Oxygenated derivatives of cholesterol promote hepatitis B virus gene expression through nuclear receptor LXRα activation

Hepatitis B virus (HBV) gene expression and replication are regulated by the activation of a number of liver-enriched transcription factors dependent on intracellular and extracellular stimuli. However, the association between the metabolic events and HBV gene expression remains unclear. In this study, we assessed the effects of cholesterol metabolism on HBV viral replication and gene expression. Exposure of oxygenated derivatives of cholesterol (oxysterols) increased HBV gene expression and viral promoter activity. This increase in HBV transcription and replication was directed by nuclear receptor LXRα induction in the presence of oxysterols. In addition, HBV viral expression by oxysterol was inhibited through small heterodimer partner and sterol regulatory element-binding protein 2, key regulators of cholesterol synthesis. When IFNα and oxysterols were co-incubated, oxysterols and LXRα significantly reduced the anti-HBV effects of IFNα. These results point to a novel mechanism of oxysterol-mediated gene regulation in HBV replication and a potent mechanism underlying the failure of IFNα-based treatment.