t0901317 and Hepatitis-B

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 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.. 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.

Topics: Antigens, Viral; Antiviral Agents; Benzoates; Benzylamines; Cells, Cultured; Cholesterol 7-alpha-Hydroxylase; DNA, Viral; Drug Evaluation, Preclinical; Gene Knockdown Techniques; Hepatitis B; Hepatitis B virus; Hepatocytes; Heterocyclic Compounds, 4 or More Rings; Humans; Hydrocarbons, Fluorinated; Indazoles; Liver; Liver X Receptors; Primary Cell Culture; RNA, Viral; Signal Transduction; Sulfonamides; Virus Replication

HBV (hepatitis B virus) is a primary cause of chronic liver disease, which frequently results in hepatitis, cirrhosis and ultimately HCC (hepatocellular carcinoma). Recently, we showed that HBx (HBV protein X) expression induces lipid accumulation in hepatic cells mediated by the induction of SREBP1 (sterol-regulatory-element-binding protein 1), a key regulator of lipogenic genes in the liver. However, the molecular mechanisms by which HBx increases SREBP1 expression and transactivation remain to be clearly elucidated. In the present study, we demonstrated that HBx interacts with LXRalpha (liver X receptor alpha) and enhances the binding of LXRalpha to LXRE (LXR-response element), thereby resulting in the up-regulation of SREBP1 and FAS (fatty acid synthase) in the presence or absence of the LXR agonist T0901317 in the hepatic cells and HBx-transgenic mice. Furthermore, HBx also augments the ability to recruit ASC2 (activating signal co-integrator 2), a transcriptional co-activator that controls liver lipid metabolic pathways, to the LXRE with LXRalpha. These studies place LXRalpha in a key position within the HBx-induced lipogenic pathways, and suggest a molecular mechanism through which HBV infection can stimulate the SREBP1-mediated control of hepatic lipid accumulation.

Topics: Animals; Carcinoma, Hepatocellular; Cell Line; Cell Line, Tumor; DNA-Binding Proteins; Fatty Acid Synthases; Fatty Liver; Genes, Reporter; Hepatitis B; Hepatitis C; Humans; Hydrocarbons, Fluorinated; Lipids; Liver Neoplasms; Liver X Receptors; Mice; Mice, Transgenic; Orphan Nuclear Receptors; Receptors, Cytoplasmic and Nuclear; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; Sterol Regulatory Element Binding Protein 1; Sulfonamides; Trans-Activators; Transfection; Viral Regulatory and Accessory Proteins