Transactivation of the Hepatitis B Virus Core Promoter by the Nuclear Receptor FXRα

Hepatitis B virus (HBV) core promoter activity is positively and negatively regulated by nuclear receptors, a superfamily of ligand-activated transcription factors, via cis-acting sequences located in the viral genome. In this study, we investigated the role of farnesoid X receptor alpha (FXRα) in modulating transcription from the HBV core promoter. FXRα is a liver-enriched nuclear receptor activated by bile acids recognizing hormone response elements by forming heterodimers with retinoid X receptor alpha (RXRα). Electrophoretic mobility shift assays demonstrated that FXRα-RXRα heterodimers can bind two motifs on the HBV enhancer II and core promoter regions, presenting high homology to the consensus (AGGTCA) inverted repeat FXRα response elements. In transient transfection of the human hepatoma cell line Huh-7, bile acids enhanced the activity of a luciferase reporter containing the HBV enhancer II and core promoter sequences through FXRα. Moreover, using a greater-than-genome-length HBV construct, we showed that FXRα also increased synthesis of the viral pregenomic RNA and DNA replication intermediates. The data strongly suggest that FXRα is another member of the nuclear receptor superfamily implicated in the regulation of HBV core promoter activity and that bile acids could play an important role in the natural history of HBV infection.