Implication de FXR, récepteur nucléaire des acides biliaires, dans la réplication des virus des hépatites B et C

Abstract

Hepatitis C virus (HCV) infected patients with high serum levels of bile acids (BA) usually fail to respond to antiviral therapy. Using the HCV-replicon model containing a luciferase reporter gene, we demonstrated that BAs up-regulate HCV RNA replication by more than ten fold. In this study, their effect is mediated by their nuclear receptor, the farnesoid X receptor (FXR). FXR directly interacts with 2 viral proteins NS3 and NS5A. The phytosterol Guggulsterone and FXR silencing blocked the effect of BA activation. Guggulsterone also inhibited basal level of HCV replication and this effect was additive to the inhibition due to interferon. This compound will be tested soon in clinical assays. FXR recruitment by viral proteins should further explain the metabolic syndrome associated to HCV pathology. As FXR is mainly expressed in the liver, we studied if it could participate to the tropism of other hepatic viruses like hepatitis B virus (HBV), which replication is highly regulated by nuclear factors. We characterized 2 putative FXR response elements on the HBV enhancer II and Core promoter regions. In transient transfection assays, bile acids enhanced the activity of a luciferase reporter containing the HBV enhancer II and Core promoter sequences, through FXR. Moreover, using a greater-than-genome HBV construct, we showed that FXR also increased synthesis of the viral pregenomic RNA and DNA replication intermediates. In conclusion, we demonstrated that BAs play an important role in the natural history of 2 viruses, likely explaining their tropism for the liver. FXR antagonists may be foreseen as therapeutical agents to improve treatments of HBV and HCV-infected patientsLYON1-BU.Sciences (692662101) / SudocSudocFranceF