Let-7 underlies metformin-induced inhibition of hepatic glucose production

文献类型： 外文期刊

第一作者： Chen, Fan

作者： Chen, Fan;Zhang, Yuanyuan;Sun, Xiaoli;Xie, Di;Chen, Fan;Zhang, Yuanyuan;Zhang, Gary J.;Sun, Xiaoli;Taylor, Hugh S.;Huang, Yingqun;Xie, Di;Huang, Yingqun;Shi, Bei;Song, Jiahui;Li, Da;Chaudhari, Kiran;Yang, Shao-Hua

作者机构：

关键词： metformin; Let-7; TET3; liver; diabetes

期刊名称：PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA （ 影响因子：12.779； 五年影响因子：13.45 ）

ISSN： 0027-8424

年卷期： 2022 年 119 卷 14 期

页码：

收录情况： SCI

摘要： Metformin, the frontline antidiabetic drug, has gained increasing attention for the prevention and treatment of aging, cancer, and cardiovascular disease. Yet a clear mechanistic understanding of its action is still lacking, largely due to the suprapharmacological concentrations of metformin used in most studies. Here, we report an inhibition of glucose production by primary hepatocytes from dietary and genetic mouse models of type 2 diabetes (T2D) using metformin at clinically relevant concentrations. Mechanistically, metformin up-regulates microRNA let-7 that in turn down-regulates TET3, evoking a change in the ratio of hepatocyte nuclear factor 4 alpha (HNF4 alpha) isoforms and subsequent inhibition of key gluconeogenic genes. Importantly, this let-7-mediated mechanism is faithfully recapitulated in mice with T2D chronically treated with therapeutic doses of metformin. Furthermore, hepatic delivery of let-7 ameliorates hyperglycemia and improves glucose homeostasis in diabetic mice, whereas liver-specific inhibition of let-7 abrogates these beneficial effects of metformin. Moreover, let-7 overexpression decreases glucose production from primary hepatocytes from obese humans. Thus, we propose the reactivation of a let-7-dependent pathway that is pathologically repressed in the liver of diabetes as a major mechanism of metformin action and that liver-specific delivery of let-7 represents a potential therapeutic for T2D. Our findings are also pertinent to the development of therapeutic strategies for other chronic diseases.

分类号：

  • 相关文献
作者其他论文 更多>>

微信小程序