Identification of the mechanisms underlying transcriptional cofactor CITED2-mediated regulation of feeding state-dependent metabolic gene expression in the liver
| Project/Area Number |
26713033
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| Research Category |
Grant-in-Aid for Young Scientists (A)
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| Allocation Type | Partial Multi-year Fund |
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| Research Field |
Metabolomics
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| Research Institution | National Center for Global Health and Medicine |
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Principal Investigator |
Sakai Mashito 国立研究開発法人国立国際医療研究センター, その他部局等, その他 (40643490)
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| Project Period (FY) |
2014-04-01 – 2016-03-31
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| Project Status |
Completed (Fiscal Year 2015)
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| Budget Amount *help |
¥23,660,000 (Direct Cost: ¥18,200,000、Indirect Cost: ¥5,460,000)
Fiscal Year 2015: ¥11,700,000 (Direct Cost: ¥9,000,000、Indirect Cost: ¥2,700,000)
Fiscal Year 2014: ¥11,960,000 (Direct Cost: ¥9,200,000、Indirect Cost: ¥2,760,000)
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| Keywords | 糖尿病 / 遺伝子転写 / 転写共役因子 / ヒストンアセチル基転移酵素 |
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| Outline of Final Research Achievements |
We investigated the mechanisms by which the transcriptional cofactor CITED2 regulates feeding state-dependent metabolic gene expression in the liver and found that (1) the histone acetyltransferase GCN5 interacts with PKA in a CITED2-dependent manner, (2) PKA phosphorylates GCN5 at Ser275 during fasting, and (3) phosphorylated GCN5 promotes gluconeogenic gene induction. Therefore, the GCN5-CITED2-PKA module functions as an essential regulator of gluconeogenesis. Hepatic GCN5 phosphorylation was significantly higher in obese insulin-resistant db/db mice; disruption of the GCN5-CITED2-PKA module by CITED2 depletion reduced gluconeogenic gene expression and hyperglycemia in these mice. Inhibiting GCN5-CITED2-PKA module formation may be the therapeutic target for accelerated hepatic gluconeogenesis in diabetes.
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Report
(3 results)
Research Products
(17 results)
