Aurantio-Obtusin Attenuates Non-Alcoholic Fatty Liver Disease Through AMPK-Mediated Autophagy and Fatty Acid Oxidation Pathways.

Fei Zhou,Jianchao Li,Mingning Ding,Guifang Fan,Yiqing Gu,Chuanyang Liu,Yijie Li,Hongjuan Li,Rong Sun,Xiaoyong Xue,Jianzhi Wu,Xiaojiaoyang Li

doi:10.3389/fphar.2021.826628

Abstract

Nonalcoholic fatty liver disease (NAFLD), manifested as the aberrant accumulation of lipids in hepatocytes and inflammation, has become an important cause of advanced liver diseases and hepatic malignancies worldwide. However, no effective therapy has been approved yet. Aurantio-obtusin (AO) is a main bioactive compound isolated from Cassia semen that has been identified with multiple pharmacological activities, including improving adiposity and insulin resistance. However, the ameliorating effects of AO on diet-induced NAFLD and underlying mechanisms remained poorly elucidated. Our results demonstrated that AO significantly alleviated high-fat diet and glucose-fructose water (HFSW)-induced hepatic steatosis in mice and oleic acid and palmitic acid (OAPA)-induced lipid accumulation in hepatocytes. Remarkably, AO was found to distinctly promote autophagy flux and influence the degradation of lipid droplets by inducing AMPK phosphorylation. Additionally, the induction of AMPK triggered TFEB activation and promoted fatty acid oxidation (FAO) by activating PPARα and ACOX1 and decreasing the expression of genes involved in lipid biosynthesis. Meanwhile, the lipid-lowing effect of AO was significantly prevented by the pretreatment with inhibitors of autophagy, PPARα or ACOX1, respectively. Collectively, our study suggests that AO ameliorates hepatic steatosis via AMPK/autophagy- and AMPK/TFEB-mediated suppression of lipid accumulation, which opens new opportunities for pharmacological treatment of NAFLD and associated complications.

Highlights

Nonalcoholic fatty liver disease (NAFLD), characterized by excess hepatic fat accumulation, inflammation and oxidative stress, has become a burgeoning worldwide epidemic liver disease, affecting approximately one-quarter of the entire global population (Diehl and Day, 2017)
We examined the accumulation of abdominal fat and measured the thoracoabdominal temperature and found that AO resulted in a less weight of white adipose tissue and a greater liver temperature than that in the high-fat diet and glucose-fructose water (HFSW) group (Figure 1D), suggesting that AO improved metabolic syndrome of HFSW mice
A series of other and our studies recently reported the important role of AMP-activated protein kinase (AMPK) played in maintaining physiological functions and alleviating fatty liver, which might attribute to the regulation of autophagy and lipid metabolism (Zhao et al, 2020; Wu et al, 2021)

Summary

Introduction

Nonalcoholic fatty liver disease (NAFLD), characterized by excess hepatic fat accumulation, inflammation and oxidative stress, has become a burgeoning worldwide epidemic liver disease, affecting approximately one-quarter of the entire global population (Diehl and Day, 2017). Progress over the last decade was substantial in the roles of lipotoxicity, oxidative stress, inflammation, genetics and metabolism in NAFLD pathogenesis (Marra and SvegliatiBaroni, 2018). Gut microbiome and various dietary components as other gastrointestinal hits with proinflammatory potential have been demonstrated (Tilg et al, 2021). Among these pathogenic factors, lipotoxicity, resulting from excessive accumulation of harmful lipids and hepatocyte injury, has gained remarkable attention and represents a critical step in NAFLD progression (Marra and Svegliati-Baroni, 2018)

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