Berberine Ameliorates Hepatic Steatosis and Suppresses Liver and Adipose Tissue Inflammation in Mice with Diet-induced Obesity.

Ting Guo,Xiaoqiu Xiao,Xin Guo,Chaodong Wu,Ya Pei,Tianshu Zeng,Qifu Li,Mengyang Liu,Yuqing Huo,Rachel Botchlett,Shih-Lung Woo,Lulu Chen,Hang Xu,Yuli Cai,Honggui Li,Juan Zheng,Xiaodong Li

doi:10.1038/srep22612

Abstract

Increasing evidence demonstrates that berberine (BBR) is beneficial for obesity-associated non-alcoholic fatty liver disease (NAFLD). However, it remains to be elucidated how BBR improves aspects of NAFLD. Here we revealed an AMP-activated protein kinase (AMPK)-independent mechanism for BBR to suppress obesity-associated inflammation and improve hepatic steatosis. In C57BL/6J mice fed a high-fat diet (HFD), treatment with BBR decreased inflammation in both the liver and adipose tissue as indicated by reduction of the phosphorylation state of JNK1 and the mRNA levels of proinflammatory cytokines. BBR treatment also decreased hepatic steatosis, as well as the expression of acetyl-CoA carboxylase and fatty acid synthase. Interestingly, treatment with BBR did not significantly alter the phosphorylation state of AMPK in both the liver and adipose tissue of HFD-fed mice. Consistently, BBR treatment significantly decreased the phosphorylation state of JNK1 in both hepatoma H4IIE cells and mouse primary hepatocytes in both dose-dependent and time-dependent manners, which was independent of AMPK phosphorylation. BBR treatment also caused a decrease in palmitate-induced fat deposition in primary mouse hepatocytes. Taken together, these results suggest that BBR actions on improving aspects of NAFLD are largely attributable to BBR suppression of inflammation, which is independent of AMPK.

Highlights

The exact mechanisms underlying the pathogenesis of nonalcoholic fatty liver disease (NAFLD) remain to be explored
Upon feeding of a high-fat diet (HFD) for 4 weeks, C57BL/6J mice started to demonstrate a significant increase in body weight compared with age- and gender-matched mice on a low-fat diet (LFD) (Fig. 1A)
HFD-fed and BBR-treated (HFD-BBR) mice displayed a significant decrease in the severity of obesity-associated systemic insulin resistance and glucose intolerance (Fig. 1C,D) compared with HFD-phosphate-buffered saline (PBS) mice

Summary

Introduction

Because of the close relationship between obesity and NAFLD, obesity-associated inflammation and insulin resistance are accepted as key factors that initiate or exacerbate NAFLD Both inflammation and insulin resistance can cause hepatic steatosis through increasing liver expression of genes for lipogenic enzymes such as acetyl-CoA carboxylase 1 (ACC1) and fatty acid synthase (FAS) and decreasing liver expression of genes for fatty acid oxidation including carnitine palmitoyltransferase 1a (CPT1a)[11,12,13]. BBR displays a potent effect on reducing hepatic steatosis as supported by the results from both animal and clinical investigations[19,20,21] This anti-hepatic steatosis effect of BBR is attributable to, at least in part, the actions of BBR on reducing the methylation of the microsomal triglyceride transfer protein (MTTP) promoter[19] and on decreasing the DNA demethylation and histone acetylation in regulation of L-pyruvate kinase[22]. Our novel findings suggested an AMPK-independent mechanism for BBR actions on improving obesity-associated hepatic steatosis and inflammation

Methods

Results

Conclusion