Hepatitis C virus nonstructural protein 5A perturbs lipid metabolism by modulating AMPK/SREBP-1c signaling

Ziyu Meng,Qiang Liu,Fujun Sun,Ling Qiao

doi:10.1186/s12944-019-1136-y

Ziyu Meng, Qiang Liu + Show 2 more

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https://doi.org/10.1186/s12944-019-1136-y

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Abstract

BackgroundSteatosis is an important clinical manifestation associated with chronic hepatitis C virus (HCV) infection. AMP-activated protein kinase (AMPK), a major mediator of lipid metabolism, regulates HCV-associated hepatic steatosis, but the underlying mechanisms remain obscure. Here we investigated the mechanism of HCV nonstructural protein 5A (NS5A)-induced lipid accumulation by the AMPK/SREBP-1c pathway.MethodsWe generated model mice by injecting recombinant lentiviral particles expressing the NS5A protein (genotype 3a) via the tail vein. The serum levels of alanine aminotransferase (ALT), free fatty acids (FFAs) and triglycerides (TG) were examined. H&E and Oil Red O staining were used to examine lipid droplets. Immunohistochemistry staining, quantitative real-time PCR and Western blotting were used to determine the expression of lipogenic genes.ResultsOur results showed that the serum levels of ALT, FFAs and TG, as well as the accumulation of hepatic lipid droplets, were increased significantly in mice infected with NS5A-expressing lentiviral particles. NS5A inhibited AMPK phosphorylation and increased the expression levels of sterol regulatory element binding protein-1c (SREBP-1c), acetyl-coenzyme A carboxylase 1 (ACC1) and fatty acid synthase (FASN) in vivo and in vitro. Further investigation revealed that pharmacological activation or ectopic expression of AMPK neutralized the upregulation of SREBP-1c, ACC1 and FASN, and ameliorated hepatic lipid accumulation induced by NS5A. Ectopic expression of SREBP-1c enhanced NS5A-induced hepatic lipid accumulation, which was dramatically reversed by pharmacological activation of AMPK.ConclusionsCollectively, we demonstrate that NS5A induces hepatic lipid accumulation via the AMPK/SREBP-1c pathway.

Highlights

Steatosis is an important clinical manifestation associated with chronic hepatitis C virus (HCV) infection
nonstructural protein 5A (NS5A) induced lipid metabolic alterations in vivo To investigate whether the NS5A protein is involved in HCV-associated hepatic steatosis in vivo, we generated model mice by injecting recombinant lentiviral particles expressing the NS5A protein via the tail vein
No significant differences in the serum levels of Alanine aminotransferase (ALT), Free fatty acids (FFA) and TG were observed between the enhanced green fluorescent protein (EGFP) group and the

Summary

Introduction

Steatosis is an important clinical manifestation associated with chronic hepatitis C virus (HCV) infection. AMP-activated protein kinase (AMPK), a major mediator of lipid metabolism, regulates HCV-associated hepatic steatosis, but the underlying mechanisms remain obscure. We investigated the mechanism of HCV nonstructural protein 5A (NS5A)-induced lipid accumulation by the AMPK/SREBP-1c pathway. Hepatitis C virus (HCV) infection is a global health problem that has caused a tremendous burden with regard to public health. It is a leading cause of liver diseases including chronic hepatitis, steatosis, fibrosis, cirrhosis and hepatocellular carcinoma [1]. Recent studies imply that the NS5A protein may play an important role in the pathological changes of HCVassociated hepatic steatosis by interacting with a variety of cellular proteins, the underlying molecular mechanisms remain largely elusive [11,12,13,14]

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