Metformin Alleviates Steatohepatitis in Diet-Induced Obese Mice in a SIRT1-Dependent Way.

Wan-Rong Guo,Li-Dan Cheng,Fen Xu,Xiao-Bin Zheng,Juan Liu,Zi-Yu Liu,Hua Liang

doi:10.3389/fphar.2021.704112

Abstract

Metformin is the first-line anti-diabetic drug for type 2 diabetes. It has been found to significantly reduce liver aminotransferase in nonalcoholic fatty liver disease (NAFLD). However, whether metformin improves NAFLD progression remains controversial. Sirtuin 1 (SIRT1), an NAD+-dependent deacetylase, plays a vital role in hepatic steatosis and inflammation. Here, we investigated the effect of metformin on steatohepatitis and the role of SIRT1 in diet-induced obese (DIO) mice. The results showed that metformin significantly reduced body weight and fat mass of DIO mice. In addition, metformin also alleviated adiposity and hepatic steatosis, and greatly upregulated uncoupling protein 1 (UCP1) expression in adipose tissues of DIO mice. Unexpectedly, the effects of metformin on reducing body weight and alleviating hepatic steatosis were not impaired in Sirt1 heterozygous knockout (Sirt1 +/−) mice. However, SIRT1-deficiency remarkably impaired the effects of metformin on lowering serum transaminases levels, downregulating the mRNA expression of proinflammatory factors, and increasing the protein level of hepatic Cholesterol 25-Hydroxylase (CH25H), a cholesterol hydroxylase in cholesterol catabolism. In summary, we demonstrated that metformin alleviates steatohepatitis in a SIRT1-dependent manner, and modulation of M1 polarization and cholesterol metabolism may be the underlying mechanism.

Highlights

Nonalcoholic fatty liver disease (NAFLD), characterized by hepatic lipid accumulation over 5% of liver weight, includes a broad spectrum ranging from steatosis to non-alcoholic steatohepatitis (NASH), to fibrosis and cirrhosis
The result of energy intake calculated by food intake detected every 2 weeks did not show a reduction with metformin treatment (Figure 1C)
Sirtuin 1 (SIRT1) protein level in liver of Sirt1+/− mice was confirmed to be significantly lower than that in WT mice (Figure 4J). These results suggest that SIRT1 heterozygous deficiency does not impair the effect of metformin on body weight, fasting blood glucose (FBG), and hepatic steatosis

Summary

Introduction

Nonalcoholic fatty liver disease (NAFLD), characterized by hepatic lipid accumulation over 5% of liver weight, includes a broad spectrum ranging from steatosis to non-alcoholic steatohepatitis (NASH), to fibrosis and cirrhosis. The global prevalence of NAFLD has been estimated to be approximately 23.75–30.45% in general population (Younossi et al, 2019). The pathogenesis of NAFLD remains a topic of discussion. Several studies suggested a bidirectional link between NAFLD and type 2 diabetes (T2D). Insulin resistance is considered to be a key factor in this connection (Anstee et al, 2013). There are no effective FDA-approved drugs for NAFLD. Due to the common pathophysiological features of NAFLD and T2D, antidiabetic drugs such as insulin sensitizers have been evaluated in patients with NAFLD. Metformin is one of these drugs (Sumida and Yoneda, 2018)

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