Distinct Roles for Intracellular and Extracellular Lipids in Hepatitis C Virus Infection.
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.
Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, United States of America.|Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, United States of America.
Sowmya
S
Narayanan
Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, United States of America.
Albert H
AH
Nieh
Department of Pharmacology, University of Virginia, Charlottesville, United States of America.
Brandon M
BM
Kenwood
Department of Biology, University of Richmond, Richmond, United States of America.
Christine A
CA
Davis
Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, United States of America.
Annie-Carole
AC
Tosello-Trampont
Cropsolution Inc., Morrisville, United States of America.
Tedd D
TD
Elich
Cropsolution Inc., Morrisville, United States of America.
Steven D
SD
Breazeale
Cropsolution Inc., Morrisville, United States of America.
Eric
E
Ward
Cropsolution Inc., Morrisville, United States of America.
Richard J
RJ
Anderson
Division of Gastroenterology and Hepatology, University of Virginia, Charlottesville, United States of America.
Stephen H
SH
Caldwell
Department of Pharmacology, University of Virginia, Charlottesville, United States of America.
Kyle L
KL
Hoehn
Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, United States of America.|Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, United States of America.
Young S
YS
Hahn
D000103:Acetyl-CoA Carboxylase / Q000037:antagonists & inhibitors; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005227:Fatty Acids / Q000378:metabolism*; D016174:Hepacivirus / Q000187:drug effects / Q000502:physiology*; D006526:Hepatitis C / Q000188:drug therapy / Q000378:metabolism / Q000821:virology*; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D050155:Lipogenesis / Q000502:physiology*; D012367:RNA, Viral / Q000235:genetics; D014779:Virus Replication / Q000187:drug effects
D004791:Enzyme Inhibitors; D005227:Fatty Acids; D012367:RNA, Viral; D000103:Acetyl-CoA Carboxylase