Study for the metabolic regulation and NASH pathophysiology through the insulin-mTOR signaling
Project/Area Number |
18K08478
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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 54040:Metabolism and endocrinology-related
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Research Institution | Kobe University |
Principal Investigator |
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Project Period (FY) |
2018-04-01 – 2021-03-31
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Project Status |
Completed (Fiscal Year 2020)
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Budget Amount *help |
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2020: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2019: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
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Keywords | インスリン抵抗性 / 代謝異常 / 非アルコール性脂肪性肝炎 / 脂肪細胞 / PDK1 / FoxO1 / NASH / LTB4 / TSP-1 / mTOR / PDK1-mTOR経路 |
Outline of Final Research Achievements |
The pathological mechanism of metabolic disorders as well as non-alcoholic steatohepatitis (NASH) based on systemic insulin resistance remained unclear. By this study using adipocyte-specific PDK1/FoxO1 deficient mice, it was shown that dysregulation of the PDK1-FoxO1 pathway causes systemic insulin resistance through the lipid mediator LTB4. The significance of the novel adipokine TSP-1 in NASH pathology was also studied using TSP-1 deficient mice. Furthermore, downregulation of the mTOR pathway in adipocytes was shown to contribute to a part of the pathology of metabolic disorders and NASH.
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Academic Significance and Societal Importance of the Research Achievements |
本研究において、脂肪細胞のPDK1-FoxO1と呼ばれる経路の異常が全身のインスリン抵抗性や糖代謝異常、非アルコール性脂肪性肝炎(NASH)の原因として重要であることが解明された。さらに、インスリン抵抗性のメカニズムとして脂質メディエーターLTB4が関与すること、NASHの原因として新規アディポカインTSP-1が関与する可能性が示された。本研究によって同定された分子メカニズムは、インスリン抵抗性や糖脂質代謝異常症、NASHに対する新規治療標的に資することが期待され、臨床的に有意義な成果と考えられる。
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Report
(4 results)
Research Products
(19 results)
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[Journal Article] The PDK1-FoxO1 Signaling in Adipocytes Controls Systemic Insulin Sensitivity Through the 5-lipoxygenase-leukotriene B 4 Axis2020
Author(s)
Hosooka T, Hosokawa Y, Matsugi K, Shinohara M, Senga Y, Tamori Y, Aoki C, Matsui S, Sasaki T, Kitamura T, Kuroda M, Sakaue H, Nomura K, Yoshino K, Nabatame Y, Itoh Y, Yamaguchi K, Hayashi Y, Nakae J, Accili D, Yokomizo T, Seino S, Kasuga M, Ogawa W.
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Journal Title
Proc Natl Acad Sci U S A.
Volume: Online ahead of print
Issue: 21
Pages: 11674-11684
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Hyperglycemia induces skeletal muscle atrophy via a WWP1-KLF15 axis.2019
Author(s)
Hirata Y, Nomura K, Senga Y, Okada Y, Kobayashi K, Okamoto S, Minokoshi Y, Imamura M, Takeda S, Hosooka T, Ogawa W.
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Journal Title
JCI Insight.
Volume: 4
Issue: 4
Pages: 124952-124952
DOI
Related Report
Peer Reviewed / Open Access
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