| Project/Area Number |
16390260
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Metabolomics
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| Research Institution | University of Tsukuba |
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Principal Investigator |
YAMADA Nobuhiro University of Tsukuba, Graduate School of Comprehensive Human Sciences, Professor, 大学院・人間総合科学研究科, 教授 (40200729)
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| Co-Investigator(Kenkyū-buntansha) |
SHIMANO Hitoshi University of Tsukuba, Graduate School of Comprehensive Human Sciences, Associate Professor, 大学院・人間総合科学研究科, 助教授 (20251241)
TOYOSHIMA Hideo University of Tsukuba, Graduate School of Comprehensive Human Sciences, Assistant Professor, 大学院・人間総合科学研究科, 講師 (20197966)
SONE Hirohito University of Tsukuba, Graduate School of Comprehensive Human Sciences, Assistant Professor, 大学院・人間総合科学研究科, 講師 (30312846)
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| Project Period (FY) |
2004 – 2005
|
| Project Status |
Completed (Fiscal Year 2005)
|
| Budget Amount *help |
¥14,400,000 (Direct Cost: ¥14,400,000)
Fiscal Year 2005: ¥5,500,000 (Direct Cost: ¥5,500,000)
Fiscal Year 2004: ¥8,900,000 (Direct Cost: ¥8,900,000)
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| Keywords | Metabolic syndrome / Insulin sensitivity / transcription factor / Diabetes / SREBP |
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| Research Abstract |
Insulin receptor substrate 2 (IRS-2) is the main mediator of insulin signalling in the liver, controlling insulin sensitivity. Sterol regulatory element binding proteins (SREBPs) have been established as transcriptional regulators of lipid synthesis. Here, we show that SREBPs directly repress transcription of IRS-2 and inhibit hepatic insulin signalling. The IRS-2 promoter is activated by forkhead proteins through an insulin response element (IRE). Nuclear SREBPs effectively replace and interfere in the binding of these transactivators, resulting in inhibition of the downstream PI(3)K/Akt pathway, followed by decreased glycogen synthesis. These data suggest a molecular mechanism for the physiological switching from glycogen synthesis to lipogenesis and hepatic insulin resistance that is associated with hepatosteatosis.
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