Metformin lowers blood glucose levels via inhibition of ChREBP activity
| Project/Area Number |
20K11628
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 59040:Nutrition science and health science-related
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| Research Institution | Health Sciences University of Hokkaido |
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Principal Investigator |
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| Project Period (FY) |
2020-04-01 – 2023-03-31
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| Project Status |
Completed (Fiscal Year 2022)
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| Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
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| Keywords | ChREBP / メトホルミン |
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| Outline of Research at the Start |
糖尿病治療薬メトホルミンが薬効を発現する分子メカニズムの1つに、糖尿病の原因タンパク質として考えられている転写因子Carbohydrate response element-binding protein (ChREBP)の活性阻害があることを明らかにする。本研究では、ChREBPの活性を阻害した細胞やChREBP KOマウスを用いることにより、ChREBPを機能不全、または欠損させた条件下でメトホルミンの作用を調べることにより、メトホルミンの薬効発現におけるChREBPの役割を明らかにする。
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| 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.
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| 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。
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Report
(4 results)
Research Products
(10 results)
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[Journal Article] The structure of importin alpha and the nuclear localization peptide of ChREBP, and small compound inhibitors of ChREBP-importin alpha interactions.2020
Author(s)
Jung H, Takeshima T, Nakagawa T, MacMillan KS, Wynn RM, Wang H, Sakiyama H, Wei S, Li Y, Bruick RK, Posner BA, De Brabander JK, Uyeda K.
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Journal Title
Biochemical Journal
Volume: 477
Issue: 17
Pages: 3253-3269
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Book] Glycosignals in Cancer2023
Author(s)
Eiji Miyoshi, Kazutoshi Fujita, Koichi Morishita, Tsunenori Ouchida, Tsutomu Nakagawa, Shinji Takamatsu, Jumpei Kondo
Total Pages
238
Publisher
Springer
ISBN
9789811977329
Related Report
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