Relationship between glucose metabolism and FOXO1 acetylation through acetyl-CoA

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K08193
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Applied molecular and cellular biology
• Research Institution: University of Tsukuba
• Principal Investigator: Daitoku Hiroaki 筑波大学, 生存ダイナミクス研究センター, 講師 (30361314)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: FOXO / アセチル化 / 糖代謝 / グルコース / 線虫 / 寿命

Outline of Final Research Achievements

It has been known that transcription factor FOXO1, a key mediator of blood sugar levels and lifespan extension, is regulated by phosphorylation under the insulin-Akt signaling pathway. In addition, FOXO1 is known to be acetylated by a histone acetyltransferase CBP; however, the physiological condition that trigger acetylation remains unclear. In this study, I tested a hypothesis under which “an excess glucose metabolism increases the amounts of acetyl-CoA and thereby enhances acetylation of FOXO1” and uncovered that high glucose condition induces FOXO1 acetylation through the glycolytic pathway in human cell lines. Furthermore, I found that high glucose condition also induces acetylation of DAF-16, the nematode orthologue of FOXO1, and shortens the lifespan of C. elegans independent on phosphorylation pathway.

Free Research Field

分子生物学

Academic Significance and Societal Importance of the Research Achievements

本研究成果から、糖新生（空腹時に血糖値を維持する仕組み）の調節を担う転写因子FOXO1には、血中インスリン濃度に応じたリン酸化による抑制に加えて、血糖そのものの濃度に応じたアセチル化による抑制も受けることが明らかとなった。この第２のブレーキの発見は、２型糖尿病の主たる要因であるインスリン抵抗性においても、糖新生を抑える手段を提示するものであり、新たな創薬のターゲットになり得るものと期待される。