1. Academic Validation
  2. MiR-34a-5p promotes hepatic gluconeogenesis by suppressing SIRT1 expression

MiR-34a-5p promotes hepatic gluconeogenesis by suppressing SIRT1 expression

  • Exp Cell Res. 2022 Nov 1;420(1):113336. doi: 10.1016/j.yexcr.2022.113336.
Yiru Wang 1 Feiye Zhou 2 Mingzhu Li 3 Yumei Zhang 3 Na Li 4 Li Shao 5
Affiliations

Affiliations

  • 1 School of Medicine, Tongji University, Shanghai, China.
  • 2 Department of Endocrine and Metabolic Diseases/ Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 3 Department of VIP Clinic, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.
  • 4 Department of Gastroenterology, Zibo Central Hospital, Zibo, China. Electronic address: linajian3818@sina.com.
  • 5 Department of VIP Clinic, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China. Electronic address: lxia0312@163.com.
Abstract

Elevated hepatic gluconeogenesis is a major contributor of fasting hyperglycemia in diabetes. MicroRNAs (miRNAs) are tightly linked to glucose metabolism, but their role in hepatic gluconeogenesis remains largely unkown. In this current study, miR-34a-5p expression was significantly increased in liver tissues of db/db mice. Overexpression of miR-34a-5p promoted hepatic glucose production in mouse primary hepatocytes with increased expressions of gluconeogenic genes while miR-34a-5p inhibition displayed a contrary action. MiR-34a-5p overexpression in mouse primary hepatocytes repressed SIRT1 expression. SIRT1 inhibition by EX527 blocked phosphoenolpyruvate carboxykinase (PEPCK) protein degradation and enhanced hepatic gluconeogenesis. Treatment of A485 (a CBP/p300 inhibitor) decreased miR-34a-5p and PEPCK expressions in the livers of db/db mice, but elevated SIRT1 protein expression. In mouse primary hepatocytes, A485 exhibited a similar result. Overexpression of miR-34a-5p attenuated A485-inhibited gluconeogenic gene expressions and A485-induced SIRT1 protein expression. Finally, after miR-34a-5p was inhibited in the livers of db/db mice, hepatic glucose production and gluconeogenic gene expressions were markedly lowered. Our findings highlight a critical role of miR-34a-5p in the regulation of hepatic gluconeogenesis and miR-34a-5p may be a potential target in the treatment of type 2 diabetes.

Keywords

A485; Hepatic gluconeogenesis; PEPCK; SIRT1; miR-34a-5p.

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