More details Close

    BACKGROUND: Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors and commonly play an important role in the regulation of lipid homeostasis. To identify human PPARs-responsive genes, we established tetracycline-regulated human hepatoblastoma cell lines that can be induced to express each human PPAR and investigated the gene expression profiles of these cells. RESULTS: The expression of each introduced PPAR gene was investigated using the various concentrations of doxycycline in the culture media. We found that the expression of each PPAR subtype was tightly controlled by the concentration of doxycycline in these established cell lines. DNA microarray analyses using these cell lines were performed with or without adding each subtype ligand and provided much important information on the PPAR target genes involved in lipid metabolism, transport, storage and other activities. Interestingly, it was noted that while ligand-activated PPARdelta induced target gene expression, unliganded PPARdelta repressed these genes. The real-time RT-PCR was used to verify the altered expression of selected genes by PPARs and we found that these genes were induced to express in the same pattern as detected in the microarray analyses. Furthermore, we analysed the 5'-flanking region of the human adipose differentiation-related protein (adrp) gene that responded to all subtypes of PPARs. From the detailed analyses by reporter assays, the EMSAs, and ChIP assays, we determined the functional PPRE of the human adrp gene. CONCLUSION: The results suggest that these cell lines are important tools used to identify the human PPARs-responsive genes.

  92. Deficiency of the very low-density lipoprotein (VLDL) receptors in streptozotocin-induced diabetic rats: Insulin dependency of the VLDL receptor Peer-reviewed

    T Iwasaki, S Takahashi, M Takahashi, Y Zenimaru, T Kujiraoka, M Ishihara, M Nagano, J Suzuki, Miyamori, I, H Naiki, J Sakai, T Fujino, NE Miller, TT Yamamoto, H Hattori

    ENDOCRINOLOGY　146　(8)　3286-3294　2005/08

    DOI： 10.1210/en.2005-0043 　

    ISSN： 0013-7227

  93. Identification of N-arachidonylglycine, U18666A, and 4-androstene-3,17-dione as novel insulin secretagogues Peer-reviewed

    Y Ikeda, H Iguchi, M Nakata, RX Ioka, T Tanaka, S Iwasaki, K Magoori, S Takayasu, TT Yamamoto, T Kodama, T Yada, T Sakurai, M Yanagisawa, J Sakai

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS　333　(3)　778-786　2005/08

    DOI： 10.1016/j.bbrc.2005.06.005 　

    ISSN： 0006-291X

  94. SOX6のインスリン分泌制御機構の研究

    井口 晴久, 岡村 将史, 池田 勧夫, 岩崎 聡, 高安 忍, 浅場 浩, 田中 十志也, 馬郡 健太, 柳沢 正史, 酒井 寿郎

    糖尿病　48　(Suppl.2)　S171-S171　2005/04

    Publisher: (一社)日本糖尿病学会

    ISSN： 0021-437X

    eISSN： 1881-588X

  95. SOX6のインスリン分泌制御機構の研究

    井口 晴久, 岡村 将史, 池田 勧夫, 岩崎 聡, 高安 忍, 浅場 浩, 田中 十志也, 馬郡 健太, 柳沢 正史, 酒井 寿郎

    日本内分泌学会雑誌　81　(1)　193-193　2005/04

    Publisher: (一社)日本内分泌学会

    ISSN： 0029-0661

    eISSN： 2186-506X

  96. Angiopoietin-related growth factor antagonizes obesity and insulin resistance Peer-reviewed

    Y Oike, M Akao, K Yasunaga, T Yamauchi, T Morisada, Y Ito, T Urano, Y Kimura, Y Kubota, H Maekawa, T Miyamoto, K Miyata, S Matsumoto, J Sakai, N Nakagata, M Takeya, H Koseki, Y Ogawa, T Kadowaki, T Suda

    NATURE MEDICINE　11　(4)　400-408　2005/04

    DOI： 10.1038/nm1214 　

    ISSN： 1078-8956

  97. PPAR delta activation enhances fatty acid oxidation in skeletal muscle and attenuates metabolic syndrome Peer-reviewed

    Juro Sakai

    YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN　125　47-48　2005

    ISSN： 0031-6903

  98. Wnt coreceptor low density lipoprotein receptor related protein 5 (LRP5) mediates the bone formation and glucose induced insulin secretion

    SAKAI Juro

    Ronen biyou　41　(6)　625-628　2004/11/25

    Publisher: The Japan Geriatrics Society

    DOI： 10.3143/geriatrics.41.625 　

    ISSN： 0300-9173

  99. A Kruppel-like factor KLF15 contributes fasting-induced transcriptional activation of mitochondrial acetyl-CoA synthetase gene AceCS2 Peer-reviewed

    J Yamamoto, Y Ikeda, H Iguchi, T Fujino, T Tanaka, H Asaba, S Iwasaki, RX Ioka, IW Kaneko, K Magoori, S Takahashi, T Mori, H Sakaue, T Kodama, M Yanagisawa, TT Yamamoto, S Ito, J Sakai

    JOURNAL OF BIOLOGICAL CHEMISTRY　279　(17)　16954-16962　2004/04

    DOI： 10.1074/jbc.M312079000 　

    ISSN： 0021-9258

  100. The very low-density lipoprotein (VLDL) receptor: characterization and functions as a peripheral lipoprotein receptor. Peer-reviewed

    Takahashi S, Sakai J, Fujino T, Hattori H, Zenimaru Y, Suzuki J, Miyamori I, Yamamoto TT

    Journal of atherosclerosis and thrombosis　11　(4)　200-208　2004

    DOI： 10.5551/jat.11.200 　

    ISSN： 1340-3478

    More details Close

    The very low-density lipoprotein (VLDL) receptor is a member of the low-density lipoprotein (LDL) receptor family. In vitro and in vivo studies have shown that VLDL receptor binds triglyceride (TG)-rich lipoproteins but not LDL, and functions as a peripheral remnant lipoprotein receptor. VLDL receptor is expressed abundantly in fatty acid-active tissues (heart, skeletal muscle and fat), the brain and macrophages. It is likely that VLDL receptor functions in concert with lipoprotein lipase (LPL), which hydrolyses TG in VLDL and chylomicron. In contrast to the LDL receptor, VLDL receptor binds apolipoprotein (apo) E2/2 VLDL particles as well as apoE3/3 VLDL, and the expression is not down-regulated by intracellular lipoproteins. Recently, various functions of the VLDL receptor have been reported in lipoprotein metabolism, metabolic syndrome/atherosclerosis, cardiac fatty acid metabolism, neuronal migration and angiogenesis/tumor growth. Gene therapy of VLDL receptor into the liver showed a benefit effect for lipoprotein metabolism in both LDL receptor knockout and apoE mutant mice. Beyond its function as a peripheral lipoprotein receptor, possibilities of its physiological function have been extended to include signal transduction, angiogenesis and tumor growth.

  101. 動脈硬化Update 2003 Wnt/LRP5シグナルによる糖・脂質代謝,インスリン分泌及び血管代謝調節機構

    浅場 浩, 藤野 貴広, 池田 勧夫, 柳沢 正史, 山本 徳男, 酒井 寿郎

    Therapeutic Research　24　(12)　2189-2189　2003/12

    Publisher: ライフサイエンス出版(株)

    ISSN： 0289-8020

  102. Activation of peroxisome proliferator-activated receptor delta induces fatty acid beta-oxidation in skeletal muscle and attenuates metabolic syndrome Peer-reviewed

    T Tanaka, J Yamamoto, S Iwasaki, H Asaba, H Hamura, Y Ikeda, M Watanabe, K Magoori, RX Ioka, K Tachibana, Y Watanabe, Y Uchiyama, K Sumi, H Iguchi, S Ito, T Doi, T Hamakubo, M Naito, J Auwerx, M Yanagisawa, T Kodama, J Sakai

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA　100　(26)　15924-15929　2003/12

    DOI： 10.1073/pnas.0306981100 　

    ISSN： 0027-8424

  103. Wnt/LRP5シグナルによる糖・脂質代謝調節機構

    浅場 浩, 藤野 貴広, 池田 勧夫, 柳沢 正史, 山本 徳男, 酒井 寿郎

    日本動脈硬化学会総会プログラム・抄録集　35回　175-175　2003/09

    Publisher: (一社)日本動脈硬化学会

    ISSN： 1347-7099

  104. LDL受容体関連蛋白5(LRP-5)とアポリポ蛋白Eを欠損するマウスにおける重症高コレステロール血症,耐脂肪能障害,進行性粥状硬化症(Severe Hypercholesterolemia,Impaired Fat Tolerance and Advanced Atherosclerosis in Mice Lacking Both LDL Receptor-Related Protein 5 (LRP5) and Apolipoprotein E)

    馬郡 健太, 藤野 貴広, 酒井 寿郎, 山本 徳男

    日本動脈硬化学会総会プログラム・抄録集　35回　175-175　2003/09

    Publisher: (一社)日本動脈硬化学会

    ISSN： 1347-7099

  105. 新しいglycosylphosphatidylinositol固定化高比重リポ蛋白結合蛋白,GPI-HBPIの発現クローニングと特徴描写(Expression cloning and characterization of a novel glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein,GPI-HBP1)

    井岡 亮一, 藤野 貴広, 酒井 寿郎, 山本 徳男

    日本動脈硬化学会総会プログラム・抄録集　35回　189-189　2003/09

    Publisher: (一社)日本動脈硬化学会

    ISSN： 1347-7099

  106. The very low density lipoprotein (VLDL) receptor - a peripheral lipoprotein receptor for remnant lipoproteins into fatty acid active tissues Peer-reviewed

    S Takahashi, J Sakai, T Fujino, Miyamori, I, TT Yamamoto

    MOLECULAR AND CELLULAR BIOCHEMISTRY　248　(1-2)　121-127　2003/06

    DOI： 10.1023/A:1024184201941 　

    ISSN： 0300-8177

  107. Severe hypercholesterolemia, impaired fat tolerance, and advanced atherosclerosis in mice lacking both low density lipoprotein receptor-related protein 5 and apolipoprotein E Peer-reviewed

    K Magoori, MJ Kang, MR Ito, H Kakuuchi, RX Ioka, A Kamataki, DH Kim, H Asaba, S Iwasaki, YA Takei, M Sasaki, S Usui, M Okazaki, S Takahashi, M Ono, M Nose, J Sakai, T Fujino, TT Yamamoto

    JOURNAL OF BIOLOGICAL CHEMISTRY　278　(13)　11331-11336　2003/03

    DOI： 10.1074/jbc.M211987200 　

    ISSN： 0021-9258

  108. Expression cloning and characterization of a novel glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein, GPI-HBP1 Peer-reviewed

    RX Ioka, MJ Kang, S Kamiyama, DH Kim, K Magoori, A Kamataki, Y Ito, YA Takei, M Sasaki, T Suzuki, H Sasano, S Takahashi, J Sakai, T Fujino, TT Yamamoto

    JOURNAL OF BIOLOGICAL CHEMISTRY　278　(9)　7344-7349　2003/02

    DOI： 10.1074/jbc.M211932200 　

    ISSN： 0021-9258

  109. Low-density lipoprotein receptor-related protein 5 (LRP5) is essential for normal cholesterol metabolism and glucose-induced insulin secretion Peer-reviewed

    T Fujino, H Asaba, MJ Kang, Y Ikeda, H Sone, S Takada, DH Kim, RX Ioka, M Ono, H Tomoyori, M Okubo, T Murase, A Kamataki, J Yamamoto, K Magoori, S Takahashi, Y Miyamoto, H Oishi, M Nose, M Okazaki, S Usui, K Imaizumi, M Yanagisawa, J Sakai, TT Yamamoto

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA　100　(1)　229-234　2003/01

    DOI： 10.1073/pnas.0133792100 　

    ISSN： 0027-8424

  110. Amyloid beta-protein affects cholesterol metabolism in cultured neurons: Implications for pivotal role of cholesterol in the amyloid cascade Peer-reviewed

    JS Gong, N Sawamura, K Zou, J Sakai, K Yanagisawa, M Michikawa

    JOURNAL OF NEUROSCIENCE RESEARCH　70　(3)　438-446　2002/11

    DOI： 10.1002/jnr.10347 　

    ISSN： 0360-4012

  111. アセチルCoA合成酵素遺伝子(AceCS1)転写制御のメカニズム

    山本 譲司, 池田 勧夫, 藤野 貴広, 竹内 和久, 山本 徳男, 酒井 寿郎, 伊藤 貞嘉

    動脈硬化　(34回抄集)　171-171　2002/06

    Publisher: (一社)日本動脈硬化学会

    ISSN： 0386-2682

  112. Remnant lipoprotein particles are taken up into myocardium through VLDL receptor - a possible mechanism for cardiac fatty acid metabolism Peer-reviewed

    A Kamataki, S Takahashi, K Masamura, T Iwasaki, H Hattori, H Naiki, K Yamada, J Suzuki, Miyamori, I, J Sakai, T Fujino, TT Yamamoto

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS　293　(3)　1007-1013　2002/05

    DOI： 10.1016/S0006-291X(02)00323-6 　

    ISSN： 0006-291X

  113. SREBP及びSp1によるアセチルCoA合成酵素遺伝子(AceCS1)転写制御

    山本 譲司, 池田 勧夫, 岡村 将史, 藤野 貴広, 竹内 和久, 山本 徳男, 酒井 寿郎, 伊藤 貞嘉

    日本内分泌学会雑誌　78　(1)　90-90　2002/04

    Publisher: (一社)日本内分泌学会

    ISSN： 0029-0661

    eISSN： 2186-506X

  114. Transcriptional regulation of the murine acetyl-CoA synthetase 1 gene through multiple clustered binding sites for sterol regulatory element-binding proteins and a single neighboring site for Sp1 Peer-reviewed

    Y Ikeda, J Yamamoto, M Okamura, T Fujino, S Takahashi, K Takeuchi, TF Osborne, TT Yamamoto, S Ito, J Sakai

    JOURNAL OF BIOLOGICAL CHEMISTRY　276　(36)　34259-34269　2001/09

    DOI： 10.1074/jbc.M103848200 　

    ISSN： 0021-9258

  115. Molecular identification and characterization of two medium-chain Acyl-CoA synthetases, MACS1 and the Sa gene product Peer-reviewed

    T Fujino, YA Takei, H Sone, RX Ioka, A Kamataki, K Magoori, S Takahashi, J Sakai, TT Yamamoto

    JOURNAL OF BIOLOGICAL CHEMISTRY　276　(38)　35961-35966　2001/09

    DOI： 10.1074/jbc.M106651200 　

    ISSN： 0021-9258

  116. Evidence of macrophage foam cell formation by very low-density lipoprotein receptor - Interferon-gamma inhibition of very low-density lipoprotein receptor expression and foam cell formation in macrophages Peer-reviewed

    S Kosaka, S Takahashi, K Masamura, H Kanehara, J Sakai, G Tohda, E Okada, K Oida, T Iwasaki, H Hattori, T Kodama, T Yamamoto, Miyamori, I

    CIRCULATION　103　(8)　1142-1147　2001/02

    ISSN： 0009-7322

  117. cDNA cloning of mouse and human cholesterol 25-hydroxylases, polytopic membrane proteins that synthesize a potent oxysterol regulatory of lipid metabolism Peer-reviewed

    EG Lund, TA Kerr, J Sakai, WP Li, DW Russell

    JOURNAL OF BIOLOGICAL CHEMISTRY　273　(51)　34316-34327　1998/12

    ISSN： 0021-9258

  118. Molecular identification of the sterol-regulated luminal protease that cleaves SREBPs and controls lipid composition of animal cells Peer-reviewed

    J Sakai, RB Rawson, PJ Espenshade, D Cheng, AC Seegmiller, JL Goldstein, MS Brown

    MOLECULAR CELL　2　(4)　505-514　1998/10

    ISSN： 1097-2765

  119. Expression and characterization of a very low density lipoprotein receptor variant lacking the O-linked sugar region generated by alternative splicing Peer-reviewed

    H Iijima, M Miyazawa, J Sakai, K Magoori, MR Ito, H Suzuki, M Nose, Y Kawarabayasi, TT Yamamoto

    JOURNAL OF BIOCHEMISTRY　124　(4)　747-755　1998/10

    ISSN： 0021-924X

  120. Second-site cleavage in sterol regulatory element-binding protein occurs at transmembrane junction as determined by cysteine panning Peer-reviewed

    EA Duncan, UP Dave, J Sakai, JL Goldstein, MS Brown

    JOURNAL OF BIOLOGICAL CHEMISTRY　273　(28)　17801-17809　1998/07

    ISSN： 0021-9258

  121. Cleavage of sterol regulatory element-binding proteins (SREBPs) at site-1 requires interaction with SREBP cleavage-activating protein - Evidence from in vivo competition studies Peer-reviewed

    J Sakai, A Nohturfft, JL Goldstein, MS Brown

    JOURNAL OF BIOLOGICAL CHEMISTRY　273　(10)　5785-5793　1998/03

    ISSN： 0021-9258

  122. Complementation cloning of S2P, a gene encoding a putative metalloprotease required for intramembrane cleavage of SREBPs Peer-reviewed

    RB Rawson, NG Zelenski, D Nijhawan, J Ye, J Sakai, MT Hasan, TY Chang, MS Brown, JL Goldstein

    MOLECULAR CELL　1　(1)　47-57　1997/12

    ISSN： 1097-2765

  123. Identification of complexes between the COOH-terminal domains of sterol regulatory element-binding proteins (SREBPs) and SREBP cleavage-activating protein Peer-reviewed

    J Sakai, A Nohturfft, D Cheng, YK Ho, MS Brown, JL Goldstein

    JOURNAL OF BIOLOGICAL CHEMISTRY　272　(32)　20213-20221　1997/08

    ISSN： 0021-9258

  124. Cleavage site for sterol-regulated protease localized to a Leu-Ser bond in the lumenal loop of sterol regulatory element-binding protein-2 Peer-reviewed

    EA Duncan, MS Brown, JL Goldstein, J Sakai

    JOURNAL OF BIOLOGICAL CHEMISTRY　272　(19)　12778-12785　1997/05

    ISSN： 0021-9258

  125. Sterol-regulated release of SREBP-2 from cell membranes requires two sequential cleavages, one within a transmembrane segment Peer-reviewed

    J Sakai, EA Duncan, RB Rawson, XX Hua, RS Brown, JL Goldstein

    CELL　85　(7)　1037-1046　1996/06

    ISSN： 0092-8674

  126. Human apolipoprotein E receptor 2 - A novel lipoprotein receptor of the low density lipoprotein receptor family predominantly expressed in brain Peer-reviewed

    DH Kim, H Iijima, K Goto, J Sakai, H Ishii, HJ Kim, H Suzuki, H Kondo, S Saeki, T Yamamoto

    JOURNAL OF BIOLOGICAL CHEMISTRY　271　(14)　8373-8380　1996/04

    ISSN： 0021-9258

  127. Regulated cleavage of sterol regulatory element binding proteins requires sequences on both sides of the endoplasmic reticulum membrane Peer-reviewed

    XX Hua, J Sakai, MS Brown, JL Goldstein

    JOURNAL OF BIOLOGICAL CHEMISTRY　271　(17)　10379-10384　1996/04

    ISSN： 0021-9258

  128. Cleavage of sterol regulatory element binding proteins (SREBPs) by CPP32 during apoptosis Peer-reviewed

    XD Wang, NG Zelenski, JX Yang, J Sakai, MS Brown, JL Goldstein

    EMBO JOURNAL　15　(5)　1012-1020　1996/03

    ISSN： 0261-4189

  129. HAIRPIN ORIENTATION OF STEROL REGULATORY ELEMENT-BINDING PROTEIN-2 IN CELL-MEMBRANES AS DETERMINED BY PROTEASE PROTECTION Peer-reviewed

    XX HUA, J SAKAI, YK HO, JL GOLDSTEIN, MS BROWN

    JOURNAL OF BIOLOGICAL CHEMISTRY　270　(49)　29422-29427　1995/12

    ISSN： 0021-9258

  130. THE VLDL RECEPTOR AND RELATED MOLECULES - ROLES AND FUNCTION Peer-reviewed

    T YAMAMOTO, J SAKAI

    ATHEROSCLEROSIS X　1066　457-460　1995

    ISSN： 0531-5131

  131. THE ROLE OF THE VERY-LOW-DENSITY LIPOPROTEIN RECEPTOR IN THE METABOLISM OF PLASMA-LIPOPROTEINS CONTAINING APOE Peer-reviewed

    T YAMAMOTO, A HOSHINO, S TAKAHASHI, Y KAWARABAYASI, H IIJIMA, J SAKAI

    ATHEROSCLEROSIS III: RECENT ADVANCES IN ATHEROSCLEROSIS RESEARCH　748　217-225　1995

    ISSN： 0077-8923

  132. CGG TRIPLE REPEAT POLYMORPHISM IN VLDL RECEPTOR (VLDL-R) GENE Peer-reviewed

    E JOKINEN, J SAKAI, T YAMAMOTO, HH HOBBS

    HUMAN MOLECULAR GENETICS　3　(3)　521-521　1994/03

    ISSN： 0964-6906

  133. STRUCTURE, CHROMOSOME LOCATION, AND EXPRESSION OF THE HUMAN VERY-LOW-DENSITY LIPOPROTEIN RECEPTOR GENE Peer-reviewed

    J SAKAI, A HOSHINO, S TAKAHASHI, Y MIURA, H ISHII, H SUZUKI, Y KAWARABAYASI, T YAMAMOTO

    JOURNAL OF BIOLOGICAL CHEMISTRY　269　(3)　2173-2182　1994/01

    ISSN： 0021-9258

  134. RABBIT VERY LOW-DENSITY-LIPOPROTEIN RECEPTOR - A LOW-DENSITY-LIPOPROTEIN RECEPTOR-LIKE PROTEIN WITH DISTINCT LIGAND SPECIFICITY Peer-reviewed

    S TAKAHASHI, Y KAWARABAYASI, T NAKAI, J SAKAI, T YAMAMOTO

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA　89　(19)　9252-9256　1992/10

    ISSN： 0027-8424

Show all ︎Show first 5

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  1. 交感神経-エピゲノム軸による脂肪細胞の環境適応機構

    伊藤亮, 高橋宙大, 荒井誠, 稲垣毅, 米代武司, 松村欣宏, 酒井寿郎

    実験医学　41　(20)　29-37　2023/12

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    高橋宙大, 米代武司, 伊藤亮, 稲垣毅, 松村欣宏, 酒井寿郎, 酒井寿郎

    Bio Industry　40　(5)　45-56　2023/05

    ISSN： 0910-6545

  3. Multi-omics in lifestyle-related diseases

    松村欣宏, 高橋宙大, 伊藤亮, 米代武司, 米代武司, 稲垣毅, 稲垣毅, 酒井寿郎, 酒井寿郎

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  4. 【環境の影響とその遺伝・DOHaD】環境の影響とその遺伝・精子による獲得性の形質遺伝と生活習慣病

    酒井 寿郎

    遺伝子医学　12　(4)　40-47　2022/10

    Publisher: (株)メディカルドゥ

    ISSN： 1343-0971

  5. 【温度を感じる脳と身体の科学】熱産生脂肪細胞を誘導するエピゲノム酵素リン酸化スイッチの解明

    酒井 寿郎

    BRAIN and NERVE: 神経研究の進歩　74　(2)　0151-0158　2022/02

    Publisher: (株)医学書院

    ISSN： 1881-6096

    eISSN： 1344-8129

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    稲垣毅, 酒井寿郎, 酒井寿郎

    医学のあゆみ　280　(11)　2022

    ISSN： 0039-2359

  7. 【動脈硬化UPDATE】基礎 肥満・生活習慣病におけるエピゲノム研究

    酒井 寿郎

    医学のあゆみ　268　(5)　359-364　2019/02

    Publisher: 医歯薬出版(株)

    ISSN： 0039-2359

  8. 肥満のバイオロジー 脂肪細胞研究の最前線から次世代医療を視る 脂肪細胞研究の最前線、エピゲノムスイッチによる熱産生遺伝子誘導

    酒井 寿郎

    Clinical Calcium　29　(3)　374-379　2019/02

    Publisher: (株)医薬ジャーナル社

    ISSN： 0917-5857

  9. 【糖尿病とがんを解きほぐす-臨床・基礎・疫学が織りなす両者の関係-】糖尿病とがんの接点 高血糖

    荒井 誠, 酒井 寿郎

    プラクティス　35　(5)　511-515　2018/09

    Publisher: 医歯薬出版(株)

    ISSN： 0289-4947

  10. 生活習慣病の解明、遺伝子からエピゲノムへ

    酒井 寿郎

    東北医学雑誌　129　(2)　163-166　2017/12

    Publisher: 東北医学会

    ISSN： 0040-8700

  11. 【エピゲノムとメタボリズムのクロストーク】プロテオーム解析から解明されたリジン脱メチル化酵素の熱産生における新たな役割

    阿部 陽平, 松村 欣宏, 稲垣 毅, 酒井 寿郎

    The Lipid　28　(3)　242-247　2017/07

    Publisher: (株)メディカルレビュー社

    ISSN： 0915-6607

  12. 【エピゲノムとメタボリズムのクロストーク】次世代シークエンサー解析から解明された脂肪細胞分化におけるエピゲノム制御

    松村 欣宏, 酒井 寿郎

    The Lipid　28　(3)　256-262　2017/07

    Publisher: (株)メディカルレビュー社

    ISSN： 0915-6607

  13. Discovery of non-canonical bivalent chromatin that regulates Adipogenic master regulator genes

    44　(6)　425-431　2017/06

    Publisher: 科学評論社

    ISSN： 1884-2917

  14. Metabolic syndrome and Epigenome

    49　(2)　56-62　2017/02

    Publisher: ニューサイエンス社

    ISSN： 1346-7557

  15. Nuclear receptors and their role in aging

    Anti-aging medicine　13　(1)　79-93　2017/02

    Publisher: メディカルレビュー社

    ISSN： 1880-1579

  16. ヒストンメチル化酵素SETDB1のユビキチン化は細胞内局在を制御する

    松村欣宏, 鹿野優佳, 吉田文乃, 川村猛, 稲垣毅, 酒井寿郎

    日本生化学会大会(Web)　89th　ROMBUNNO.2P‐280 (WEB ONLY)-280]　2016/09

    Publisher: (公社)日本生化学会

  17. Formation of a Super-Enhancer Loop Contributes to Transactivation of Cebpa Expression by PPAR. during Adipocyte Differentiation

    Tomohisa Aoyama, Hironori Waki, Ken-Ichi Wakabayashi, Tsuyoshi Inoue, Masahiro Nakamura, Jing Yu, Atsushi Okabe, Shuichi Tsutsumi, Masato Iwabu, Miki Iwabu, Kohjiro Ueki, Youichiro Wada, Juro Sakai, Hiroyuki Aburatani, Tatsuhiko Kodama, Toshimasa Yamauchi, Takashi Kadowaki

    DIABETES　65　A31-A31　2016/06

    ISSN： 0012-1797

    eISSN： 1939-327X

  18. 肥満とエピゲノム (特集 目指せ! 肥満症のトータルケア : 減量に苦戦する患者について考える) -- (肥満研究最前線)

    酒井 寿郎, 阿部 陽平, 松村 欣宏

    内科　117　(1)　101-108　2016/01

    Publisher: 南江堂

    ISSN： 0022-1961

  19. 代謝のエピジェネティクス制御 病態解明から治療まで 脂肪細胞における新規エピゲノム制御機構

    稲垣 毅, 阿部 陽平, Rozqie Royhan, 松村 欣宏, 川村 猛, 仲木 竜, 鶴谷 悠也, 谷村 恭子, 田中 十志也, 児玉 龍彦, 油谷 浩幸, 酒井 寿郎

    日本臨床分子医学会学術総会プログラム・抄録集　52回　43-43　2015/04

    Publisher: 日本臨床分子医学会

  20. Epigenetics of diabetes

    252　(5)　456-462　2015/01/31

    Publisher: 医歯薬出版

    ISSN： 0039-2359

  21. Epigenome and adipogenesis

    250　(9)　790-795　2014/08/30

    Publisher: 医歯薬出版

    ISSN： 0039-2359

  22. Long-Range Transactivation of C/EBPa Gene Expression by PPAR gamma through Distal Enhancers during Adipocyte Differentiation

    Tomohisa Aoyama, Hironori Waki, Toshimasa Yamauchi, Ken-Ichi Wakabayashi, Tsuyoshi Inoue, Masahiro Nakamura, Jing Yu, Kazumi Take, Wei Sun, Masato Iwabu, Miki Okada-Iwabu, Kohjiro Ueki, Youichiro Wada, Shuichi Tsutsumi, Tatsuhiko Kodama, Juro Sakai, Hiroyuki Aburatani, Takashi Kadowaki

    DIABETES　63　A436-A436　2014/06

    ISSN： 0012-1797

    eISSN： 1939-327X

  23. エネルギー代謝における世代間連関 交感神経刺激による脂肪燃焼と肥満におけるエピゲノム変化の役割

    酒井 寿郎, 稲垣 毅, 阿部 陽平, Rozquie Royhan, 鶴谷 悠也, 川村 猛, 松村 欣宏, 谷村 恭子

    日本内分泌学会雑誌　90　(1)　169-169　2014/04

    Publisher: (一社)日本内分泌学会

    ISSN： 0029-0661

  24. ヒストン脱メチル化酵素Jmjd1aによる新規の代謝制御機構の解明

    稲垣毅, 川村猛, 阿部陽平, 谷村恭子, 松村欣宏, 酒井寿郎

    日本内分泌学会雑誌　90　(1)　262-262　2014/04/01

    Publisher: (一社)日本内分泌学会

    ISSN： 0029-0661

  25. Epigenome and obesity, insulin resistance and diabetes

    61　(8)　599-607　2013/08

    Publisher: 医学の世界社

    ISSN： 0045-7167

  26. Obesity and Metabolic Syndrome : Genome to Epigenome

    68　(1)　35-44　2013/01

    Publisher: 最新医学社

    ISSN： 0370-8241

  27. ヒストンメチル化酵素SETDB1の細胞内局在の解析

    後藤英子, 橘敬祐, 内原佳恵, 川又那津子, 石本憲司, 岩成宏子, 川村猛, 望月康弘, 酒井寿郎, 浜窪隆雄, 児玉龍彦, 土井健史

    生化学　84回　ROMBUNNO.4P-0402-0402　2011/09

    Publisher: (公社)日本生化学会

    ISSN： 0037-1017

  28. Epigenome and metabolic syndrome

    237　(6)　628-638　2011/05/07

    Publisher: 医歯薬出版

    ISSN： 0039-2359

  29. ヒストンメチル化酵素SETDB1に対するモノクローナル抗体の作製

    後藤英子, 橘敬祐, 内原佳恵, 石本憲司, 吉田卓也, 岩成宏子, 川村猛, 望月康弘, 大久保忠恭, 酒井寿郎, 浜窪隆雄, 児玉龍彦, 土井健史

    日本薬学会年会要旨集　131st　(3)　127-127　2011/03/05

    Publisher: (公社)日本薬学会

    ISSN： 0918-9823

  30. 糖尿病とエピゲノム (糖尿病) -- (基礎分野での進歩)

    酒井 寿郎, 稲垣 毅

    Annual review. 糖尿病・代謝・内分泌　2011　34-43　2011

    Publisher: 中外医学社

  31. Cholesterol feedback: the SREBP pathway

    Japanese journal of clinical medicine　69　241-258　2011/01

    Publisher: 日本臨床社

    ISSN： 0047-1852

  32. QRFP plays a critical role in regulating feeding behavior as a molecular link between the arcuate nucleus and nucleus accumbens

    Kitaro Okamoto, Junko Hara, Juro Sakai, Masahiko Watanabe, Masashi Yanagisawa, Takeshi Sakurai

    NEUROSCIENCE RESEARCH　71　E62-E63　2011

    DOI： 10.1016/j.neures.2011.07.265 　

    ISSN： 0168-0102

  33. Epigenome and metabolic syndrome

    235　(10)　1021-1029　2010/12/04

    Publisher: 医歯薬出版

    ISSN： 0039-2359

  34. Genome-Wide Profiling of Cell-Type Specific Chromatin Regulatory Elements in Adipocytes Using ChIP-seg for PPAR gamma/RXR alpha and FAIRE (Formalin-Assisted Isolation of Regulatory Elements)-seq

    Hironori Waki, Ken-Ichi Wakabayashi, Toshimasa Yamauchi, Jing Yu, Takanori Fujita, Lisa Hirose, Shuichi Tsutsumi, Tatsuhiko Kodama, Hiroyuki Aburatani, Juro Sakai, Takashi Kadowaki

    DIABETES　59　A384-A384　2010/06

    ISSN： 0012-1797

  35. 酢酸とアセチル-CoA合成酵素による飢餓・絶食時における体温維持,運動能の維持機構 (特集 インスリン抵抗性)

    酒井 寿郎

    ホルモンと臨床　58　(5)　431-438　2010/05

    Publisher: 医学の世界社

    ISSN： 0045-7167

  36. Analysis of adipogenesis and metabolic disease through next generation sequencer

    Endocrinology, diabetology & metabolism　30　(4)　334-344　2010/04

    Publisher: 科学評論社

    ISSN： 1884-2917

  37. Genome-wide ChIP-seq profiling of PPAR gamma/RXR alpha binding sites in adipocytes revealed PPAR response elements in the infron 1 of AdipoR2

    Hironori Waki, Toshimasa Yamauchi, Ken-ichi Wakabayashi, Jing Yu, Tatsuhiko Kodama, Hiroyuki Aburatani, Juro Sakai, Takashi Kadowaki

    ENDOCRINE JOURNAL　57　S422-S423　2010/03

    ISSN： 0918-8959

  38. Obesity and metabolic syndrome in histone demethylase JHDM2a deficient mice

    Juro Sakai, Takeshi Inagaki, Makoto Tachibana, Toshiya Tanaka, Kenta Magoori, Tatsuhiko Kodama, Yoichi Shinkai

    ENDOCRINE JOURNAL　57　S261-S262　2010/03

    ISSN： 0918-8959

  39. LXRαによるSERPINE1遺伝子の発現制御機構の解明

    河井恵, 石本憲司, 中村太樹, 橘敬祐, 山崎大典, 田中十志也, 浜窪隆雄, 酒井寿郎, 児玉龍彦, 土井健史

    生化学　ROMBUNNO.1P-0003　2010

    ISSN： 0037-1017

  40. SREBP‐2とNF‐Yによるヒトファルネシルピロリン酸合成酵素の遺伝子発現調節と細胞増殖への影響

    石本憲司, 橘敬祐, 花野郁子, 山崎大典, 中村太樹, 河井恵, 浦野泰臣, 田中十志也, 浜窪隆雄, 酒井寿郎, 児玉龍彦, 土井健史

    生化学　ROMBUNNO.1P-0004　2010

    ISSN： 0037-1017

  41. 核内受容体PPAR deltaの翻訳後修飾の解析

    上原光太郎, 橘敬祐, 山下雅礼, 秋山恵麻, 前川貴志, 後藤英子, 山崎大典, 石本憲司, 田中十志也, 酒井寿郎, 浜窪隆雄, 児玉龍彦, 土井健史

    生化学　ROMBUNNO.1P-0363　2010

    ISSN： 0037-1017

  42. 核内受容体PPARによるヒトMBL2の発現制御機構の解析

    竹内健太郎, 橘敬祐, 稲田大彦, 杉本研, 山崎大典, 山下雅礼, 前川貴志, 石本憲司, 田中十志也, 楽木宏実, 酒井寿郎, 浜窪隆雄, 児玉龍彦, 土井健史

    生化学　ROMBUNNO.1P-0362　2010

    ISSN： 0037-1017

  43. 核内受容体PPARδの欠失変異体を用いた転写制御機構の解析

    上原光太郎, 橘敬祐, 山下雅礼, 秋山恵麻, 山崎大典, 石本憲司, 田中十志也, 酒井寿郎, 浜窪隆雄, 児玉龍彦, 土井健史

    生化学　ROMBUNNO.4P-240　2009/09/25

    ISSN： 0037-1017

  44. Epigenetic regulations on adipocyte differentiation and metabolic syndrome

    Cell technology.　28　(8)　806-811　2009/08

    Publisher: 秀潤社

    ISSN： 0287-3796

  45. 転写調節とエネルギー代謝 (代謝) -- (基礎分野での進歩)

    酒井 寿郎

    Annual review 糖尿病・代謝・内分泌　2009　86-98　2009

    Publisher: 中外医学社

  46. Peroxisome proliferator-activated receptors (PPAR) in glucose and lipid metabolism

    Genome medicine　8　(1)　37-47　2008/02

    Publisher: メディカルレビュー社

    ISSN： 1346-4671

  47. ヒト肝癌由来細胞株におけるPPARによる新規標的遺伝子の転写活性化機構の解析

    稲田大彦, 橘敬祐, 竹内健太郎, 山崎大典, 石本憲司, 田中十志也, 酒井寿郎, 浜窪隆雄, 児玉龍彦, 土井健史

    生化学　1P-0369　2008

    ISSN： 0037-1017

  48. LXRαの新しい生理機能の探索

    石本憲司, 中村太樹, 橘敬祐, 山崎大典, 田中十志也, 浜窪隆雄, 酒井寿郎, 児玉龍彦, 土井健史

    生化学　2P-0717　2008

    ISSN： 0037-1017

  49. バキュロウイルスgp64ディスプレイシステムを用いた転写共役因子に対するモノクローナル抗体の作製

    秋山恵麻, 橘敬祐, 谷本恵一, 山崎大典, 石本憲司, 岩成宏子, 田中十志也, 望月康弘, 酒井寿郎, 浜窪隆雄, 児玉龍彦, 土井健史

    生化学　1P-1354　2008

    ISSN： 0037-1017

  50. 細胞内ステロールによるヒトlipin1遺伝子の転写制御機構の解析

    中村太樹, 石本憲司, 橘敬祐, 山崎大典, 田中十志也, 浜窪隆雄, 酒井寿郎, 児玉龍彦, 土井健史

    生化学　2P-0720　2008

    ISSN： 0037-1017

  51. フェノフィブラートによる子宮癌細胞の増殖抑制効果の観察

    吉本祐子, 山崎大典, 橘敬祐, 田子秀典, 石本憲司, 田中十志也, 酒井寿郎, 児玉龍彦, 土井健史

    生化学　3P-1088　2008

    ISSN： 0037-1017

  52. Peroxisome proliferator-activated receptors (PPARs) in glucose and lipid metabolism

    62　(10)　2380-2391　2007/10

    Publisher: 最新医学社

    ISSN： 0370-8241

  53. Hepatocyte nuclear factor 4α(HNF4α)によるType 1 lodothyronine Deiodinase(D1)の発現制御機構

    田中 十志也, 大口 裕人, 児玉 龍彦, 酒井 寿郎

    日本内分泌学会雑誌　83　(1)　142-142　2007/04

    Publisher: (一社)日本内分泌学会

    ISSN： 0029-0661

  54. A neuropeptide ligand of the G protein-coupled receptor GPR103 regulates feeding, behavioral arousal, and blood pressure

    220　(13)　1072-1077　2007/03/31

    Publisher: 医歯薬出版

    ISSN： 0039-2359

  55. ヒト肝癌細胞株における核内受容体PPARαリガンド応答遺伝子の解析

    山崎大典, 河邊奈津子, 中村仁美, 橘敬祐, 岡田欣晃, 石本憲司, 宮地弘幸, 影近弘之, 田中十志也, 酒井寿郎, 児玉龍彦, 土井健史

    日本薬学会年会要旨集　127th　(2)　90-90　2007/03/05

    Publisher: (公社)日本薬学会

    ISSN： 0918-9823

  56. 核内受容体PPARαリガンドによるヒト乳癌細胞株の増殖抑制効果の分子機構解析

    河邊奈津子, 山崎大典, 中村仁美, 橘敬祐, 岡田欣晃, 石本憲司, 影近弘之, 宮地弘幸, 田中十志也, 酒井寿郎, 児玉龍彦, 土井健史

    日本薬学会年会要旨集　127th　(2)　12-12　2007/03/05

    Publisher: (公社)日本薬学会

    ISSN： 0918-9823

  57. 核内受容体PPARδによる肥満と改善機構 (第1土曜特集 PPARと疾患) -- (基礎病態)

    酒井 寿郎

    医学のあゆみ　220　(1)　10-20　2007/01/06

    Publisher: 医歯薬出版

    ISSN： 0039-2359

  58. ヒトファルネシルピロリン酸合成酵素の遺伝子発現解析

    石本憲司, 橘敬祐, 花野郁子, 山崎大典, 住友美賀子, 中村太樹, 浦野泰臣, 田中十志也, 浜窪隆雄, 酒井寿郎, 児玉龍彦, 土井健史

    生化学　2P-1076　2007

    ISSN： 0037-1017

  59. フェノフィブラートによる肝癌細胞(Huh7)の増殖抑制に関与する遺伝子の網羅的発現解析

    山崎大典, 中村仁美, 河邊奈津子, 田子秀典, 橘敬祐, 石本憲司, 宮地弘幸, 田中十志也, 酒井寿郎, 児玉龍彦, 土井健史

    生化学　2P-0300　2007

    ISSN： 0037-1017

  60. 核内受容体PPARαリガンドによるヒト乳癌細胞株の増殖抑制効果の分子機構解析

    河邊奈津子, 山崎大典, 中村仁美, 橘敬祐, 石本憲司, 田中十志也, 酒井寿郎, 児玉龍彦, 土井健史

    生化学　4P-0829　2007

    ISSN： 0037-1017

  61. 生活習慣病--転写因子SOX6とPDX1によるインスリン分泌調節機構 (第1土曜特集 システム生物医学) -- (疾患のシステム生物医学)

    酒井 寿郎

    医学のあゆみ　219　(9)　737-744　2006/12/02

    Publisher: 医歯薬出版

    ISSN： 0039-2359

  62. メタボリックシンドローム発症要因としての内臓肥満・脂肪細胞機能異常 脂肪細胞の分化・増殖にかかわる因子 PPARα,PPARγ,PPARδ (メタボリックシンドローム--病因解明と予防・治療の最新戦略) -- (発症機序)

    高橋 貞夫, 酒井 寿郎

    日本臨床　64　259-262　2006/12

    Publisher: 日本臨床社

    ISSN： 0047-1852

  63. PPARalpha, PPARgamma, PPARdelta

    Sadao Takahashi, Juro Sakai

    Nippon rinsho. Japanese journal of clinical medicine　64　259-262　2006

    ISSN： 0047-1852

  64. PPARδ

    髙橋 貞夫, 田中十志也, 酒井寿郎

    内分泌・糖尿病科　22　(1)　88-92　2006

  65. PPARs

    髙橋 貞夫, 酒井寿郎

    循環器科　59　(2)　160-167　2006

  66. LRP5/Wntシグナルと老化・成人病

    髙橋 貞夫, 酒井寿郎

    整形・災害外科　49　(3)　198-199　2006

  67. Wnt/LRP5シグナルと生活習慣病

    髙橋 貞夫, 酒井寿郎

    内分泌・糖尿病科　22　(6)　661-668　2006

  68. PPARα，PPARγ，PPARδ

    髙橋 貞夫, 酒井寿郎

    日本臨床　64　(9)　259-262　2006

  69. 動脈硬化発症にかかわるプレーヤー １．PPARs

    髙橋 貞夫, 酒井寿郎

    最新医学　61　(10)　2116-2121　2006

  70. 肥満と血管機能 内皮細胞における血管疾患(動脈硬化症,肥満)誘発刺激応答に関する研究

    南敬, 酒井寿郎, AIRD William C, 児玉龍彦

    日本動脈硬化学会総会プログラム・抄録集　37th　150-150　2005/07/01

    Publisher: (一社)日本動脈硬化学会

    ISSN： 1347-7099

  71. 核内受容体PPARαリガンドは乳癌治療薬となりうるか?

    山崎 大典, 橘 敬祐, 中村 仁美, 小林 由美, 片山 達也, 上田 智尋, 石本 憲司, 花野 郁子, 住友 美賀子, 榊田 悟, 田中 十志也, 酒井 寿郎, 油谷 浩幸, 児玉 龍彦, 土井 健史

    日本薬学会年会要旨集　125年会　(3)　56-56　2005/03

    Publisher: (公社)日本薬学会

    ISSN： 0918-9823

  72. 肝臓におけるヒトPPARαによるCLAMPの発現調節機構

    上田 智尋, 橘 敬祐, 片山 達也, 桐野 貴圭, 高橋 梨佳, 山崎 大典, 石本 憲司, 田中 十志也, 安西 尚彦, 上田 之彦, 新井 洋由, 酒井 寿郎, 児玉 龍彦, 土井 健史

    日本薬学会年会要旨集　125年会　(3)　56-56　2005/03

    Publisher: (公社)日本薬学会

    ISSN： 0918-9823

  73. コレステロールホメオスタシスを担う転写因子SREBP

    佐藤 隆一郎, 酒井 寿郎

    生化学　76　(6)　503-508　2004/06/25

    Publisher: 日本生化学会

    ISSN： 0037-1017

  74. 「脂肪燃焼センサー」PPARδ活性化によるメタボリックシンドローム改善機構

    酒井 寿郎

    生化学　76　(6)　517-524　2004/06/25

    Publisher: 日本生化学会

    ISSN： 0037-1017

  75. 高脂血症治療薬による血中脂質改善作用に関するトランスクリプトーム解析

    山崎大典, 橘敬祐, 小林由美, 片山達也, 石本憲司, 上田智尋, 田中十志也, 酒井寿郎, 児玉龍彦

    Pharmaco-Hematologyシンポジウム講演要旨集　5th　22　2004

    ISSN： 1347-5398

  76. Low-density lipoprotein receptor-related protein 5 (LRP5) is essential for normal cholesterol metabolism and glucose-induced insulin secretion

    H Asaba, T Fujino, Y Ikeda, M Yanagisawa, T Yamamoto, J Sakai

    ATHEROSCLEROSIS SUPPLEMENTS　4　(2)　225-225　2003/09

    ISSN： 1567-5688

  77. PPAR delta agonist ameliorates obesity and insulin resistance through coordinate regulation of fatty acid metabolism in skeletal muscle

    T Tanaka, S Iwasaki, H Asaba, H Hamura, W Mitsuhiro, K Tachibana, Y Watanabe, Y Uchiyama, K Sumi, K Magoori, RX Ioka, T Doi, M Naito, J Auwerx, T Hamakubo, J Sakai, T Kodama

    ATHEROSCLEROSIS SUPPLEMENTS　4　(2)　217-217　2003/09

    ISSN： 1567-5688

  78. 低密度リポタンパク受容体類似タンパク5(LRP5)/Wntシグナルによるインスリン分泌並びに脂質代謝調節機構

    酒井 寿郎

    脂質生化学研究　45　3-3　2003/06/20

    ISSN： 0285-1520

  79. LDL receptor-related protein 5 (LRP5) is essential for normal glucose-induced insulin secretion.

    H Asaba, T Fujino, MJ Kang, Y Ikeda, T Yamamoto, M Yanagisawa, J Sakai

    JOURNAL OF PHARMACOLOGICAL SCIENCES　91　170P-170P　2003

    ISSN： 1347-8613

  80. Sources of acetyl-CoA:acetyl CoA aynthetase 1 and 2

    Fujino, T, Ikeda, Y, Osborne T, F, Takahashi, S, Yamomoto, T. T, Sakai, J

    Curr. Med. Chem.-Imun., Endoc. & Metab. Agents　3　207-210　2003

  81. The sterol regulatory element-binding protein pathway: control of lipid homeostasis through regulated intracellular transport

    J Sakai, RB Rawson

    CURRENT OPINION IN LIPIDOLOGY　12　(3)　261-266　2001/06

    ISSN： 0957-9672

  82. 転写因子とマルチプルリスクファクター

    酒井 寿郎

    動脈硬化 = The journal of Japan Atherosclerosis Society　29　127-127　2001/05/15

    ISSN： 0386-2682

  83. The SREBP pathway : Regulation of cholesterol metabolism by two step proteolysis of a membrane-bound transcription factor and molecular identification of sterol-regulated sitel-protease

    SAKAI Juro

    Journal of Atherosclerosis and Thrombosis　28　(4)　97-102　2001/03/05

    Publisher: Japan Atherosclerosis Society

    ISSN： 0386-2682

    More details Close

    Objective: Animal cells must regulate their cholesterol biosynthesis and uptake to supply sufficent amounts of cholesterol without risking overproduction. This coordination is achieved by a family of membrane-bound transcription factors called sterol regulatory element binding proteins (SREBPs). To enhance transcrtiption of genes encoding enzymes of cholesterol and fatty acid biosynthesis, the active NH2 terminal domain of SREBP is released from membranes of endoplasmic reticulum (ER) by two sequential cleavages. The first, regulated by sterols, is catalyzed Site-1 protease (S1P) that cleaves luminal loop of SREBPs. This reaction is mediated by a polytopic membrane protein called SREBP cleavage activating protein (SCAP) that complexes with SREBPs. SCAP appears to be a regulatory protein and serves as a sterol sensor. The second, not regulated by sterols, catalyzed by a hydrophobic zinc metallprotease, cleaves SREBPs within the first trans-membrane domain. Excess cholesterol block S1P activity thereby inhibits SREBP processing.<br>A cruial component of this regulatory pathway is the Site-1 protease (S1P) that initiates sterol-regulated release from the ER by making the first cut in the SREBPs. S1P is the target of the feedback regulation, but nothing is known about the structure and properties of S1P. To identify S1P, we carried out expression cloning.<br>Results: To clone S1P, we newly developed pCMV-PLAP-BP2, which encodes a fusion protein that contains placental alkaline phosphatase (PLAP) in the ER lumen flanked by cleavage sites for signal peptidase and S1P. In sterol deprived cells, cleavage by both proteases leads to PLAP secretion, but PLAP was not secreted in S1P deficient cells (SRD12B cells). We transfected pCMV-PLAP-BP2 plus pools of CHO cDNAs into SRD12B cells and monitored the PLAP secretion. We succeeded in identifying a cDNA that restores Site-1 cleavage. The cDNA encodes S1P; an intraluminal 1052-amino acid membrane bound subtilisin-like protease. We concluded that S1P is the sterol-regulated luminal protease that cleaves SREBPs and controls lipid metabolism in animal cells.

  84. 細胞内コレステロール調節機構の最前線-膜結合型転写因子SREBPとプロテアーゼによるプロセッシングによるコレステロールホメオスタシス維持機構および発現クローニングによるステロール応答性プロテアーゼの発見

    酒井 寿郎

    東北医学雑誌　112　(2)　175-179　2001/02/28

    ISSN： 0040-8700

  85. The SREBP pathway: Controlling lipid metabolism by two-step proteolysis of a membrane-bound transcription factor

    SAKAI Juro

    72　(6)　437-450　2000/06/25

    Publisher: 日本生化学会

    ISSN： 0037-1017

  86. コレステロール代謝の分子制御機構--コレステロールホメオスタシスを司る転写因子SREBPとプロテアーゼによるプロセッシング

    酒井 寿郎

    医学のあゆみ　193　(9)　763-767　2000/05/27

    Publisher: 医歯薬出版

    ISSN： 0039-2359

  87. THE VERY-LOW-DENSITY LIPOPROTEIN RECEPTOR - A 2ND LIPOPROTEIN RECEPTOR THAT MAY MEDIATE UPTAKE OF FATTY-ACIDS INTO MUSCLE AND FAT-CELLS

    T YAMAMOTO, S TAKAHASHI, J SAKAI, Y KAWARABAYASI

    TRENDS IN CARDIOVASCULAR MEDICINE　3　(4)　144-148　1993/07

    ISSN： 1050-1738

Show all ︎Show first 5

Books and Other Publications 7

  1. Thermal Biology

    Editors:Makoto Tominaga, Masahiro Takagi, Co-author:Yoshihiro Matsumura, Timothy F. Osborne, Ryo Ito, Hiroki Takahashi, Juro Sakai 他

    Springer　2024/10

  2. 温度ストレスによる生体応答ダイナミクス

    永島計, 酒井寿郎

    エヌ・ティー・エス　2023/05

    ISBN: 9784860438302

  3. 糖尿病と食

    植木浩二郎, 酒井寿郎, 松村欣宏 他

    朝倉書店　2021/11

    ISBN: 9784254361872

  4. 膜タンパク質工学ハンドブック

    津本浩平, 浜窪隆雄, 酒井寿郎

    エヌ・ティー・エス　2020/04

    ISBN: 9784860435370

  5. シンプル生化学

    野口正人, 五十嵐和彦, 林典夫, 廣野治子, 酒井寿郎 他

    南江堂　2020/03

    ISBN: 9784524246595

  6. 糖尿病学2016

    小坂樹徳, 赤沼安夫, 葛谷健, 金沢康徳, 菊池方利, 岡芳知, 谷澤幸生, 門脇孝, 山内敏正, 酒井寿郎, 阿部陽平, 松村欣宏, 稲垣毅 他

    診断と治療社　2016/05/30

    ISBN: 4787822403

  7. 栄養とエピジェネティクス : 食による身体変化と生活習慣病の分子機構

    小川, 佳宏, ネスレ栄養科学会議, 加藤, 茂明, 塩田, 邦郎, 中尾, 光善, 酒井, 寿郎, 福岡, 秀興

    建帛社　2012/04

    ISBN: 9784767961668

Show all Show first 5

Presentations 85

  1. 内臓脂肪組織におけるエピゲノム制御と代謝適応：グルコース応答性回路の解明 Invited

    酒井寿郎

    第57回日本動脈硬化学会総会　2025/07/05

  2. 中枢におけるエピゲノムを介したエネルギーバランス制御機構の解明

    高橋宙大, 荒井誠, 遠藤拓哉, 稲葉理帆, 清水佑一, 稲垣毅, 松村欣宏, 高橋かおり, 若森実, 中田正範, 米代武司, 酒井寿郎

    第98回日本内分泌学会学術総会　2025/06/07

  3. 脂肪細胞の分化におけるエピゲノムの役割 Invited

    酒井寿郎

    令和7年度第１回名古屋産学官・医連携研究会　2025/06/02

  4. 褐色脂肪組織の経世代的機能制御と代謝調節 Invited

    米代武司, 浜岡隆文, 斉藤昌之, 酒井寿郎

    第68回日本糖尿病学会年次学術集会　2025/05/29

  5. 環境記憶による褐色脂肪組織の機能制御とエネルギー代謝

    米代武司, 浜岡隆文, 斉藤昌之, 酒井寿郎

    第130回日本解剖学会/第102回日本生理学会/第98回日本薬理学会合同大会　2025/03/19

  6. 動脈硬化疾患の解明、遺伝子からエピゲノムへ Invited

    酒井寿郎

    第25回日本動脈硬化教育フォーラム　2025/02/09

  7. ゲノムと環境による肥満・代謝異常症の新機軸 Invited

    酒井寿郎

    第38回湘南循環器セミナー　2024/11/16

  8. SETD5は食事性脂肪蓄積と肝線維化を抑制する

    魏宇辰, 内田あおい, 米代武司, 伊藤亮, 崔賢美, 荒井誠, 松村欣宏, 酒井寿郎

    第97回日本生化学会大会　2024/11/07

  9. 中枢におけるエピゲノムを介したレプチン抵抗性発症機構の解明

    高橋宙大, 荒井 誠, 中田正範, 遠藤拓哉, 清水佑一, 稲垣 毅, 松村欣宏, 米代武司, 酒井寿郎

    第45回日本肥満学会・第42回日本肥満症治療学会学術集会　2024/10/20

  10. 脂肪組織特異的 JMJD1A 欠損マウスにおける持久運動能力の低下

    魏 宇辰, 金 紫越, 崔 賢美, 米代武司, 伊藤 亮, 荒井 誠, 榊原伊織, 酒井寿郎

    第45回日本肥満学会・第42回日本肥満症治療学会学術集会　2024/10/19

  11. Mitochondrial biogenesis in white adipose tissue mediated by JMJD1A-PGC-1 axis limits metabolic disease Invited

    伊藤亮, 謝詩雨, Myagmar Tumenjargal, 荒井誠, 高橋宙大, 米代武司, 松村欣宏, 酒井寿郎

    DESIRE Conference 2024　2024/07/27

  12. 生活習慣病の解明、遺伝子からエピゲノムへ Invited

    酒井寿郎

    2024十全医学会総会・学術集会　2024/06/18

  13. ヒストン脱メチル化酵素 JMJD1A と PGC1 によるミトコンドリア増生とベージュ化による肥満抑制機構

    謝詩雨, 伊藤亮, Tumenjargal Myagmar, 松村欣宏, 米代武司, 酒井寿郎

    第27回アディポサイエンス・シンポジウム　2024/03/08

  14. 脂肪組織におけるヒストン脱メチル化酵素JMJD1A の代謝調節機構の解明

    寒河江陽菜, 伊藤亮, 荒井誠, Myagmar Tumenjargal, 崔賢美, 趙亞楠, 寺西仁志, 花田礼子, 米代武司, 松村欣宏, 酒井寿郎

    第44回日本肥満学会　2023/11/26

  15. 父性寒冷刺激は脂肪組織の熱産生活性して食事性肥満とインスリン抵抗性を軽減する

    魏宇辰, 米代武司, 金紫越, 高橋宙大, 崔賢美, 伊藤亮, MYAGMAR TUMENJARGAL, 荒井誠, 松村欣宏, 酒井寿郎

    第44回日本肥満学会　2023/11/26

  16. ヒストン脱メチル化酵素JMJD1A による白色脂肪組織のミトコンドリア生合成は代謝障害を阻害する

    伊藤亮, 謝詩雨, Myagmal Tumenjargal, 米代武司, 松村欣宏, 酒井寿郎

    第44回日本肥満学会　2023/11/26

  17. 環境シグナル感知とエピゲノム機構による脂肪組織熱産生と抗肥満機構 の解明

    高橋宙大, 楊歌, 米代武司, 阿部陽平, 伊藤亮 楊超然, 川村猛, 石濱泰, 松村欣宏, 酒井寿郎

    第44回日本肥満学会　2023/11/25

  18. Cold-signal-sensing histone demethylase regulates brown and beige adipocyte activation by distinct mechanisms to prevent obesity Invited

    Juro Sakai

    Host-Directed Antiviral Research Center Seminar　2023/11/06

  19. Cold-signal-sensing histone demethylase regulates brown and beige adipocyte activation by distinct mechanisms to prevent obesity Invited

    Juro Sakai

    The 10th Federation of the Asian and Oceanian Physiological Societies Congress　2023/11/02

  20. Control of adipose thermogenesis and obesity through epigenomic reprogramming by a cold stress-responsive histone demethylase that is sensitive to β-adrenergic signaling Invited

    Juro Sakai

    2023/10/31

  21. 父性寒冷刺激は仔マウスにおいて熱産生脂肪細胞の分化を誘導してエネルギー代謝を調節する

    魏宇辰, 米代武司, 金紫越, 荒井誠, 岡本真由美, 楊超然, 永江玄太, 油谷浩幸, 松村欣宏, 酒井寿郎

    第96回日本生化学会大会　2023/10/31

  22. Epigenetic mechanisms of cell fate determination toward thermogenic adipocytes by environmental changes Invited

    高橋宙大, 楊歌, 米代武司, 阿部陽平, 伊藤亮, 楊超然, 岡本真由美, 川村猛, 石濱泰, 松村欣宏, 酒井寿郎

    DESIRE Conference 2023　2023/07/15

  23. Signal Sensing and Epigenomic Rewriting by JMJD1A Induces Mitochondria Biogenesis and Prevent Obesity Invited

    Juro Sakai

    Japan-China Atherosclerosis Symposium2023　2023/07/10

  24. 環境シグナル感知とエピゲノム機構による脂肪組織熱産生と抗肥満機構の解明

    高橋宙大, 楊歌, 米代武司, 伊藤亮, 楊超然, 岡本真由美, 油谷浩之, 川村猛, 石濱泰, 松村欣宏, 酒井寿郎

    第55回日本動脈硬化学会総会・学術集会　2023/07/09

  25. 環境ストレス感知とエピゲノム機構を介した肥満改善機構 Invited

    酒井寿郎

    第41回日本内分泌学会 内分泌代謝学サマーセミナー　2023/07/06

  26. 父性寒冷刺激による次世代の熱産生脂肪細胞の運命決定機構

    菅原優人, 魏宇辰, 金紫越, 岡本真由美, 楊超然, 張琳, 安澤隼人, 西羽美, 木下賢吾, 米代武司, 松村欣宏, 酒井寿郎

    日本生化学会東北支部 第89回例会・シンポジウム　2023/06/03

  27. 妊娠前の親の寒冷曝露が子の褐色脂肪組織 の活性と肥満度に与える影響

    米代武司, 松下真美, 布施沙由理, 黒岩美幸, 黒澤裕子, 山本恭子, 山岡敏明, 飯田誠, 隈健一, 中村尚, 浜岡隆文, 酒井寿郎, 斉藤昌之

    第77回日本栄養・食糧学会大会　2023/05/14

  28. ヒト褐色脂肪組織と妊娠前の親の寒冷曝露：FDG-PETとNIR-TRSでの評価

    米代武司, 松下真美, 布施沙由理, 黒岩美幸, 黒澤裕子, 山本恭子, 飯田誠, 隈健一, 中村尚, 浜岡隆文, 酒井寿郎, 斉藤昌之

    第43回日本肥満学会 / 第40回日本肥満症治療学会学術集会　2022/12/03

  29. 妊娠前の父性寒冷刺激と褐色脂肪細胞の活性化：視床下部の関与

    魏宇辰, 米代武司, 金紫越, 岡本(勝山, 真由美, 楊超然, 太田聡, 堤修一, 油谷浩幸, 松村欣宏, 酒井寿郎

    第43回日本肥満学会 / 第40回日本肥満症治療学会学術集会　2022/12/03

  30. 環境ストレス感知機構とエピゲノム機構を介した肥満改善機構 Invited

    酒井寿郎

    第43回日本肥満学会 / 第40回日本肥満症治療学会学術集会　2022/12/02

  31. JMJD1Aのヒストン脱メチル化活性はミトコンドリア生合成に必要である

    謝詩雨, 伊藤亮, Tumenjargal Myagmar, 松村欣宏, 米代武司, 酒井寿郎

    第95回日本生化学会大会　2022/11/11

  32. 脂肪細胞分化におけるグルコース感知センサーであるヒストン脱メチル化酵素KDM3Aの解析

    張吉, 松村欣宏, Ariyanto Eko Fuji, 楊超然, 高橋宙大, 伊藤亮, 米代武司, 曽我朋義, 幡野敦, 松本雅紀, 酒井寿郎

    第95回日本生化学会大会　2022/11/11

  33. 脂肪細胞のエンハンサーを制御するヒストンアセチル化・脱アセチル化

    松村欣宏, 伊藤亮, 矢島あゆむ, 山口玲, 田中十志也, 川村猛, 馬郡健太, 内田あおい, 米代武司, 張吉, 楊超然, 高橋宙大, 稲垣毅, 油谷浩幸, 野出孝一, 酒井寿郎

    第95回日本生化学会大会　2022/11/10

  34. G12共役型GPCRはβ3アドレナリン刺激依存的な白色脂肪のベージュ化を亢進する

    小野雄基, 伊藤亮, 酒井寿郎, 井上飛鳥

    第95回日本生化学会大会　2022/11/09

  35. 生活習慣病の解明、遺伝子からエピゲノムへ Invited

    酒井寿郎

    第18回日本病理学会カンフアレンス　2022/07/30

  36. 父性寒冷刺激による仔の褐色脂肪細胞の運命決定機構の解明

    魏宇辰, 米代武司, 金紫越, 岡本(勝山, 真由美, 楊超然, 太田聡, 堤修一, 油谷浩幸, 松村欣宏, 酒井寿郎

    第76回日本栄養・食糧学会　2022/06/11

  37. 精子を介した寒冷曝露記憶の経世代エピゲノムの解明

    岡本(勝山, 真由美, 米代武司, 魏宇辰, 金紫越, 楊超然, 永江玄太, 吉田圭介, 松村欣宏, 酒井寿郎

    第76回日本栄養・食糧学会　2022/06/11

  38. 父性寒冷刺激は白色脂肪組織のベージュ化を誘導する

    金紫越, 米代武司, 魏宇辰, 岡本(勝山, 真由美, 松村欣宏, 酒井寿郎

    第76回日本栄養・食糧学会　2022/06/11

  39. SETD5-NCoR-HDAC3 複合体の時空間ダイナミクスは脂肪細胞分化のエンハンサー活性化を制御する

    松村欣宏, 伊藤亮, 矢島あゆむ, 山口 玲, 田中十志也, 川村猛, 馬郡健太, 内田あおい, 米代 武司, 張吉, 楊超然, 高橋宙大, 稲垣毅, 油谷浩幸, 野出孝一, 酒井寿郎

    第95回日本内分泌学会　2022/06/02

  40. 褐色脂肪組織と白色脂肪組織で異なるヒストン脱メチル化酵素JMJD1Aの寒冷適応に対する役割

    伊藤亮, 謝詩雨, Myagmar Tumenjargal, 楊超然, 米代武司, 松村欣宏, 酒井寿郎

    第95回日本内分泌学会　2022/06/02

  41. MYPT1-PP1β脱リン酸化酵素複合体によるベー ジュ化制御機構の解明

    高橋宙大, 楊歌, 米代武司, 伊藤亮, 松村欣宏, 酒井寿郎

    第95回日本内分泌学会　2022/06/02

  42. シグナル感知とヒストン脱メチル化による熱産生・エネルギー消費制御機構 Invited

    酒井寿郎

    第95回日本内分泌学会　2022/06/02

  43. 褐色脂肪組織と白色脂肪組織におけるヒストン脱メチル化酵素JMJD1Aの寒冷適応に対する組織特異的な役割

    伊藤亮, 謝詩雨, Tumenjargal Myagmar, 楊超然, 米代武司, 松村欣宏, 酒井寿郎

    第65回日本糖尿病学会　2022/05/12

  44. エピゲノム変化とアクトミオシン緊張を制御する脱リン酸化酵素同定と同酵素によるベージュ化制御の解明

    酒井寿郎, 高橋宙大, 楊歌, 米代武司, 楊超然, 伊藤亮, 松村欣宏

    第99回日本生理学会大会　2022/03/17

  45. 褐色脂肪組織と白色脂肪組織で異なるヒストン脱メチル化酵素JMJD1Aの寒冷適応に対する役割

    伊藤 亮, 謝詩雨, ミグマル トゥメンジャルガル, 楊超然, 米代武司, 松村欣宏, 酒井寿郎

    第99回日本生理学会大会　2022/03/16

  46. エネルギー感知ヒストン脱メチル化酵素は脂肪細胞分化において脂肪蓄積のための糖代謝を促進する

    松村欣宏, エコ フジ アリヤント, 楊超然, 張吉, 曽我朋義, 酒井寿郎

    第99回日本生理学会大会　2022/03/16

  47. 妊娠前の父性寒冷刺激と白色脂肪のベージュ化：前駆脂肪細胞の運命決定

    金紫越, 米代武司, 魏宇辰, 岡本(勝山, 真由美, 楊超然, 油谷浩幸, 松村欣宏, 酒井寿郎

    第43回日本肥満学会 / 第40回日本肥満症治療学会学術集会　2022/12/02

  48. A Phosphatase Protein Complex Orchestrates Uncoupled Respiration via a Histone Demethylase and YAP/TAZ Mediated Actomyosin Pathway in White Adipose Tissue Invited

    Juro SAKAI

    2021/10/26

  49. 生活習慣病におけるエピゲノムの役割 Invited

    酒井寿郎

    日本スポーツ栄養学会第7回大会　2021/07/03

  50. A Concerted Thermogenic Response via A Phosphor-switch of An Epigenetic Modifier Invited

    酒井寿郎

    第１回健康長寿代謝制御研究センター国際シンポジウム　2021/05/28

  51. 熱産生性脂肪のエピジェネティクス Invited

    稲垣毅, 酒井寿郎

    第64回日本糖尿病学会　2021/05/20

  52. 肥満発症に関与するエピゲノム酵素のシグナル感知とヒストン脱メチル化機構の解明 Invited

    酒井寿郎

    第41回日本肥満学会　2021/03/21

  53. Histone demethylase JMJD1A mediates adaptive thermogenesis via two independent mechanisms and in two different type of adipose tissue under cold environment

    2020/12/03

  54. JMJD1Aのヒストン脱メチル化活性はミトコンドリア生合成に必要である

    謝詩雨, 伊藤亮, Tumenjargal Myagmar, 松村欣宏, 米代武司, 酒井寿郎

    第95回日本生化学会大会　2020/11/11

  55. SETDB1 represses H3K4/H3K9me3 bivalent genes by ubiquitination-dependent and -independent mechanisms.

  56. SETDB1 represses H3K4/H3K9me3 bivalent genes by ubiquitination-dependent and -independent mechanisms.

    2020/09/14

  57. 脂肪細胞分化を制御するヒストンメチル化・脱メチル化反応

    松村欣宏, Eko Fuji Ariyanto, 曽我朋義, 酒井寿郎

    第93回 日本生化学会大会　2020/09/16

  58. 脂肪細胞の機能制御に関わるヒストン修飾とクロマチン構造の変化

    酒井寿郎

    第42回日本分子生物学会　2019/12/05

  59. "Histone demethylase-mediated adaptive thermogenesis” International-presentation

    Juro SAKAI

    71th Annual Korean Physiological Society Meeting　2019/11/01

  60. 脂肪細胞における栄養環境の感知とエピゲノムによる代謝制御

    松村欣宏, Eko Fuji Ariyanto, 曽我朋義, 酒井寿郎

    第92回日本生化学会大会　2019/09/18

  61. Epigenome in Endocrine system Invited

    Juro SAKAI

    2019/05/11

  62. JMJD1A mediates acute and chronic thermogenic responses through complementary mechanisms International-presentation Invited

    Juro SAKAI

    The 9th Federation of Asian and Oceanian Physiological Societies Congress　2019/03/30

  63. A histone demethylase JMJD1A mediates acute and chronic thermogenic responses through complementary Mechanisms International-presentation Invited

    Juro SAKAI

    The 4th IMCR Symposium on Endocrine and Metabolism: At the Cutting Edge of Metabolic Regulation Research　2018/11/09

  64. JMJD1A Mediates Acute and Chronic Thermogenic Responses through Complementary Mechanisms International-presentation Invited

    Juro SAKAI

    THE 15TH NIKKO INTERNATIONAL SYMPOSIUM 2018 Genomic Approach for Non-communicable Diseases　2018/10/19

  65. JMJD1A Mediates Acute and Chronic Thermogenic Responses through Complementary Mechanisms International-presentation Invited

    Juro SAKAI

    Padjadjaran Integrated Health Science Conference 2018: The 5th Bandung International Biomolecular Medicine Conference　2018/10/03

  66. Histone Demethylates JMJD1A Coordinates Acute and Chronic Adaptation to Cold Stress via Thermogenic Phosphor-switch Invited

    Juro SAKAI

    2018/07/12

  67. Beta-Adrenergic Signaling Regulates a Concerted Thrmogenic Tesponse in Brown Adipose Tissue and subcutaneous White Adipose Tissue. International-presentation Invited

    Juro SAKAI

    American Diabetes Association 78th Scientific Sessions　2018/06/22

  68. ヒストン脱メチル化酵素による寒冷環境への適応機構 Invited

    酒井 寿郎

    第91回日本内分泌学会　2018/04/26

  69. ヒストン脱メチル化酵素による脂肪細胞の熱産生機構と糖代謝制御機構 Invited

    酒井 寿郎

    第52回糖尿病学の進歩　2018/03/02

  70. 脂肪細胞を特徴づける代謝によるエピゲノム制御 Invited

    松村欣宏, Eko Fuji Ariyanto, 曽我朋義, 酒井寿郎

    2017年度生命科学系学会合同年次大会　2017/12/18

  71. 寒冷刺激による翻訳後修飾とエピゲノム変化による脂肪細胞のベージュ化機構

    酒井寿郎, 阿部陽平, 藤原庸右, 高橋宙大, 児玉龍彦, 油谷浩幸, 松村欣宏, 稲垣毅

    2017年度生命科学系学会合同年次大会　2017/12/08

  72. エピゲノムを介した白色脂肪細胞分化の制御機構 Invited

    松村欣宏, 仲木竜, 稲垣毅, 油谷浩幸, 酒井寿郎

    第35回内分泌学代謝学サマーセミナー　2017/07/14

  73. ヒストン脱メチル化酵素のリン酸化と脱メチル化による白色脂肪細胞の褐色化機構 Invited

    酒井 寿郎

    第11回エピジェネティクス研究会年会　2017/05/22

  74. ヒストン脱メチル化酵素JMJD1Aの肥満、糖尿病における機能解析 Invited

    稲垣毅, 酒井寿郎

    第31回日本糖尿病・肥満動物学会年次学術集会　2017/02/11

  75. 脂肪細胞における代謝産物とエピゲノムによるエネルギー代謝調節 Invited

    Eko F. Ariyanto, 松村欣宏, 曽我朋義, 稲垣毅, 酒井寿郎

    日本がん分子標的治療学会 第12回トランスレーショナルリサーチワークショップ　2017/01/17

  76. Environmental cues and Epigenetic Regulation of Adipogenesis and Obesity Invited

    Juro SAKAI

    2016/12/09

  77. 生活習慣病、遺伝子からエピゲノムへ Invited

    酒井 寿郎

    第24回日本ステロイドホルモン学会学術集会　2016/12/03

  78. JMJD1A複合体による熱産生のエピゲノム制御機構 Invited

    稲垣毅, 阿部陽平, Rozqie Royhan, 松村欣宏, 仲木竜, 川村猛, 梶村真吾, 児玉龍彦, 油谷浩幸, 酒井寿郎

    第39回日本分子生物学会年会　2016/11/30

  79. Nutritin,metabolic state,and Epigenomic Regulation of Adipogenesis and Obesity Invited

    Juro SAKAI

    2016/10/08

  80. H3K4/H3K9me3 Bivalent Chromatin Domains Targeted by Lineage-Specific DNA Methylation Pauses Adipogenesis. International-presentation

    Yoshihiro Matsumura, Ryo Nakaki, Takeshi Inagaki, Ayano Yoshida, Yuka Kano, Hiroshi Kimura, Toshiya Tanaka, Shuichi Tsutsumi, Mitsuyoshi Nakao, Takefumi Doi, Kiyoko Fukami, Timothy F. Osborne, Tatsuhiko Kodama, Hiroyuki Aburatani, Juro Sakai

    The Keystone Symposia -Chromatin and Epigenetics-　2016/03/23

  81. Regulation of Higher-order Chromatin Structure during Thermogenesis in Brown Adipocytes. International-presentation Invited

    Takeshi Inagaki, Yohei Abe, Royhan Rozqie, Yoshihiro Matsumura, Shingo Kajimura, Juro Sakai

    The 46th NIPS International Symposium　2015/10/03

  82. A Role of Isocitrate Dehydrogenase 3 in Regulation of Epigenome and Transcription during Adipogenesis. International-presentation Invited

    Juro Sakai, Yoshihiro Matsumura, Ariyanto Fuji Eko, Takeshi Inagaki

    12th Asian Congress of Nutrirtion　2015/05/16

  83. PKA-dependent phosphorylation of JMJD1A drives energy expenditure through Higher-Order Chromatin Regulation via SWI/SNF and PPARγ Association in Brown Adipocytes. International-presentation Invited

    Juro SAKAI

    The 18th International Vascular Biology Meeting,　2014/04/15

  84. MYPT1-PP1 β脱リン酸化酵素はクロマチン構造と共活性化因子誘導の調整を介してベージュ化を抑制する

    高橋宙大, 楊歌, 米代武司, 阿部陽平, 伊藤亮, 楊超然, 岡本真由美, 川村猛, 石濱泰, 松村欣宏, 酒井寿郎

    第26回アディポサイエンスシンポジウム　2023/01/28

  85. SETD5-NCoR-HDAC3複合体の動的変化は脂肪細胞のエンハンサーを活性化する

    松村欣宏, 伊藤亮, 矢島あゆむ, 山口玲, 田中十志也, 川村猛, 馬郡健太, 内田あおい, 米代武司, 張吉, 楊超然, 高橋宙大, 稲垣毅, 油谷浩幸, 野出孝一, 酒井寿郎

    第26回アディポサイエンスシンポジウム　2023/01/28

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Research Projects 27

  1. A Study on Elucidating Obesity and Lifestyle Diseases through the Epigenome-RNA Modification Axis

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (S)

    Institution: Tohoku University

    2024/04 - 2029/03

  2. モジュールタンパク質の時空間的インタープレイによるエンハンサー活性化機構の解明

    酒井 寿郎

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 挑戦的研究(開拓)

    Institution: 東北大学

    2022/06 - 2026/03

  3. 生活習慣病予防に働く早期ライフステージの生活環境記憶の解明

    松村欣宏, 米代武司, 堤修一, 永江玄太

    Offer Organization: 日本医療研究開発機構

    System: 革新的先端研究開発支援事業（AMED-CREST）

    Category: 健康・医療の向上に向けた早期ライフステージにおける生命現象の解明

    Institution: 東北大学

    2020/10 - 2026/03

  4. シグナル感知エピゲノム酵素による世代を超えた環境適応機構の解明

    酒井 寿郎

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 基盤研究(A)

    Institution: 東北大学

    2021/04 - 2024/03

  5. 栄養-代謝-エピゲノム軸による細胞機能調節の仕組みを解明

    酒井 寿郎

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 挑戦的研究(萌芽)

    Institution: 東京大学

    2020/07 - 2022/03

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    成熟脂肪細胞は高グルコース下で分化すると大量のグルコースを解糖系で代謝する能力を獲得する。この分子メカニズムとしてTCA回路の代謝物 αケトグルタル酸（αKG）を介して、解糖系遺伝子の発現が脱メチル化により制御されることを見出した。また、αKGを補酵素とするH3K9me2の脱メチル化酵素の系統的RNA干渉法によるノックダウン実験から、グルコース濃度変化によって解糖系遺伝子群の転写を制御するヒストン脱メチル化酵素としてJMJD1Aを特定し、栄養（グルコースの有無）がエピゲノムを介して転写を制御することを見出した（エピゲノム書き換え：2nd step）。このメカニズムとしては、現段階ではグルコース応答性にJMJD1Aが標的遺伝子に呼び込まれる可能性と、グルコース応答性にJMJD1Aリン酸化 (シグナル感知：1st step) されることで、転写複合体が構成され、αKGが補酵素として機能するとの双方の可能性がある。端緒的にJMJD1Aのプロテオミクス解析から、リン酸化の候補酵素 （CDC-like kinase2, casein kinase II）と、JMJD1Aリン酸化候補部位（S446とS448）を見出した。

  6. 代謝入力による脂肪細胞の遺伝子発現機構の解明

    酒井 寿郎

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 新学術領域研究(研究領域提案型)

    Institution: 東京大学

    2020/04 - 2022/03

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    成熟脂肪細胞は高グルコース下で分化すると大量のグルコースを解糖系で代謝する能力を獲得する。この分子メカニズムとしてグルコースがTCA回路の代謝物 αケトグルタル酸（αKG） を介して脱メチル化制御されることを見出した。αKG はJMJドメインを有するヒストン脱メチル化酵素の補酵素として必須である。分化に伴い αKG が上昇すると、解糖系遺伝子（HK2など）上で H3K9me2 の脱メチル化が亢進し、遺伝子発現が誘導される。αKG 合成酵素IDH3β の発現を抑制すると、分化誘導時に αKG は上昇せず、解糖系遺伝子上の3K9me2 の脱メチル化と遺伝子発現誘導が抑制された。αKG を補酵素とする6 種類すべてのH3K9me2 の脱メチル化酵素を各々発現抑制したところ、脱メチル化酵素JMJD1Aが解糖系遺伝子の脱メチル化を担うことを見出した。栄養（グルコースの有無）がエピゲノムを介して転写を制御することを見出した（エピゲノム書き換え：2nd step）。このメカニズムとしては現段階ではグルコース応答性にJMJD1Aが標的遺伝子に呼び込まれる可能性と、グルコース応答性にJMJD1Aリン酸化 (シグナル感知：1st step) されることで、転写複合体が構成され、αKGが補酵素として機能するとの双方の可能性がある。 さらに、JMJD1Aのプロテオミクス解析から、リン酸化の候補酵素 （CDC-like kinase2, casein kinase II）と、JMJD1Aリン酸化部位（S446とS448）を見出した。

  7. Elucidation of lifestyle-related diseases development due to environmental factors and epigenetic memory

    SAKAI Juro

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (S)

    Category: Grant-in-Aid for Scientific Research (S)

    2016/05 - 2021/03

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    Adipose tissue plays an important role in the development of obesity and lifestyle-related diseases. Adipose tissue plays a major role in the adaptation of individuals to their living environment: white adipocytes store fat and become hypertrophied under nutritional surpluses, while they turn browning and develop heat-producing capacity in cold environments. Failure of this adaptation can lead to lifestyle-related diseases. Epigenomics is a mechanism to control gene expression by chemical modification of histones and DNA. We have elucidated a stepwise mechanism by which epigenomic modification enzymes undergo post-translational modification in response to environmental stimuli to form specific protein complexes (1st step) and continuously induce heat-producing gene expression via histone demethylation (2nd step) to adapt to cold environment. We also demonstrated the possibility of targeting this mechanism for the treatment of lifestyle-related diseases.

  8. 熱産生脂肪細胞を誘導するエピゲノム酵素リン酸化スイッチの解明

    酒井 寿郎

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 新学術領域研究(研究領域提案型)

    Institution: 東京大学

    2018/04 - 2020/03

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    ① S265D-JMJD1A点変異マウスを作製した。繁殖させたのち、実験に供している。 高脂肪食摂餌下30℃で飼育したのちに、16℃の准寒冷刺激を与えている。体重にWTとS265D変異マウスとで今のところ差は見られないが、摂餌量は16℃にすると変異マウスでWTと比べ優位に増えている。このことは、変異マウスがより脂肪を燃焼していることをうかがわせる。今後、インスリン感受性を解析するとともに、8℃などさらに寒冷の状態、また30℃におけるサーモニュートラルの条件でも解析を進める。 ② 遺伝子発現・エピゲノム解析。S265D-JMJD1A点変異マウスの脂肪組織におけるS265D-JMJD1Aマウスの脂肪組織中の熱産生関連遺伝子の発現量をRT-PCR法により解析した。さらにそれらの遺伝子上のエピゲノム（H3K9のメチル化修飾）をクロマチン免疫降法 （ChIP）とChIP Seqにより明らかにし、リン酸化持続でクロマチン変化が誘導されることを確証する。 ③ リン酸化JMJD1Aの脱リン酸化酵素複合体を特定した。より特異性が高いと考えられる調節サブユニットについて解析を進めている。その結果、この調節サブユニットをノックダウンすると、皮下白色脂肪組織から採取したstromal vascular fraction (SVF) の熱産生遺伝子の発現が数倍に上昇することが見いだされた。またSV40でライン化した前駆脂肪細胞では40数倍の上昇がみられ、熱産生も同様に亢進が観察された。 以上よりこの調節サブユニットを新規ベージュ化抑制因子とした。

  9. エピゲノム変化に伴う摂食中枢制御と肥満生活習慣病に関する研究

    酒井 寿郎, FALLAH OMRAN SIMIN

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 特別研究員奨励費

    Institution: 東京大学

    2016/07 - 2018/03

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    「ベージュ脂肪細胞」とよばれる第二の熱産生脂肪細胞の存在が近年明らかにされている。褐色脂肪細胞が特に新生児に多く存在するのに比べ、ベージュ脂肪細胞は寒さに適応していくために新たにつくられる「誘導型」の熱産生脂肪細胞である。先行研究で短期の寒冷刺激に伴いJMJD1A の 265 番目のセリン残基がリン酸化され、急性期の熱産生に必要な機能を獲得することを見出した（Nature Communications 2015）。今回、265 番目のセリン残基をリン酸化されないアラニン残基に置換した変異型 JMJD1A をもつマウスを作製し、寒さに対する適応を解析した。急激な寒冷刺激下では、変異体マウスは寒冷を感知できないため、通常のマウスと比べて顕著に体温が低下した。また長期の寒冷刺激下では、変異体マウスは寒冷刺激をエピゲノムに伝えることができないため、野生型マウスと比較して、脂肪燃焼、熱産生、そして白色脂肪組織のベージュ化が顕著に抑制され、寒冷への適応力が低下していることが明らかになった。今回の研究から、寒冷環境への適応のしくみについて、（1）恒温動物が寒さに直面すると、褐色脂肪組織のJMJD1Aが寒さを感知することで急速な熱産生を行い、（2）寒さが長期に持続すると白色脂肪組織のJMJD1Aが寒さをエピゲノムに伝え、脂肪を燃焼し熱を産生する「誘導型」のベージュ脂肪細胞を新たにつくる、ということがわかりました。また、白色脂肪組織のベージュ化では、寒さの感知によるJMJD1Aのリン酸化（第一段階）、ヒストン脱メチル化によるエピゲノムの変化（第二段階）、という機構を介して、「休止中」の脂肪燃焼と熱産生に関わる遺伝子を「活動中」にし、慢性的な寒さに適応することが初めて明らかとなった。

  10. 寒冷感知センサーとして働くエピゲノム酵素によるベージュ脂肪細胞の解明

    酒井 寿郎

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 新学術領域研究(研究領域提案型)

    Institution: 東京大学

    2016/04 - 2018/03

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    白色脂肪組織は、エネルギーを脂肪として貯めることが主たる役割であるため、熱産生に関与する遺伝子は発現していない。しかし、寒冷環境が長期に持続すると、熱産生に関わる遺伝子が誘導され、寒冷環境に個体が耐えられるよう適応する。本来、細胞には「エピゲノム」というゲノムの後天的な調節機構が備わっており、エピゲノムのしくみにより細胞の種類ごとに働く遺伝子（活動中）と働かない遺伝子（休止中）が明確に決められている。脂肪を貯める機能を担う白色脂肪細胞では、通常は脂肪燃焼や熱産生に関わる遺伝子は「休止中」で、働くことができない。では、恒温動物が長期の寒冷刺激を受けると、どのようにして遺伝子に寒冷環境に適応した体質への変化を促すのか？我々は、寒冷刺激を受けるとアドレナリン作用によってヒストン脱メチル化酵素JMJD1Aがリン酸化され、寒冷刺激が持続すると必要な機能を獲得したJMJD1A がエピゲノム変化を介して「休止中」だった脂肪燃焼と熱産生に関わる遺伝子群を「活動中」にし、遺伝子を発現させて、ベージュ化を誘導し、寒冷環境に慢性的に適応するしくみがあることを解明した。265 番目のセリン残基をリン酸化されないアラニン残基に置換した変異型 JMJD1A をもつマウスを作製し、寒さに対する適応を解析した。急激な寒冷刺激下では、変異体マウスは寒冷を感知できないため、通常のマウスと比べて顕著に体温が低下した。また長期の寒冷刺激下では、変異体マウスは寒冷刺激をエピゲノムに伝えることができないため、野生型マウスと比較して、脂肪燃焼、熱産生、そして白色脂肪組織のベージュ化が顕著に抑制され、寒冷への適応力が低下していることが解明された。

  11. Elucidation of chromatin dynamics by an energy sensor histone demethylase

    SAKAI Juro, KAWAMURA Takeshi, KIMURA Hiroshi, ABURATANI Hiroyuki, INAGAKI Takeshi, MATSUMURA Yoshihiro, ABE Yohei

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Challenging Exploratory Research

    Category: Grant-in-Aid for Challenging Exploratory Research

    Institution: The University of Tokyo

    2016/04 - 2018/03

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    AMP Activated Protein Kinase (AMPK) is a serine / threonine phosphorylating enzyme and plays an extremely important role in metabolism, cell proliferation and reprogramming as an intracellular energy sensor. Since histone demethylase JMJD1A has multiple motifs of AMPK from “ScanSite”, we analyzed whether AMPK phosphorylated JMJD1A and was functioning. The JMJD1A recombinant protein was found to be phosphorylated AMP dependent in vitro by Phos-tag gel separation and immunoblotting (IB) with JMJD1A antibody and IB analysis using AMPK substrate antibody. Furthermore, phospho-proteomic analysis demonstrated that there are more than ten serine and/or threonine residues phosphorylated by AMPK. Identification of phosphorylated amino acid residues of endogenous JMJD1A by AMPK is still on the way.

  12. The function of histone demethylase JMJD1A as a signal-sensing scaffold

    INAGAKI TAKESHI, SAKAI JURO, ABURATANI HIROYUKI, FUJITA TOSHIRO, KAWAMURA TAKESHI

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)

    Category: Grant-in-Aid for Scientific Research (B)

    2013/04 - 2018/03

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    Regulating metabolic diseases including diabetes mellitus and obesity is an important research issue for human health. We previously elucidated that the mouse lucking histone demethylase JMJD1A is obesity, diabetes, and cold-sensitive. In this study, we elucidated that JMJD1A is phosphorylated at S265 by β-adrenergic stimulation in response to acute cold exposure. Phosphorylated JMJD1A forms complex with SWI/SNF chromatin remodeler and nuclear transcription factor PPARγ. The P-JMJD1A-SWI/SNF-PPARγ complex induces enhancer-promoter proximity by forming long-range chromatin loop and, in turn, regulates thermogenic gene expression. Thus, phosphorylated histone demethylase JMJD1A regulates metabolic gene expression by mediating long-range genomic interactions in response to β-adrenergic stimulation.

  13. 生活習慣病発症における環境と栄養を感知するエピゲノム制御機構の解明

    酒井 寿郎, 川村 猛

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 基盤研究(A)

    Institution: 東京大学

    2016/04 - 2017/03

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    研究目的：エピゲノムは塩基配列を変えず、DNAやヒストンの化学修飾により遺伝子発現を変える環境への適応機構であり、生活習慣病発症に深く関与する。しかし、多様な外的環境の変化に対応して、どのように特異的にエピゲノムが変化するのか、その一連のメカニズム解明は不十分である。申請者は、環境変化に対するエピゲノム修飾酵素の翻訳後修飾とこれによって規定されるタンパク質複合体形成がクロマチン構造変化の初期応答 (1st step) として鍵となることを解明した。本研究では翻訳後修飾とタンパク質複合体解析を行い、環境刺激による初期応答からエピゲノム変化をともなう持続応答 (2nd step) へ至るまでのメカニズムを解明する。 成果：環境からの刺激（寒冷）がエピゲノムに統合されるかを解析した。マウスを寒冷下で飼育し、皮下脂肪組織を採取し、遺伝子の発現解析を行い、さらに、クロマチン免疫沈降法によってヒストンH3の9番目のリジンのメチル化を解析した（ChIP解析）。この結果、30℃で飼育したマウスに比べ、寒冷(4℃)で飼育したマウスは抑制系のクロマチンの修飾が減少した。これに対応して白色脂肪組織において熱産生遺伝子の上昇がみられ、白色脂肪組織がベージュ化していることが確認された。 さらに、ヒストンリジンの脱メチル化酵素KDMの遺伝子欠損マウス（KOマウス）と野生型マウスを寒冷環境下で飼育し同様の実験を行った。この結果、野生型マウスでは白色脂肪組織の褐色化の組織像が得られたのに対し、KOマウスでは褐色化が著しく減弱していた。ヒストンリジン残基の抑制修飾もKOマウスでは高値にとどまった。以上より、KDMが寒冷を感知しヒストンの抑制化修飾を脱メチル化することによって遺伝子発現に寄与することが示された。 本研究は現在、基盤Ｓ(課題番号16H06390)にて継続進行中である。

  14. 栄養環境によるヒストンメチル化制御機構の解明

    酒井 寿郎

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 新学術領域研究(研究領域提案型)

    Institution: 東京大学

    2014/04 - 2016/03

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    脂肪細胞分化において転写抑制に働くH3K9ジメチルをはずすヒストン脱メチル化酵素を系統的にRNA干渉法（siRNA）によってノックダウンしたところ、白色脂肪細胞のモデル細胞である3T3-L1脂肪細胞で解糖系遺伝子の発現をエピジェネティックに制御するJMJDヒストン脱メチル化酵素を同定した。JMJDヒストン脱メチル化酵素のノックダウンで、Fabp4やアディポネクチンなど脂肪細胞の分化マーカー遺伝子は概ねコントロールのsiRNAと同レベルまで上昇したが、解糖系遺伝子のSlc2a4, Hk2, Gpi1, Pfkp, Gapdhなどはほとんど上昇せず、ヒストンH3K9のジメチルが外れていないことが示唆された。 今後、IDH3の酵素活性を半分に減らす程度の変異体を発現させるなどして検証を進める。同様にJMJDヒストン脱メチル化酵素活性部位の変異体を発現させてレスキューできるかなど検証する。 αKGは解糖系が亢進することでTCAサイクルでの産生が上昇する。産生されたαKGはJMJDヒストン脱メチル化酵素を補酵素として活性化し、さらに解糖系遺伝子発現を上昇させ、結果として解糖系を亢進させ、脂肪蓄積を増加させることから、この系はポジティブフィードバックループをつくり、高グルコース高インスリン血症を誘導する過栄養、肥満の状況を栄養学的に悪化させるサイクルにも関与しうることが判明した。

  15. Elucidation of locus specific chromatin complex formation and energy expenditure gene expressions using enChIP

    SAKAI Juro, ABURATANI Hiroyuki, KAWAMURA Takeshi, INAGAKI Takeshi, MATSUMURA Yoshihiro, FUJII Hotaka

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Challenging Exploratory Research

    Category: Grant-in-Aid for Challenging Exploratory Research

    Institution: The University of Tokyo

    2014/04 - 2016/03

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    CISPR-CAS9 system is a recently developed gene editing method and its applied method, namely, engineered DNA-binding molecule-mediated chromatin immunoprecipitation (enChIP) is beneficial to identify specific nucleotides or proteins that specifically interact to the specific gene loci. In the current study, using these methods, we showed that distal enhancer of β1 adrenergic receptor gene Adrb1, whose transcription is induced upon adrenergic stimulation and whose gene product is important in the activation of brown fat, interacts with Adrb1 promoter via long-lange chromatin looping: deletion of E1 enhancer blunted β-AR induced gene transcription and higher order chromatin structure changes.

  16. The Epigenomic Analysis of Obesity and Insulin Resistance

    SAKAI Juro, KAWAMURA Takeshi, ABURATANI Hiroyuki, SHINKAI Yoichi, SAKURAI Takeshi

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (S)

    Category: Grant-in-Aid for Scientific Research (S)

    Institution: The University of Tokyo

    2010/04 - 2016/03

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    Together with genetic predisposition for the development of life style-related diseases, environmental factors are greatly involved. Stimuli from the environment are responded through changes in the epigenome (i.e. DNA methylation and histone modifications) and chromatin 3D structure. We, from research in the fat cells, discovered a new “bivalent chromatin structure” that epigenome modifying enzyme forms to poise precursor fat cells undifferentiated. We also discovered that the initial response to environmental change such as cold was phosphorylation of epigenome modifying enzyme and the following protein complex formation plays a key role in response to cold for the regulate thermogenic gene transcription.

  17. ヒストン修飾酵素の細胞内エネルギー感知機構の解明

    酒井 寿郎

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 新学術領域研究(研究領域提案型)

    Institution: 東京大学

    2012/04 - 2014/03

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    脂肪細胞分化過程における代謝を、細胞外フラックスアナライザーを用いて解析したところ、分化にともない、解糖系、酸素消費量が大きく亢進した。脂肪細胞分化過程におけるメタボローム解析から、解糖系ならびにTCAサイクル代謝物に顕著な変化が見られた。なかでもαKGは3倍上昇し、JmjCヒストン脱メチル化酵素（JHDM）を制御している可能性が考えられた。αKGはTCAサイクルでイソクエン酸からイソクエン酸デヒドロゲナーゼ（IDH） によって合成される。マイクロアレイ解析から、IDH3α,β、γ遺伝子の発現が分化とともに急上昇した。さらにIDH3γ をノックダウンしたところ、PPARγならびに脂肪細胞分化マーカー (Fabp4, AdipQ) の発現にはほとんど影響をおよぼさず、解糖系遺伝子 (Slc2a4, Hk2) の発現が低下し、これに伴い脂肪の蓄積が激減することを見出した。以上より、脂肪細胞において内在性IDH3によるαKGの産生が、JHDMの活性化を制御して、ヒストン修飾・クロマチン構造変化を誘導する可能性を見いだした。このことは、IDH3は脂肪細胞での脂肪のためやすさ、脂肪の燃えやすさを決定している可能性をも示唆する。

  18. PPARbata/delta activation of CD300a controls intestinal immunity

    SAKAI Juro, TANAKA Toshiya

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Challenging Exploratory Research

    Category: Grant-in-Aid for Challenging Exploratory Research

    Institution: The University of Tokyo

    2012/04 - 2014/03

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    we show that PPARbeta/delta (peroxisome proliferator-activated receptor beta/delta) directly regulates CD300a in macrophages that express the immunoreceptor tyrosine based-inhibitory motif (ITIM)-containing receptor. In mice lacking CD300a, high-fat diet (HFD) causes chronic intestinal inflammation with low numbers of intestinal lymph capillaries and dramatically expanded mesenteric lymph nodes. As a result, these mice exhibit triglyceride malabsorption and reduced body weight gain on HFD. Peritoneal macrophages from Cd300a-/- mice on HFD are classically M1 activated. Activation of toll-like receptor 4 (TLR4)/MyD88 signaling by lipopolysaccharide (LPS) results in prolonged IL-6 secretion in Cd300a-/- macrophages. Bone marrow transplantation confirmed that the phenotype originates from CD300a deficiency in leucocytes. These results identify CD300a-mediated inhibitory signaling in macrophages as a critical regulator of intestinal immune homeostasis.

  19. Histone demethylase Jmjd1a as a regulator of glycolipid metabolism

    INAGAKI Takeshi, SAKAI Juro, SHINKAI Yoichi, TACHIBANA Makoto, ABURATANI Hiroyuki, KODAMA Tatsuhiko, KAWAMURA Takeshi, OKAMURA Hitoshi, DOI Masao

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (A)

    Category: Grant-in-Aid for Young Scientists (A)

    Institution: The University of Tokyo

    2009 - 2012

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    Jmjd1a (also known as Jhdm2a and KDM3a) catalyzes removal of H3K9 mono- and dimethylation. We established JMJD1a deficient mice (JMJD1A -/-) and discovered that the mice develop adult onset obesity, hypertriglyceridemia, hypercholesterolemia, and insulin insensitivity, that are hallmarks of metabolic syndrome. To investigate the molecular mechanism of Jmjd1a working machinery, we sought to elucidate Jmjd1a target genes and working complex using techniques of chromatin immonoprecipitation and mass spectrometry. We raised monoclonal antibodies against mouse and human Jmjd1a protein prepared by baculovirus expression system. ChIP sequence using Jmjd1a antibody as well as methylated histone antibodies showed a specific binding region which codes a retrotransposon. Whole cell extracted protein from HeLa cells was immunoprecipitated using the established Jmjd1a antibodies and the precipitated protein complex was analyzed using shotgun mass spectrometry. Interestingly, a series of splicing factors and sin3a complex forming proteins appeared in the list of shotgun proteomics. It is also elucidated that there is a functional phosphorylated site in Jmjd1a. Our result indicates that Jmjd1a regulates gene transcription through changing the chromatin formation.

  20. 肥満発症と脂肪細胞分化におけるエピジェネティックスの解明

    酒井 寿郎, 川村 猛

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 基盤研究(A)

    Institution: 東京大学

    2010 - 2010

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    エピゲノム修飾酵素であるJMJD1A、SETDB1、および活性未同定のSET蛋白の抗原となるタンパクを昆虫細胞Sf9および大腸菌から精製し、免疫を開始した。また全長のタンパクを精製し、in vitroにおけるアッセイを開始した。活性未同定のSET蛋白はmesenchymal stem cellで発現させFLAGタグで免疫沈降を行い、これをヒストンメチル化アッセイに供し、活性を新規に同定することができたため、どのヒストンテールにメチル化を入れるか、質量分析器で解析することとした。さらに、このSET蛋白の発現量が骨分化に関与するという知見を得て、トランスクリプトームを細かい時間分解能で解析することとした。 本研究は現在、基盤S (課題番号22229009) にて継続進行中である。

  21. Comprehensive analyses of signals of Wnt and nuclear receptors in adipogenesis through proteomics

    SAKAI Juro, TANAKA Toshiya, KAWAMURA Takeshi

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)

    Category: Grant-in-Aid for Scientific Research (B)

    Institution: The University of Tokyo

    2008 - 2009

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    We revealed that PPARγ regulates several genes involved in histone lysine methyltransferase genes thereby regulates adipogenesis. We also revealed that the mechanism by which Wnt/β-catenin inhibits adipogenesis. Wnt/β-catenin stimulates COUP-TFII gene expressions, whose gene product inhibits PPARγ2 gene expression through the recruitment of HDAC to the transcription regulatory region of PPARγ2.

  22. リガンドスクリーニングのためのケミカルプロテオミクス手法の開発

    酒井 寿郎

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 萌芽研究

    Institution: 東京大学

    2007 - 2008

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    微量に存在する核内受容体蛋白質をターゲットに高親和性抗体-磁気ビーズを用いたプロテオミクスを行うことで、複合体のストイキオメトリーを壊さずに、転写複合体が構造の類似した合成リガンドの濃度・時間によって遷移する様を追跡する系を樹立した。本研究ではバキュロウィルス上に融合蛋白を発現させた蛋白質を免疫する方法によって作成した高親和性抗体(Kd 10-8以下)を低ノイズ磁気ビーズに固定化させ、サンプル調整を行うことにより、現在のプロテオミクス解析を更に効果的なものとした。 3T3-L1脂肪細胞では、スプライソゾームや蛋白のinitiation complexに関わる蛋白など、これまであまり報告のない蛋白が再現良く取れた。さらに、生体内の核内受容体によるシグナルはリガンドの多様性により決定されることから、PPARγの合成された種々近縁の多様なアゴニストリガンドによって変動するデータを比較検討することを行っている。これはアゴニスト作用のある種々類似の薬剤でのプロテオミクスは、大量のデータを意味づけるうえで重要である。しかしながら、PGC1やその他、よく知られたmediator複合体などが逆に検出することが出来なかった。これまでの過剰発現系で見られてきた複合体がネイティブ蛋白レベルで見られない理由については不明である。本研究ではネイティブ蛋白とのストイキオメトリュに重きを置いた研究であるが、アゴニストリガンドによる変動も必ずしも再現が取れるわけではなく更なる最適化が必要である。また、今回新たにPPAγはRXRαのみならずRXRβと複合体を形成することが明らかにされた。さらに、mRNA transportとmRNA locanzationにかかわるミオシン、Translation initiationにかかわるEIF4ファミリーも検出された。ただしこれらは通常細胞質に存在する蛋白であるため、さらに注意深い検討が必要である。CTCFとの複合体コンプレックスも見られ、PPARγの広範囲な機能が推測された。

  23. アセチルCoA合成酵素遺伝子欠損マウスの肥満抵抗性の分子基盤の解析

    酒井 寿郎

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 特定領域研究

    Institution: 東京大学

    2006 - 2007

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    アセチル-CoA合成酵素(AceCS)は酢酸とCoAから、アセチル-CoAを合成する。AceCS2は骨格筋・心筋に主に発現し、絶食やI型糖尿病など、血中のグルコースが低下するとき、もしくはI型糖尿病などブドウ糖の利用が傷害されケトン体合成・利用が重要となるときに顕著に発現が上昇するが、個体レベルでの役割は不明である。そこで我々はアセチル-CoA合成酵素(II型)(AceCS2)遺伝子の欠損マウスの作成によってこの酵素の個体における役割を解析した。 AceCS2はケトン体である3-hydroxy-butyric acidやacetoacetateを基質とすることが予測されたが、これらの血中レベルは量群間で差は認められず、in vivoのRIのラベル体を腹腔内投与したクリアランス実験では、その後TCAサイクルでの代謝産物である^<14>CO_2の量にも差は認められなかった。しかしながら、AceCS2の最も強い基質であるアセテートは血中から代謝されず、呼気中へCO_2の代謝産物もほとんど検出されなかった。ガスクロマトフィーによる解析では、血中のアセテート濃度はAceCS2-/-マウスで6倍程度の増加が見られた。以上より、アセテートは、低血糖、糖尿病などのケトジェニックな状態で生産され、ケトン体や長鎖脂肪酸同様エネルギー源として必須なものであることが示された。そしてケトジェニックな状態で転写が上昇するAceCS2はこれらの代謝に必須であることが示された。KLF15はアミノ酸を分解する酵素群の転写制御を担い、絶食などでおこる低血糖時にグルコースを新生する重要な役割を担う転写因子であるが、これに加え、KLF15の標的遺伝子としてのAceCS2は絶食などグルコースを利用できないときに、アセテートをエネルギー源、あるいは糖新生に寄与する重要な役割を担うことが示唆された。

  24. Transcriptional network of β-cell compensation in the face of obesity induced insulin resistance

    SAKAI Juro

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)

    Category: Grant-in-Aid for Scientific Research (B)

    Institution: The University of Tokyo

    2006 - 2007

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    In obesity-related insulin resistance, pancreatic islets compensate for chronic insulin insensitivity by expanding β-cell mass and increasing insulin secretory capacity. In a previous study, we identified sex-determining region Y-box (SOX) 6 as a down-regulated transcription factor in obesity-related insulin resistant animals. We also showed that SOX6 directly binds with pancreatic-duodenal homeobox factor 1 (PDX1) and negatively regulates glucose-stimulated insulin secretion. Based on the role of PDX1 in the development and proliferation of β-cells, insulin/insulin-like growth factor signaling pathways and the onset of type 2 diabetes, we suggested that the attenuated expression of SOX6 may contribute to β-cell adaptation in obesity-related insulin resistance. To further define the role of SOX6 in obesity-related insulin resistance, we analyzed the effects of SOX6 expression on cell proliferation. SiRNA mediated knockdown of SOX6 significantly stimulated cell proliferation, whereas induced SOX6 expression resulted in the inhibition of cell growth. In the present paper, we demonstrate the mechanism by which SOX6 suppresses cell proliferation. Our current studies reveal that SOX6 binds with β-catenin and recruits histone deacetylase 1 for suppression of cyclin D1 promoter activities induced by β-catenin. Together with the stimulation of glucose-stimulated insulin secretion, the induced cell proliferation by attenuation of SOX6 expression may account for the hyperinsulinemia and hyperplasia characteristic of insulin resistance.

  25. Wntシグナルと成長期マウスでの脂肪細胞老化との関連

    酒井 寿郎, 田中 十志也, 浅場 浩

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 特定領域研究

    Institution: 東京大学

    2004 - 2005

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    ペルオキシソーム増殖薬活性化受容体δ(PPARδ)はリガンド依存的に転写を制御する核内受容体の一つである.我々はPPARδが骨格筋の脂肪酸代謝を調節する因子の一つであることを報告した(PNAS,100,229-234,2003).選択的PPARδアゴニストGW501516(GW)の投与により,ミトコンドリアの増生,脂肪酸β酸化および代謝速度の亢進,骨格筋における顕著な脂肪滴蓄積の減少が認められ,高脂肪食(HFD)負荷によって惹起される肥満およびインスリン抵抗性を改善することを明らかにした.GWは骨格筋および肝臓において脂肪酸輸送,脂肪酸β酸化および呼吸鎖に関与する遺伝子群を誘導した.一方,普通食負荷したマウスのWATの遺伝子発現には影響を及ぼさないが,GWはHFDによって惹起されるTNFαおよびPAI-1の遺伝子発現増加を抑制した.さらに,HFD負荷したマウスの肝,骨格筋およびWATではインスリンによるPI-3キナーゼの活性化が顕著に低下していたが,GW投与群では有意な改善が認められた.以上のことより,GWは長期投与において持続的な抗肥満および抗糖尿病活性を有することが示唆された. PPARδアゴニストのインスリン感受性改善効果の一部は,肝や骨格筋での脂質蓄積抑制や脂肪細胞の肥大化を抑制し,PI-3キナーゼ介在性の糖取り込みやアディポサイトカイン産生を改善することによって発揮されていると考えられた. Oikeらとの共同研究で血管新生液性因子angiopoietin-related growth factorが抗肥満効果としてPPARδを介することを示した。 また、私たちは転写因子Kruppel-like factor KLF15が絶食時に誘導されATPを合成するアセチル-CoA合成酵素プロモーター活性を調節することを明らかにした。KLF15は脂肪細胞の分化に関与する転写因子としても知られている。

  26. Coordinate regulation of Wnt signaling and transcriptional factors in endocrine pancreatic islets in obese related insulin

    SAKAI Juro, TANAKA Toshiya, MAGOHRI Kenta

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)

    Category: Grant-in-Aid for Scientific Research (B)

    Institution: The University of Tokyo

    2004 - 2005

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    A Wnt coreceptor low density lipoprotein receptor related protein 5 plays an essential role in bone accrual and eye development. In obesity-related insulin resistance, the pancreatic islets compensate for insulin resistance by increasing their secretory capacity or increasing islet cell mass. We investigated Wnt/β-catenin signal in pancreatic islet. Here, we report the identification of SOX6, a member of the HMG box superfamily of transcription factors, as a co-repressor for pancreatic-duodenal homeobox factor-1 (PDX1). SOX6 mRNA levels were profoundly reduced by both a long term high fat feeding protocol in normal mice and in the genetically obese ob/ob mice on a normal chow diet. Overexpression of SOX6 decreased glucose stimulated insulin secretion (GSIS) which was accompanied by decreased ATP/ADP ratio, Ca^<2+> mobilization, proinsulin content and insulin genes expression. In a complementary fashion, depletion of SOX6 by small interfering RNAs augmented GSIS in insulinoma mouse MIN6 and rat INS-1E cells. These effects can be explained by our mechanistic studies that show SOX6 acts to suppress PDX1 stimulation of the insulin II promoter through a direct protein : protein interaction. Furthermore, SOX6 retroviral expression decreased acetylation of the histones H3 and H4 in chromatin from the promoter for the insulin II gene suggesting that SOX6 may decrease PDX1 stimulation through changes in chromatin structure at specific promoters. We also show that SOX6 overexpression results in a marked reduction in the expression of genes involved in mitochondrial oxidative phosphorylation, most of which were reciprocally up-regulated by PDX1 overexpression, suggesting that SOX6 may also act as a general co-repressor of other PDX1 dependent genes. Furthermore, we also demonstrated that SOX6 inhibits Wnt/β-catenin signaling pathway by physically interacting with β-catenin, recruiting histone deacetylase 1 and reduces INS-1 and NIH3T3 cell proliferation.

  27. 脂質代謝動脈硬化関連遺伝子転写因子作用機構の分子生物学的解明

    酒井 寿郎

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 奨励研究(A)

    Institution: 東北大学

    2001 - 2002

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    アセチルCoAはミトコンドリア内においては酸化的リン酸化によるエネルギー産生に使われる一方、細胞質ではコレステロール・脂肪酸合成の前駆体として利用される生体にとっては必要不可欠な物質である。細胞質におけるアセチルCoAの産生経路はクエン酸を基質とし分解するATPクエン酸リアーゼによる触媒経路が主たるものと考えられていたが、近年、酢酸をCoAとライゲーションする事でアセチルCoAを合成するアセチルCoA合成酵素(AceCS1)のcDNAクローニングがなされ(Fujino et al J Biol. Chem. 2001, Luong et al J Biol. Chem. 2000)、アセチルCoA産生の新たな経路の存在が明らかとなった。アセチルCoAを合成するAceCS1のmRNAの発現は、繊維芽細胞から脂肪細胞の分化に伴い上昇する。また個体レベルでは絶食でその発現は低下し、再食で絶食前のレベル以上に上昇する。このようにAceCS1は栄養代謝・脂肪細胞において重要な役割を担っていると考えられるが、その代謝経路における位置付けや生理的意義、またその転写調節機構は明らかではない。そこで今回我々はAceCS1のプロモーターをクローニングし転写調節機構の解析を行った結果、転写因子sterol regulatory elemennt binding protein(SREBP)がその転写調節の中心を担っていることを明らかにした。プロモーター領域には8個のSREがクラスターを形成して存在し、その下流に隣接するGC-boxとがシナジスティックに転写を調節していることが明らかとなった。さらにGC-BoxにはSp1とSp3が結合しうることがゲルシフトアッセイで示され、かつSp3による転写活性はSp1に比べ低いことからSREBPを介した転写活性はSp1/Sp3の比率で調節されているものと考えられた。

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