Enhancement of genotype 1 hepatitis C virus replication by bile acids through FXR.
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.
Scholtes
Caroline
C
INSERM U851, IFR 128 BioSciences Lyon Gerland, Lyon F-69007, France.
Diaz
Olivier
O
Icard
Vinca
V
Kaul
Artur
A
Bartenschlager
Ralf
R
Lotteau
Vincent
V
André
Patrice
P
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
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