Hepatitis C Virus Induces Proteolytic Cleavage of Sterol Regulatory Element Binding Proteins and Stimulates Their Phosphorylation via Oxidative Stress
- 1 August 2007
- journal article
- retracted article
- Published by American Society for Microbiology in Journal of Virology
- Vol. 81 (15), 8122-8130
- https://doi.org/10.1128/jvi.00125-07
Abstract
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), Ca 2+ 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.Keywords
This publication has 47 references indexed in Scilit:
- Up-regulation of fatty acid synthase promoter by hepatitis C virus core protein: Genotype-3a core has a stronger effect than genotype-1b coreJournal of Hepatology, 2006
- Regulation of the PTEN phosphataseGene, 2006
- Hepatitis C Virus Stimulates the Expression of Cyclooxygenase-2 via Oxidative Stress: Role of Prostaglandin E 2 in RNA ReplicationJournal of Virology, 2005
- PKB/Akt induces transcription of enzymes involved in cholesterol and fatty acid biosynthesis via activation of SREBPOncogene, 2005
- Production of infectious hepatitis C virus in tissue culture from a cloned viral genomeNature Medicine, 2005
- An in vitro model of hepatitis C virus genotype 3a-associated triglycerides accumulationJournal of Hepatology, 2005
- Proteolytic Activation of Sterol Regulatory Element-binding Protein Induced by Cellular Stress through Depletion of Insig-1Journal of Biological Chemistry, 2004
- Effect of treatment with peginterferon or interferon alfa-2b and ribavirin on steatosis in patients infected with hepatitis CHepatology, 2003
- Coactivator-Dependent Acetylation Stabilizes Members of the SREBP Family of Transcription FactorsMolecular and Cellular Biology, 2003
- Insulin Stimulation of the Fatty Acid Synthase Promoter Is Mediated by the Phosphatidylinositol 3-Kinase PathwayPublished by Elsevier BV ,1998