肝X受体途径的激活抑制了原代人肝细胞中的HBV复制。

StephenW

Hepatology. 2020 Mar 7. doi: 10.1002/hep.31217. [Epub ahead of print]
Activation of the liver X receptor pathway inhibits HBV replication in primary human hepatocytes.
Zeng J1, Wu D1, Hu H1, Young JAT2, Yan Z1, Gao L1.
Author information

1
    Roche Innovation Center Shanghai, Shanghai, China, 201203.
2
    Roche Innovation Center Basel, 4070, Basel, Switzerland.

Abstract

Hepatitis B virus (HBV) infection is ranked among the top health priorities worldwide. Accumulating evidence suggests that HBV infection and replication are closely associated with liver metabolism. The liver X receptors (LXRs), which belong to the superfamily of nuclear hormone receptors, are important physiological regulators of lipid and cholesterol metabolism. However, the association between the LXR pathway and HBV infection remains largely unclear. In this study, the antiviral activity of LXR agonists was investigated using multiple HBV cellular models. We observed that in HBV-infected primary human hepatocytes (PHHs), synthetic LXR agonists (T0901317, GW3965, and LXR-623), but not an LXR antagonist (SR9238), potently inhibited HBV replication and gene expression, as demonstrated by substantial reductions in viral RNA, DNA, and antigens production upon agonist treatment. However, covalently closed circular DNA (cccDNA) levels were not significantly reduced by the agonists. In addition, no rebound in viral replication was observed after treatment withdrawal, indicating a long-lasting inhibitory effect. These results suggest that LXR agonists decrease the transcriptional activity of cccDNA. In contrast, no significant anti-HBV effect was observed in HepG2-derived cell lines. Interestingly, LXR agonist treatment strongly reduced cholesterol 7α-hydroxylase 1 (CYP7A1) mRNA levels. Knockdown of CYP7A1 gene expression with siRNA inhibited HBV activity in PHHs, suggesting CYP7A1 as a potential factor contributing to the antiviral effects of LXR agonists. CONCLUSION: We found that activation of the LXR pathway with synthetic LXR agonists could elicit potent anti-HBV activity in PHHs, possibly via sustained suppression of cccDNA transcription. Our work highlights the therapeutic potential of targeting LXR pathway for the treatment of chronic HBV infection.

This article is protected by copyright. All rights reserved.
KEYWORDS:

CYP7A1 antiviral; HBV inhibition; LXR agonist; metabolovirus; primary human hepatocyte

PMID:
    32145089
DOI:
    10.1002/hep.31217

StephenW

肝病学。 2020年3月7日。doi：10.1002 / hep.31217。 [Epub提前发行]
肝X受体途径的激活抑制了原代人肝细胞中的HBV复制。
曾J1，吴D1，胡H1，青年JAT2，严Z1，高L1。
作者信息

1个
    上海罗氏创新中心，中国上海，201203。
2
    罗氏创新中心，巴塞尔，4070，瑞士巴塞尔。

抽象

乙肝病毒（HBV）感染被列为全球最重要的健康问题之一。越来越多的证据表明，HBV感染和复制与肝脏代谢密切相关。肝X受体（LXR）属于核激素受体的超家族，是脂质和胆固醇代谢的重要生理调节剂。但是，LXR途径与HBV感染之间的关联仍不清楚。在这项研究中，使用多种HBV细胞模型研究了LXR激动剂的抗病毒活性。我们观察到在HBV感染的原代人肝细胞（PHHs）中，合成的LXR激动剂（T0901317，GW3965和LXR-623）而不是LXR拮抗剂（SR9238）会有效抑制HBV复制和基因表达，这一点已得到实质性降低激动剂处理后，病毒RNA，DNA和抗原产生的能力降低。但是，激动剂并没有显着降低共价闭合的环状DNA（cccDNA）水平。此外，停药后未观察到病毒复制反弹，表明具有长期抑制作用。这些结果表明，LXR激动剂降低了cccDNA的转录活性。相反，在源自HepG2的细胞系中未观察到明显的抗HBV作用。有趣的是，LXR激动剂治疗可大大降低胆固醇7α-羟化酶1（CYP7A1）mRNA水平。用siRNA抑制CYP7A1基因表达可抑制PHH中的HBV活性，提示CYP7A1是促进LXR激动剂抗病毒作用的潜在因素。结论：我们发现合成的LXR激动剂激活LXR途径可以引起PHHs有效的抗HBV活性，可能是通过持续抑制cccDNA转录。我们的工作突出了靶向LXR途径治疗慢性HBV感染的治疗潜力。

本文受版权保护。版权所有。
关键字：

CYP7A1抗病毒药； HBV抑制； LXR激动剂；代谢病毒原代人肝细胞

PMID：
    32145089
DOI：
    10.1002 / hep.31217