FASEB J. 2018 Oct 11:fj201801181R. doi: 10.1096/fj.201801181R. [Epub ahead of print]
Farnesoid X receptor-α is a proviral host factor for hepatitis B virus that is inhibited by ligands in vitro and in vivo.
Mouzannar K1, Fusil F1, Lacombe B1, Ollivier A1, Ménard C1, Lotteau V1, Cosset FL1, Ramière C1,2, André P1.
Author information
1
Centre International de Recherche en Infectiologie (CIRI), Université Lyon, Université Claude Bernard Lyon 1, INSERM, Unité1111, Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche (UMR) 5308, École Normale Supérieure (ENS) de Lyon, Lyon, France.
2
Laboratoire de Virologie, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, Lyon, France.
Abstract
Hepatitis B virus (HBV) infection and bile acid (BA) metabolism are interdependent: infection modifies the expression of the BA nuclear receptor farnesoid X receptor (FXR)-α, and modulation of FXRα activity by ligands alters HBV replication. Mechanisms of HBV control by FXRα remain to be unveiled. FXRα silencing in HBV-infected HepaRG cells decreased the viral covalently closed circular (ccc)DNA pool size and transcriptional activity. Treatment with the FXRα agonist GW4064 inhibited FXRα proviral effect on cccDNA similarly for wild-type and hepatitis B viral X protein (HBx)-deficient virus, whereas agonist-induced inhibition of pregenomic and precore RNA transcription and viral DNA secretion was HBx dependent. These data indicated that FXRα acts as a proviral factor by 2 different mechanisms, which are abolished by FXRα stimulation. Finally, infection of C3H/HeN mice by a recombinant adeno-associated virus-2/8-HBV vector induced a sustained HBV replication in young mice in contrast with the transient decline in adult mice. Four-week GW4064 treatment of infected C3H/HeN mice decreased secretion of HBV DNA and HB surface antigen in adult mice only. These results suggest that the physiologic balance of FXRα expression and activation by bile acid is a key host metabolic pathway in the regulation of HBV infection and that FXRα can be envisioned as a target for HBV treatment.-Mouzannar, K., Fusil, F., Lacombe, B., Ollivier, A., Ménard, C., Lotteau, V., Cosset, F.-L., Ramière, C., André, P. Farnesoid X receptor α is a proviral host factor for hepatitis B virus that is inhibited by ligands in vitro and in vivo.
KEYWORDS:
1
Centre International de Recherche en Infectiologie（CIRI），里昂大学，Claude Bernard Lyon大学1，INSERM，Unité1111，国家科学研究中心（CNRS），UnitéMixtede Recherche（UMR）5308，ÉcoleNormaleSupérieure（ENS）de Lyon ，里昂，法国。
2
Laboratoire de Virologie，Hôpitaldela Croix-Rousse，Hospices Civils de Lyon，Lyon，France。