法呢醇X受体-α是乙型肝炎病毒的前病毒宿主因子，其在体外

StephenW

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:

HBx; agonist; bile acids; mouse model; rAAV-HBV

PMID:
    30307769
DOI:
    10.1096/fj.201801181R

StephenW

FASEB J. 2018年10月11日：fj201801181R。 doi：10.1096 / fj.201801181R。 [提前打印]
法呢醇X受体-α是乙型肝炎病毒的前病毒宿主因子，其在体外和体内被配体抑制。
Mouzannar K1，Fusil F1，Lacombe B1，Ollivier A1，MénardC1，Lotteau V1，Cosset FL1，RamièreC1,2，AndréP1。
作者信息

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。

抽象

乙型肝炎病毒（HBV）感染和胆汁酸（BA）代谢是相互依赖的：感染改变BA核受体法尼醇X受体（FXR）-α的表达，并且配体调节FXRα活性改变HBV复制。 FXRα控制HBV的机制仍有待公布。 HBV感染的HepaRG细胞中的FXRα沉默降低了病毒共价闭合环状（ccc）DNA库大小和转录活性。对于野生型和乙型肝炎病毒X蛋白（HBx）缺陷型病毒，FXRα激动剂GW4064的治疗对cccDNA的FXRα前病毒效应受到抑制，而激动剂诱导的前基因组和前核心RNA转录和病毒DNA分泌的抑制是HBx依赖性的。这些数据表明FXRα通过2种不同的机制作为前病毒因子，FXRα刺激消除了这些机制。最后，重组腺相关病毒-2 / 8-HBV载体感染C3H / HeN小鼠诱导年轻小鼠的持续HBV复制，与成年小鼠的短暂下降相反。感染的C3H / HeN小鼠的四周GW4064处理仅降低了成年小鼠中HBV DNA和HB表面抗原的分泌。这些结果表明，FXRα表达和胆汁酸激活的生理平衡是HBV感染调节的关键宿主代谢途径，FXRα可被设想为HBV治疗的靶点。-Mouzannar，K.，Fusil，F。 ，Lacombe，B.，Ollivier，A.，Ménard，C.，Lotteau，V.，Cosset，F.-L.，Ramière，C.，André，P。Farnesoid Xreceptorα是乙型肝炎的前病毒宿主因子在体外和体内被配体抑制的病毒。
关键词：

HBx蛋白;激动剂;胆汁酸;小鼠模型;腺相关病毒，HBV

结论：
    30307769
DOI：
    10.1096 / fj.201801181R