title: HCV 3a core protein increases lipid droplet cholesteryl ester content via a mechanism dependent on sphingolipid biosynthesis.
abstract: Hepatitis C virus (HCV) infected patients often develop steatosis and the HCV core protein alone can induce this phenomenon. To gain new insights into the pathways leading to steatosis, we performed lipidomic profiling of HCV core protein expressing-Huh-7 cells and also assessed the lipid profile of purified lipid droplets isolated from HCV 3a core expressing cells. Cholesteryl esters, ceramides and glycosylceramides, but not triglycerides, increased specifically in cells expressing the steatogenic HCV 3a core protein. Accordingly, inhibitors of cholesteryl ester biosynthesis such as statins and acyl-CoA cholesterol acyl transferase inhibitors prevented the increase of cholesteryl ester production and the formation of large lipid droplets in HCV core 3a-expressing cells. Furthermore, inhibition of de novo sphingolipid biosynthesis by myriocin - but not of glycosphingolipid biosynthesis by miglustat - affected both lipid droplet size and cholesteryl ester level. The lipid profile of purified lipid droplets, isolated from HCV 3a core-expressing cells, confirmed the particular increase of cholesteryl ester. Thus, both sphingolipid and cholesteryl ester biosynthesis are affected by the steatogenic core protein of HCV genotype 3a. These results may explain the peculiar lipid profile of HCV-infected patients with steatosis.
authors.affiliation: Department of Biochemistry, NCCR Chemical Biology, University of Geneva, Geneva, Switzerland.
authors.forename: Ursula
authors.initials: U
authors.lastname: Loizides-Mangold
authors.affiliation: Division of Clinical Pathology, University Hospital, University of Geneva School of Medicine, Geneva, Switzerland.
authors.forename: Sophie
authors.initials: S
authors.lastname: Clément
authors.affiliation: University of California Irvine, Beckman Laser Institute, Irvine, California, United States of America.
authors.forename: Alba
authors.initials: A
authors.lastname: Alfonso-Garcia
authors.affiliation: Division of Clinical Pathology, University Hospital, University of Geneva School of Medicine, Geneva, Switzerland.
authors.forename: Emilie
authors.initials: E
authors.lastname: Branche
authors.affiliation: Division of Clinical Pathology, University Hospital, University of Geneva School of Medicine, Geneva, Switzerland.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Conzelmann
authors.affiliation: Division of Clinical Pathology, University Hospital, University of Geneva School of Medicine, Geneva, Switzerland.
authors.forename: Clotilde
authors.initials: C
authors.lastname: Parisot
authors.affiliation: University of California Irvine, Beckman Laser Institute, Irvine, California, United States of America.
authors.forename: Eric O
authors.initials: EO
authors.lastname: Potma
authors.affiliation: Department of Biochemistry, NCCR Chemical Biology, University of Geneva, Geneva, Switzerland.
authors.forename: Howard
authors.initials: H
authors.lastname: Riezman
authors.affiliation: Division of Clinical Pathology, University Hospital, University of Geneva School of Medicine, Geneva, Switzerland; Divisions of Gastroenterology and Hepatology, University Hospital, University of Geneva School of Medicine, Geneva, Switzerland.
authors.forename: Francesco
authors.initials: F
authors.lastname: Negro
mesh_terms: D045744:Cell Line, Tumor; D002788:Cholesterol Esters / Q000378:metabolism*; D016174:Hepacivirus / Q000378:metabolism*; D006801:Humans; D066292:Lipid Droplets / Q000378:metabolism*; D013107:Sphingolipids / Q000096:biosynthesis / Q000378:metabolism*; D014758:Viral Core Proteins / Q000378:metabolism*
chemical_list: D002788:Cholesterol Esters; D013107:Sphingolipids; D014758:Viral Core Proteins