| 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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| 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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