Silent information regulator 1 inhibition induces lipid metabolism disorders of hepatocytes and enhances hepatitis C virus replication

Authors


  • Conflict of interest: No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.
  • Author contribution: Y. J. W. and S. L. J. proposed the study. S. L. J. wrote the first draft. Y. J. W. analyzed the data. All authors contributed to the design and interpretation of the study and to further drafts. Y. J. W. is the guarantor.

Abstract

Aim

Hepatic steatosis is an important histopathological feature of chronic hepatitis C virus (HCV) infection. Silent information regulator 1 (SIRT1) plays key role in regulation of hepatic lipid metabolism. We investigated the possible effect of HCV replication on lipid metabolism of hepatocytes and expression of SIRT1 using Huh-7.5 cells harboring HCV replicon.

Methods

The level of reactive oxygen species (ROS) and malondialdehyde (MDA), the activity of superoxide dismutase (SOD), and the value of nicotinamide adenine dinucleotide (NAD+)/NADH was detected. The level of triacylglycerol (TG), total cholesterol (TC) and fatty acid β-oxidation rate was detected. The activity and expression levels of SIRT1 and expression of its downstream lipid-metabolism genes were measured.

Results

In replicon cells, the level of ROS and MDA increased, SOD activity and the value of NAD+/NADH decreased, then the activity and expression level of mRNA and protein of SIRT1 reduced. Inhibition of SIRT1 decreased phosphorylation of forkhead box O1 (FoxO1), which not only upregulated SREBP-1c, FAS, ACC, SREBP-2, HMGR and HMGS genes and increased fatty acid synthesis; but also downregulated PPAR-α and CPT1A genes and decreased fatty acid β-oxidation. Interferon treatment restored aforementioned changes. SIRT1 activator improved lipid metabolism disorders by an increase in fatty acid β-oxidation and a decrease in TG and TC synthesis and inhibited HCV replication.

Conclusion

HCV replication decreasing NAD+/NADH ratio may downregulate the activity and the expression of SIRT1, then change the expression profile of lipid metabolism-related genes, thereby cause lipid metabolism disorders of hepatocytes and promote HCV replication. Treatment with SIRT1 activator ameliorates lipid metabolic disorders and inhibits HCV replication.

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