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Activation of the Liver X Receptor Pathway Inhibits HBV Replication in Primary Human Hepatocytes
Author(s) -
Zeng Jing,
Wu Daitze,
Hu Hui,
Young John A.T.,
Yan Zhipeng,
Gao Lu
Publication year - 2020
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.31217
Subject(s) - liver x receptor , cccdna , agonist , gene knockdown , biology , nuclear receptor , cholesterol 7 alpha hydroxylase , hepatitis b virus , viral replication , receptor , endocrinology , transcription factor , virology , cholesterol , virus , gene , biochemistry , hbsag
Background and Aims 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. Approach and Results 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 antigen production following 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 small interfering RNA inhibited HBV activity in PHHs, suggesting CYP7A1 as a potential factor contributing to the antiviral effects of LXR agonists. Conclusions We found that activation of the LXR pathway with synthetic LXR agonists could elicit potent anti‐HBV activity in PHHs, possibly through sustained suppression of cccDNA transcription. Our work highlights the therapeutic potential of targeting the LXR pathway for the treatment of chronic HBV infection.