Activation of the Liver X Receptor Pathway Inhibits HBV Replication in Primary Human Hepatocytes

Abstract

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.

Multifaceted Interaction Between Hepatitis B Virus Infection and Lipid Metabolism in Hepatocytes: A Potential Target of Antiviral Therapy for Chronic Hepatitis B

“…Moreover, a study found that oxygenated cholesterol derivatives (also named oxysterols, the endogenous agonists of LXR) increased the transcription and replication of HBV and reduced the anti-HBV effect of IFN (Kim et al, 2011). Interestingly, a recent study showed synthetic LXR agonists inhibited HBV replication and gene expression through CYP7A1 reduction in HBV-infected primary human hepatocytes, but this observation was not found in hepatocellular carcinoma cell line (Zeng et al, 2020). 25-hydroxycholesterol (25-HC) has been identified to block replication and entry of a broad range of viruses, such as VSV, HIV, EBOV, or ZIKA (Liu et al, 2013;Xiao et al, 2020;Zhao et al, 2020).…”

Strategies to Inhibit Hepatitis B Virus at the Transcript Level

“…Two agonists T0901317 and GW3965 but not antagonist SR9238 potently inhibited the gene expression and transcription of viral RNAs in HepaRG and primary hepatocytes, although cccDNA levels were not substantially reduced. Remarkably, no significant antiviral activity was observed in HepG2 NTCP cells [ 124 ]. These data suggest that the metabolic profile in HepG2 hepatoma cells might be distinctly different from that in primary hepatocytes.…”

The roles of liver X receptor α in inflammation and inflammation‐associated diseases

“…However, new insights also suggest that activation of LXRα may provide a protective possibility for the treatment of chronic HBV infection. A recent study demonstrated that activation of LXRα with synthetic LXRs agonists (T0901317, GW3965, and LXR‐623) and disruption of the expression of the downstream LXR gene cholesterol 7α‐hydroxylase 1 (CYP7A1), can inhibit HBV replication in HBV‐infected primary human hepatocytes possibly via sustained suppression of covalently closed circular DNA (cccDNA) transcription (J. Zeng et al, 2020). The contradictory results hint that further studies are warranted to understand the role of LXRα and the application of the LXRs agonist in HBV infection.…”