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J. Virol. doi:10.1128/JVI.00883-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Transactivation of the Hepatitis B virus Core Promoter by the Nuclear Receptor FXR

INSERM, U851, 21 Avenue Tony Garnier, Lyon, F-69007, France; Université de Lyon, Lyon, F-69007, France; Université Lyon 1, Lyon, F-69007, France; IFR 128, Lyon, F-69007, France; Hospices Civils de Lyon, Lyon, F-69002, France

^* To whom correspondence should be addressed. Email: patrice.andre{at}inserm.fr.

	Abstract

The 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 the Farnesoid X Receptor alpha (FXR) in modulating transcription from the HBV Core promoter. FXR is a liver-enriched nuclear receptor activated by bile acids recognizing Hormone Response Elements by forming heterodimers with the Retinoid X Receptor alpha (RXR). Electrophoretic mobility shift assays demonstrated that FXR-RXR heterodimers can bind two motifs, on the HBV enhancer II and Core promoter regions, presenting high homology to the consensus AGGTCA inverted repeat FXR 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 FXR. Moreover, using a greater-than-genome HBV construct, we showed that FXR also increased synthesis of the viral pregenomic RNA and DNA replication intermediates. The data strongly suggest that FXR is another member of the nuclear receptor superfamily implicated in the regulation of the HBV Core promoter activity and that bile acids could play an important role in the natural history of the HBV infection.