Identification of the mechanisms underlying transcriptional cofactor CITED2-mediated regulation of feeding state-dependent metabolic gene expression in the liver

2015 Fiscal Year Final Research Report

• Project/Area Number: 26713033
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Partial Multi-year Fund
• Research Field: Metabolomics
• Research Institution: National Center for Global Health and Medicine
• 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)
• Project Period (FY): 2014-04-01 – 2016-03-31
• 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

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.

Free Research Field

代謝学