The hepatitis C virus core protein inhibits adipose triglyceride lipase (ATGL)-mediated lipid mobilization and enhances the ATGL interaction with comparative gene identification 58 (CGI-58) and lipid droplets.
Liver steatosis is a common health problem associated with hepatitis C virus (HCV) and an important risk factor for the development of liver fibrosis and cancer. Steatosis is caused by triglycerides (TG) accumulating in lipid droplets (LDs), cellular organelles composed of neutral lipids surrounded by a monolayer of phospholipids. The HCV nucleocapsid core localizes to the surface of LDs and induces steatosis in cultured cells and mouse livers by decreasing intracellular TG degradation (lipolysis). Here we report that core at the surface of LDs interferes with the activity of adipose triglyceride lipase (ATGL), the key lipolytic enzyme in the first step of TG breakdown. Expressing core in livers or mouse embryonic fibroblasts of ATGL(-/-) mice no longer decreases TG degradation as observed in LDs from wild-type mice, supporting the model that core reduces lipolysis by engaging ATGL. Core must localize at LDs to inhibit lipolysis, as ex vivo TG hydrolysis is impaired in purified LDs coated with core but not when free core is added to LDs. Coimmunoprecipitation experiments revealed that core does not directly interact with the ATGL complex but, unexpectedly, increased the interaction between ATGL and its activator CGI-58 as well as the recruitment of both proteins to LDs. These data link the anti-lipolytic activity of the HCV core protein with altered ATGL binding to CGI-58 and the enhanced association of both proteins with LDs.
From the Gladstone Institute of Virology and Immunology, San Francisco, California 94158.
Gregory
G
Camus
From the Gladstone Institute of Virology and Immunology, San Francisco, California 94158, Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria.
Martina
M
Schweiger
From the Gladstone Institute of Virology and Immunology, San Francisco, California 94158, UCSF Liver Center, University of California, San Francisco, California 94158, Heinrich-Pette-Institute, Leibniz Institute for Experimental Virology, 20251 Hamburg, Germany.
Eva
E
Herker
UCSF Liver Center, University of California, San Francisco, California 94158, Gladstone Institute of Cardiovascular Disease, San Francisco, California 94158, Department of Medicine, University of California, San Francisco, California 94158, Division of Endocrinology Metabolism and Lipid Research, Washington University School of Medicine, St. Louis, Missouri 63110.
Charles
C
Harris
From the Gladstone Institute of Virology and Immunology, San Francisco, California 94158.
Andrew S
AS
Kondratowicz
From the Gladstone Institute of Virology and Immunology, San Francisco, California 94158.
Chia-Lin
CL
Tsou
UCSF Liver Center, University of California, San Francisco, California 94158, Gladstone Institute of Cardiovascular Disease, San Francisco, California 94158, Department of Medicine, University of California, San Francisco, California 94158, Department of Biochemistry and Biophysics, University of California, San Francisco, California 94158, and.
Robert V
RV
Farese
Merck Research Laboratories, Merck and Co., Inc., Kenilworth, New Jersey 07065.
Kithsiri
K
Herath
Merck Research Laboratories, Merck and Co., Inc., Kenilworth, New Jersey 07065.
Stephen F
SF
Previs
Merck Research Laboratories, Merck and Co., Inc., Kenilworth, New Jersey 07065.
Thomas P
TP
Roddy
Merck Research Laboratories, Merck and Co., Inc., Kenilworth, New Jersey 07065.
Shirly
S
Pinto
Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria.
Rudolf
R
Zechner
From the Gladstone Institute of Virology and Immunology, San Francisco, California 94158, UCSF Liver Center, University of California, San Francisco, California 94158, Department of Medicine, University of California, San Francisco, California 94158, mott@gladstone.ucsf.edu.
Melanie
M
Ott
D051103:1-Acylglycerol-3-Phosphate O-Acyltransferase / Q000378:metabolism*; D000818:Animals; D019556:COS Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D057809:HEK293 Cells; D006801:Humans; D006868:Hydrolysis; D008049:Lipase / Q000378:metabolism*; D066292:Lipid Droplets / Q000201:enzymology*; D050356:Lipid Metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D041681:NIH 3T3 Cells; D014280:Triglycerides / Q000378:metabolism; D014758:Viral Core Proteins / Q000502:physiology*; D000217:Acyltransferases
D051103:1-Acylglycerol-3-Phosphate O-Acyltransferase; D008049:Lipase; D014280:Triglycerides; D014758:Viral Core Proteins; C069130:nucleocapsid protein, Hepatitis C virus; C492986:Abhd5 protein, mouse; C494445:PNPLA2 protein, mouse; D000217:Acyltransferases
Adipose Triglyceride Lipase (ATGL); Hepatitis C Virus (HCV); Lipid Droplet; Lipolysis; Triglyceride