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J Hepatol. 2013 Sep;59(3):420-6. doi: 10.1016/j.jhep.2013.04.012. Epub 2013 Apr 23.

PTEN protein phosphatase activity regulates hepatitis C virus secretion through modulation of cholesterol metabolism.

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  • 1Department of Cellular Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland.

Abstract

BACKGROUND & AIMS:

Hepatitis C virus (HCV) infection is dependent on lipid metabolism. Hepatocyte steatosis occurs frequently in HCV infection, but the relationship between steatosis and HCV life cycle is unclear. We showed that HCV induces steatosis via the downregulation of the phosphatase and tensin homolog deleted on chromosome 10 (PTEN). We here investigated how PTEN may affect HCV production.

METHODS:

The effect of overexpression or silencing of PTEN on HCV secretion was assessed in genomic-length Jc1 infected HuH7 cells. The role of PTEN protein and lipid phosphatase activities on lipid metabolism and infectious viral particle secretion was investigated using dominant-negative PTEN mutants. The importance of cholesterol metabolism for PTEN-dependent lipid droplet biogenesis and viral particle secretion was examined using statins.

RESULTS:

PTEN silencing in Jc1 infected HuH7 cells stimulated HCV particle secretion, while PTEN overexpression decreased virus egress. Viral secretion was also increased by overexpression of protein phosphatase-deleted (PTENY138L), but not lipid phosphatase-deleted (PTENG129E), PTEN mutant, thus indicating that the protein phosphatase activity of PTEN controls viral secretion. Similarly, PTENY138L, but not PTENG129E mutant induced the formation of large lipid droplets. PTENY138L mutant did not affect biosynthesis of triglycerides, but promoted the biosynthesis of cholesterol esters. Consistently, statins prevented the increased cholesterol ester production, large lipid droplet formation, and viral secretion in cells expressing the PTENY138L mutant.

CONCLUSIONS:

Downregulation of PTEN protein phosphatase activity by HCV affects cholesterol metabolism, thereby inducing the appearance of large lipid droplets and increasing virion egress.

Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

KEYWORDS:

CE; HCC; HCV; LD; Lipid droplets; Liver; NAFLD; ORO; Oil-Red-O; PI; PTEN; Statin; Steatosis; TG; Viral particle assembly; cholesterol ester; hepatitis C virus; hepatocellular carcinoma; lipid droplet; non-alcoholic fatty liver disease; phophatase and tensin homolog deleted on chromosome 10; phosphoinositide; triglyceride

PMID:
23623999
[PubMed - indexed for MEDLINE]
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