title: Hepatitis C virus stimulates low-density lipoprotein receptor expression to facilitate viral propagation.
abstract: Lipids play a crucial role in multiple aspects of hepatitis C virus (HCV) life cycle. HCV modulates host lipid metabolism to enrich the intracellular milieu with lipids to facilitate its proliferation. However, very little is known about the influence of HCV on lipid uptake from bloodstream. Low-density lipoprotein receptor (LDLR) is involved in uptake of cholesterol rich low-density lipoprotein (LDL) particles from the bloodstream. The association of HCV particles with lipoproteins implicates their role in HCV entry; however, the precise role of LDLR in HCV entry still remains controversial. Here, we investigate the effect of HCV infection on LDLR expression and the underlying mechanism(s) involved. We demonstrate that HCV stimulates LDLR expression in both HCV-infected Huh7 cells and in liver tissue from chronic hepatitis C patients. Fluorescence activated cell sorting and immunofluorescence analysis revealed enhanced cell surface and total expression of LDLR in HCV-infected cells. Increased LDLR expression resulted in the enhanced uptake of lipoprotein particles by HCV-infected cells. Analysis of LDLR gene promoter identified a pivotal role of sterol-regulatory element binding proteins (SREBPs), in the HCV-mediated stimulation of LDLR transcription. In addition, HCV negatively modulated the expression of proprotein convertase subtilisin/kexin type 9 (PCSK9), a protein that facilitates LDLR degradation. Ectopic expression of wild-type PCSK9 or gain-of-function PCSK9 mutant negatively affected HCV replication. Overall, our results demonstrate that HCV regulates LDLR expression at transcriptional and posttranslational level via SREBPs and PCSK9 to promote lipid uptake and facilitate viral proliferation.
  
  
  OBJECTIVE
  HCV modulates host lipid metabolism to promote enrichment of lipids in intracellular environment, which are essential in multiple aspects of HCV life cycle. However, very little is known about the influence of HCV on lipid uptake from the bloodstream. LDLR is involved in uptake of cholesterol rich lipid particles from bloodstream. In this study, we investigated the effect of HCV on LDLR expression and the underlying mechanism triggered by the virus to modulate LDLR expression. Our observations suggest that HCV upregulates LDLR expression at both the protein and the transcript levels and that this upregulation likely contributes toward the uptake of serum lipids by infected hepatocytes. Abrogation of HCV-mediated upregulation of LDLR inhibits serum lipid uptake and thereby perturbs HCV replication. Overall, our findings highlight the importance of serum lipid uptake by infected hepatocytes in HCV life cycle.
authors.affiliation: Department of Medicine, Division of Infectious Diseases, University of California, San Diego, La Jolla, California, USA.
authors.forename: Gulam Hussain
authors.initials: GH
authors.lastname: Syed
authors.forename: Huihui
authors.initials: H
authors.lastname: Tang
authors.forename: Mohsin
authors.initials: M
authors.lastname: Khan
authors.forename: Tarek
authors.initials: T
authors.lastname: Hassanein
authors.forename: Jingwen
authors.initials: J
authors.lastname: Liu
authors.forename: Aleem
authors.initials: A
authors.lastname: Siddiqui
mesh_terms: D001665:Binding Sites; D002460:Cell Line; D016384:Consensus Sequence; D015870:Gene Expression; D005786:Gene Expression Regulation; D016174:Hepacivirus / Q000502:physiology*; D006526:Hepatitis C / Q000235:genetics / Q000378:metabolism / Q000821:virology; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism; D009154:Mutation; D011401:Promoter Regions, Genetic; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000235:genetics / Q000378:metabolism; D011973:Receptors, LDL / Q000235:genetics* / Q000378:metabolism; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism; D051779:Sterol Regulatory Element Binding Proteins / Q000378:metabolism; D014158:Transcription, Genetic; D014779:Virus Replication
chemical_list: D008077:Lipoproteins, LDL; D011973:Receptors, LDL; D051779:Sterol Regulatory Element Binding Proteins; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases