Metformin Alleviates Hepatic Steatosis and Insulin Resistance in a Mouse Model of High-Fat Diet-Induced Nonalcoholic Fatty Liver Disease by Promoting Transcription Factor EB-Dependent Autophagy.

Dan Zhang,Lanqing Ma,Chunjing Shi,Yu Wen,Yi Deng,Guangyu Pu,Yinglei Miao,Yunyan Ying,Yicheng Ma,Daiyan Wen,Sufeng Luo,Yuanli Chen,Chenggang Zou,Bo Zhou,Jianjun Liu,Mingke Li

doi:10.3389/fphar.2021.689111

Dan Zhang, Lanqing Ma + Show 14 more

Open Access

https://doi.org/10.3389/fphar.2021.689111

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Abstract

Nonalcoholic fatty liver disease (NAFLD) results from an abnormal accumulation of lipids within hepatocytes, and is commonly associated with obesity, insulin resistance, and hyperlipidemia. Metformin is commonly used to treat type 2 diabetes mellitus and, in recent years, it was found to play a potential role in the amelioration of NAFLD. However, the mechanisms underlying the protective effect of metformin against NAFLD remain largely unknown. Transcription factor EB (TFEB) is a master transcriptional regulator of lysosomal biogenesis and autophagy and, when activated, is effective against disorders of lipid metabolism. However, the role of TFEB in hepatic steatosis is not well understood. In this report, we demonstrate that the activity of TFEB is reduced in the liver of mice fed a high-fat diet. Metformin treatment significantly reverses the activity of TFEB, and the protective effect of metformin against hepatic steatosis and insulin resistance is dependent on TFEB. We show that metformin-induced autophagy is regulated by TFEB, and our findings reveal that TFEB acts as a mediator, linking metformin with autophagy to reverse NAFLD, and highlight that TFEB may be a promising molecular target for the treatment of NAFLD.

Highlights

Nonalcoholic fatty liver disease (NAFLD) is a major liver disease subtype and an increasingly recognized cause of other liver-related diseases
Using Western blotting, we found that metformin treatment resulted in an increased nuclear accumulation of Transcription factor EB (TFEB) (Figure 4A) and reduced phosphorylation of TEFB (Supplementary Figure 1), metformin treatment significantly upregulated the expression of the TFEB target genes, such as those encoding Cathepsin B (CTSB), a member of the lysosomal cathepsin family, which can modulate autophagy processes in adipocytes (Araujo et al, 2018), ATPase H+ transporting V0 subunit D1 (ATP6V0D1), a subunit of the lysosomal protontransporting V-type ATPase (v-ATPase) (Miles et al, 2017; Jung et al, 2018), which responsible for acidifying intracellular compartments and providing energy required for transport processes of lysosomal, mucolipin 1 (Mcoln1), which regulates lysosomal Ca2+ release (Medina et al, 2015)
NAFLD is characterized by a lipid metabolism collapse, which is often associated with insulin resistance (IR), obesity, and metabolic syndrome (Heo et al, 2019)

Summary

Introduction

Nonalcoholic fatty liver disease (NAFLD) is a major liver disease subtype and an increasingly recognized cause of other liver-related diseases. NAFLD, which is characterized by an excessive hepatic lipid accumulation, covers a wide range of liver disorders, including steatosis, steatohepatitis, fibrosis, and cirrhosis (Sliz et al, 2018). The classical pathogenesis of NAFLD is based on the “two-hit hypothesis” (Day and James, 1998; Dowman et al, 2010); the molecular mechanisms underlying the pathogenesis of NAFLD need to be explored. A growing number of studies have implicated that the pathogenesis of NAFLD, in which some risk factors, including lipid metabolic disorders, chronic inflammation, and oxidative stress, play a central role, is complex (Krawczyk et al, 2010). Due to the complex multi-hit pathogenesis of NAFLD, there are no effective pharmacological therapies for it. New therapeutic strategies that reverse or prevent lipogenesis, thereby exerting indirect effects on NAFLD need to be developed

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