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Journal of Virology, August 2007, p. 8122-8130, Vol. 81, No. 15
0022-538X/07/$08.00+0     doi:10.1128/JVI.00125-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Hepatitis C Virus Induces Proteolytic Cleavage of Sterol Regulatory Element Binding Proteins and Stimulates Their Phosphorylation via Oxidative Stress

Gulam Waris,^1, Daniel Jeffery Felmlee,¹ Francesco Negro,² and Aleem Siddiqui^1*

Department of Medicine, Division of Infectious Diseases, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093,¹ Departments of Internal Medicine and Pathology and Immunology, University of Geneva Medical Center, 1 rue Michel-Servet, Geneva 1205, Switzerland²

Received 18 January 2007/ Accepted 5 May 2007

Hepatic steatosis is a common histological feature of chronic hepatitis C. Hepatitis C virus (HCV) gene expression has been shown to alter host cell cholesterol/lipid metabolism and thus induce hepatic steatosis. Since sterol regulatory element binding proteins (SREBPs) are major regulators of lipid metabolism, we sought to determine whether genotype 2a-based HCV infection induces the expression and posttranslational activation of SREBPs. HCV infection stimulates the expression of genes related to lipogenesis. HCV induces the proteolytic cleavage of SREBPs. HCV core and NS4b derived from genotype 3a are also individually capable of inducing the proteolytic processing of SREBPs. Further, we demonstrate that HCV stimulates the phosphorylation of SREBPs. Our studies show that HCV-induced oxidative stress and subsequent activation of the phosphatidylinositol 3-kinase (PI3-K)-Akt pathway and inactivation (phosphorylation) of PTEN (phosphatase and tensin homologue) mediate the transactivation of SREBPs. HCV-induced SREBP-1 and -2 activities were sensitive to antioxidant (pyrrolidine dithiocarbamate), Ca²⁺ chelator 1,2-bis(aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-tetra(acetoxymethyl) ester (BAPTA-AM), and PI3-K inhibitor (LY294002). Collectively, these studies provide insight into the mechanisms of hepatic steatosis associated with HCV infection.

Published ahead of print on 16 May 2007.

Present address:. Department of Microbiology and Immunology, The Chicago Medical School, RFUMS, North Chicago, IL 60064.

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