Elucidation of the role of GCN5 in the regulation of hepatic metabolism

2014 Fiscal Year Final Research Report

• Project/Area Number: 24591348
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Metabolomics
• Research Institution: Research Institute, International Medical Center of Japan
• Principal Investigator: MATSUMOTO Michihiro 独立行政法人国立国際医療研究センター, 研究所 糖尿病研究センター 分子代謝制御研究部, 部長 (90467663)
• Research Collaborator: SAKAI Mashito 国立国際医療研究センター研究所, 糖尿病研究センター・分子代謝制御研究部, 室長 (40643490)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Keywords: エネルギー代謝 / 転写調節 / 糖代謝 / 糖尿病 / アセチル化酵素 / エピゲノム修飾 / グルカゴン

Outline of Final Research Achievements

De novo synthesis of glucose (gluconeogenesis) from liver is induced by fasting glucagon, and is critical to maintain blood glucose levels. Such induction is dysregulated in diabetes, causing hyperglycemia. Our research shows that the histone acetyltransferase (HAT) GCN5 is an essential component for hepatic gluconeogenesis induced by glucagon/cAMP pathway. During fasting, GCN5 and CITED2 constitute a functional complex, in which GCN5 is phosphorylated. This phosphorylation promotes GCN5’s substrate switch from a coactivator to histone H3, leading to optimal epigenetic changes and recruitment of transcriptional machinery for maximal gluconeogenic gene transcription. Discovery of the fasting-inducible GCN5-containing complex and the substrate switch of GCN5 are crucial in biology. In addition, disassembly of this module ameliorates hyperglycemia in diabetic mice, suggesting it as an attractive target to treat type 2 diabetes.

Free Research Field

糖尿病代謝学