Metformin lowers blood glucose levels via inhibition of ChREBP activity

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K11628
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 59040:Nutrition science and health science-related
• Research Institution: Health Sciences University of Hokkaido
• Principal Investigator: NAKAGAWA Tsutomu 北海道医療大学, 薬学部, 准教授 (50722063)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: ChREBP

Outline of Final Research Achievements

Metformin is known to regulate blood glucose levels by inhibiting hepatic gluconeogenesis via activation of AMPK. However, the identification of downstream substrates of AMPK has never been performed. Furthermore, the molecular basis for metformin response remains poorly understood. It is reported that metformin inhibited the activity of ChREBP, which could be a potential therapeutic target protein of type 2 diabetes mellitus. This suggests that ChREBP is one of a target protein of metformin.
In this study, metformin inhibited the formation of ChREBP-Mlx heterodimer, which is essential for DNA binding, via phosphorylation on Ser568 in ChREBP through AMPK activation. Moreover, overexpression of O-GlcNAc transferase (OGT) mitigated the effect of metformin on the binding of Mlx to ChREBP. OGT might enhance the interaction of ChREBP with Mlx in O-GlcNAcylation-independent manner because the binding of O-GlcNAc on ChREBP did not enhance the binding of Mlx to ChREBP.

Free Research Field

生化学

Academic Significance and Societal Importance of the Research Achievements

ChREBPのDNA結合を制御する因子に関する研究は少ない。特にMlxとの2量体形成を制御する因子に関しては、これまでにほとんど研究が行われておらず、Mlxの結合がAMPKによるリン酸化により制御されていることを明らかにした本研究は、ChREBPの活性化メカニズムの解明において新たな領域を開拓した重要な研究であり、学術的意義は大きいと考えられる。また、糖尿病患者数は近年急激に増加しており、次世代の治療薬の開発に対する社会的要請は極めて強い。本研究は糖尿病治療薬の開発において新たな標的部位を提案できたことから、新たな治療薬の開発に資する一助になると考えられるため、社会的意義は大きいと考えられる。