title: Enhancement of genotype 1 hepatitis C virus replication by bile acids through FXR.
abstract: OBJECTIVE
  Hepatitis C virus (HCV) infected patients with high serum levels of bile acids (BAs) usually fail to respond to antiviral therapy. Besides, BAs are essential factors for replication of the porcine enteric calicivirus by inhibiting interferon signaling. The role of BAs on HCV RNA replication was thus assessed.
  
  
  METHODS
  BAs and other compounds were tested using an HCV-replication model containing a luciferase reporter gene.
  
  
  RESULTS
  BAs, especially chenodeoxycholate and deoxycholate, up-regulated genotype 1 HCV RNA replication by more than tenfold. Only free but not conjugated BAs were active, suggesting that their effect was mediated by a nuclear receptor. Only farnesoid X receptor (FXR) ligands stimulated HCV replication while FXR silencing and FXR antagonism by guggulsterone blocked the up-regulation induced by BAs. Furthermore, guggulsterone alone inhibited basal level of HCV replication by tenfold. Modulation of HCV replication by FXR ligands occurred in the same proportion in presence or absence of type I interferon, suggesting a mechanism of action independent of this control of viral replication. However, BAs or guggulsterone did not affect replication of genotype 2a-JFH1.
  
  
  CONCLUSIONS
  Exposure to routinely measured concentrations of BAs increases HCV replication by a novel mechanism involving activation of the nuclear receptor FXR.
authors: INSERM U851, IFR 128 BioSciences Lyon Gerland, Lyon F-69007, France.
authors: Caroline
authors: C
authors: Scholtes
authors: Olivier
authors: O
authors: Diaz
authors: Vinca
authors: V
authors: Icard
authors: Artur
authors: A
authors: Kaul
authors: Ralf
authors: R
authors: Bartenschlager
authors: Vincent
authors: V
authors: Lotteau
authors: Patrice
authors: P
authors: André
mesh_terms: D001647:Bile Acids and Salts / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000502:physiology*; D005838:Genotype; D016174:Hepacivirus / Q000145:classification / Q000502:physiology*; D007372:Interferons / Q000494:pharmacology; D047493:PPAR alpha / Q000502:physiology; D012367:RNA, Viral / Q000096:biosynthesis; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology*; D014779:Virus Replication / Q000187:drug effects*; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D001647:Bile Acids and Salts; D004268:DNA-Binding Proteins; D007372:Interferons; D047493:PPAR alpha; D012367:RNA, Viral; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated