Distinct Roles for Intracellular and Extracellular Lipids in Hepatitis C Virus Infection

• Published in: PloS one Vol. 11; no. 6; p. e0156996
• Main Authors: Narayanan, Sowmya, Nieh, Albert H, Kenwood, Brandon M, Davis, Christine A, Tosello-Trampont, Annie-Carole, Elich, Tedd D, Breazeale, Steven D, Ward, Eric, Anderson, Richard J, Caldwell, Stephen H, Hoehn, Kyle L, Hahn, Young S
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 09-06-2016; Public Library of Science (PLoS)
• Subjects: Acetyl-CoA carboxylase; Acetyl-CoA Carboxylase - antagonists & inhibitors; Assembly; Biology; Biology and Life Sciences; Blood lipids; Cells, Cultured; Chronic infection; Development and progression; Enzyme Inhibitors - pharmacology; Enzymes; Fatty acids; Fatty Acids - metabolism; Gene expression; Genetic aspects; Genotype & phenotype; Health aspects; Hepacivirus - drug effects; Hepacivirus - physiology; Hepatitis; Hepatitis C; Hepatitis C - drug therapy; Hepatitis C - metabolism; Hepatitis C - virology; Hepatitis C virus; Hepatocytes; Hepatocytes - cytology; Hepatocytes - drug effects; Hepatocytes - metabolism; Hepatology; Homeostasis; Humans; Immunology; Infections; Inhibitors; Interferon; Lipids; Lipogenesis; Lipogenesis - physiology; Liver; Liver diseases; Medicine and health sciences; Metabolism; Palmitoylation; Physiological aspects; Proteins; Replication; Ribonucleic acid; RNA; RNA, Viral - genetics; Serum lipids; Viral infections; Virus replication; Virus Replication - drug effects; Viruses; West Nile virus; United States; United States > US
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0156996

Hepatitis C is a chronic liver disease that contributes to progressive metabolic dysfunction. Infection of hepatocytes by hepatitis C virus (HCV) results in reprogramming of hepatic and serum lipids. However, the specific contribution of these distinct pools of lipids to HCV infection remains ill defined. In this study, we investigated the role of hepatic lipogenesis in HCV infection by targeting the rate-limiting step in this pathway, which is catalyzed by the acetyl-CoA carboxylase (ACC) enzymes. Using two structurally unrelated ACC inhibitors, we determined that blockade of lipogenesis resulted in reduced viral replication, assembly, and release. Supplementing exogenous lipids to cells treated with ACC inhibitors rescued HCV assembly with no effect on viral replication and release. Intriguingly, loss of viral RNA was not recapitulated at the protein level and addition of 2-bromopalmitate, a competitive inhibitor of protein palmitoylation, mirrored the effects of ACC inhibitors on reduced viral RNA without a concurrent loss in protein expression. These correlative results suggest that newly synthesized lipids may have a role in protein palmitoylation during HCV infection.