Mechanism of NASH pathogenesis by nuclear receptors through qualitative changes in fatty acids
Project/Area Number |
19K07474
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Research Category |
Grant-in-Aid for Scientific Research (C)
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Allocation Type | Multi-year Fund |
Section | 一般 |
Review Section |
Basic Section 49030:Experimental pathology-related
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Research Institution | Gunma University |
Principal Investigator |
Inoue Yusuke 群馬大学, 大学院理工学府, 教授 (90304302)
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Co-Investigator(Kenkyū-buntansha) |
阪口 政清 岡山大学, 医歯薬学総合研究科, 教授 (70379840)
柿崎 暁 群馬大学, 大学院医学系研究科, 講師 (80344935)
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Project Period (FY) |
2019-04-01 – 2022-03-31
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Project Status |
Completed (Fiscal Year 2021)
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Budget Amount *help |
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2021: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2019: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
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Keywords | 脂肪肝 / 核内受容体 / 脂肪酸 / 繊維化 / NASH / 線維化 / miRNA |
Outline of Research at the Start |
NASHは肝硬変や肝癌に進行する悪性疾患であるが、その発症機構は不明で治療薬もない。Hnf4aΔHマウスはNASHを発症するが、HNF4αとPPARαを欠損させたダブル欠損マウスではNASHが改善する。しかし、PPARαの活性化機構は解明されていない。本研究では、(1)Hnf4aΔHマウスで発現上昇する脂肪酸不飽和化/伸長酵素が、脂肪酸の質的変化を引き起こし、PPARαを活性化する。(2)miRNA の発現低下が、PPARαのさらなる活性化と肝線維化を促進する。という仮説を検証することにより、NASH発症機序の解明を目指す。
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Outline of Final Research Achievements |
Non-alcoholic steatohepatitis (NASH) is a malignant disease that progresses to cirrhosis and hepatocelular carcinoma, for which there is no cure. Mice with liver-specific deficiency of the nuclear receptor HNF4α (KO mice) develop NASH, but NASH was ameliorated in double-deficient mice by crossing KO mice with PPARα-deficient mice. Therefore, KO mice develop NASH due to PPARα activation. The activation was found to be accompanied by changes in the composition of fatty acids in the liver. In particular, an increase in oleic acid was proven to activate PPARα.
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Academic Significance and Societal Importance of the Research Achievements |
本研究により、脂肪酸組成の変化による核内受容体PPARαの活性化による非アルコール性脂肪性肝炎(NASH)の新しい発症機構が解明できた。本研究で得られた知見は、2つの核内受容体であるHNF4αとPPARαのシグナルカスケードに着目したNAFLD/NASHの新しい診断・治療法の開発に貢献できることが期待される。
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Report
(4 results)
Research Products
(27 results)
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[Journal Article] Extracellular S100A11 plays a critical role in spread of the fibroblast population in pancreatic cancers2019
Author(s)
Takamatsu H, Yamamoto K, Tomonobu N, Murata H, Inoue Y, Yamauchi A, Sumardika W, Youyi C, Kinoshita R, Yamamura M, Fujiwara H, Mitsui Y, Araki K, Futami J, Saito K, Iioka H, Ruma MW, Putranto EW, Nishibori M, Kondo E, Yamamoto Y, Toyooka S, Sakaguchi M
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Journal Title
Oncol Res
Volume: -
Issue: 6
Pages: 713-727
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Neuroplastin-β mediates S100A8/A9-induced lung cancer disseminative progression.2019
Author(s)
Sumardika IW, Chen Y, Tomonobu N, Kinoshita R, Ruma IMW, Sato H, Kondo E, Inoue Y, Yamauchi A, Murata H, Yamamoto KI, Tomida S, Shien K, Yamamoto H, Soh J, Futami J, Putranto EW, Hibino T, Nishibori M, Toyooka S, Sakaguchi M
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Journal Title
Mol Carcinog.
Volume: -
Issue: 6
Pages: 980-995
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Melanoma cell adhesion molecule is the driving force behind the dissemination of melanoma upon S100A8/A9 binding in the original skin lesion.2019
Author(s)
Chen Y, Sumardika IW, Tomonobu N, Winarsa Ruma IM, Kinoshita R, Kondo E, Inoue Y, Sato H, Yamauchi A, Murata H, Yamamoto KI, Tomida S, Shien K, Yamamoto H, Soh J, Liu M, Futami J, Sasai K, Katayama H, Kubo M, Putranto EW, Hibino T, Sun B, Nishibori M, Toyooka S, Sakaguchi M
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Journal Title
Cancer Lett.
Volume: -
Pages: 178-190
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Critical role of the MCAM-ETV4 axis triggered by extracellular S100A8/A9 in breast cancer aggressiveness.2019
Author(s)
Chen Y, Sumardika IW, Tomonobu N, Kinoshita R, Inoue Y, Iioka H, Mitsui Y, Saito K, Ruma IMW, Sato H, Yamauchi A, Murata H, Yamamoto KI, Tomida S, Shien K, Yamamoto H, Soh J, Futami J, Kubo M, Putranto EW, Murakami T, Liu M, Hibino T, Nishibori M, Kondo E, Toyooka S, Sakaguchi M.
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Journal Title
Neoplasia.
Volume: 21(7)
Issue: 7
Pages: 627-640
DOI
NAID
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] exSSSRs (extracellular S100 soil sensor receptors)-Fc fusion proteins work as prominent decoys to S100A8/A9-induced lung tropic cancer metastasis.2018
Author(s)
Kinoshita R, Sato H, Yamauchi A, Takahashi Y, Inoue Y, Sumardika IW, Chen Y, Tomonobu N, Araki K, Shien K, Tomida S, Torigoe H, Namba K, Kurihara E, Ogoshi Y, Murata H, Yamamoto KI, Futami J, Putranto EW, Ruma IMW, Yamamoto H, Soh J, Hibino T, Nishibori M, Kondo E, Toyooka S, Sakaguchi M
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Journal Title
Int J Cancer.
Volume: -
Issue: 12
Pages: 3138-3145
DOI
Related Report
Peer Reviewed / Int'l Joint Research
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[Journal Article] Newly developed anti-S100A8/A9 monoclonal antibody efficiently prevents lung tropic cancer metastasis.2018
Author(s)
Kinoshita R, Sato H, Yamauchi A, Takahashi Y, Inoue Y, Sumardika IW, Chen Y, Tomonobu N, Araki K, Shien K, Tomida S, Torigoe H, Namba K, Kurihara E, Ogoshi Y, Murata H, Yamamoto KI, Futami J, Putranto EW, Ruma IMW, Yamamoto H, Soh J, Hibino T, Nishibori M, Kondo E, Toyooka S, Sakaguchi M.
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Journal Title
Int J Cancer.
Volume: 印刷中
Issue: 2
Pages: 569-575
DOI
Related Report
Peer Reviewed / Int'l Joint Research
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