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Journal of Virology, November 2008, p. 10832-10840, Vol. 82, No. 21
0022-538X/08/$08.00+0     doi:10.1128/JVI.00883-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Transactivation of the Hepatitis B Virus Core Promoter by the Nuclear Receptor FXR{alpha}{triangledown}

Christophe Ramière,1,2 Caroline Scholtès,1,2 Olivier Diaz,1 Vinca Icard,1,2 Laure Perrin-Cocon,1 Mary-Anne Trabaud,2 Vincent Lotteau,1,2 and Patrice André1,2*

INSERM U851, 21 Avenue Tony Garnier, and Université de Lyon, and Université Lyon 1, and IFR 128, Lyon F-69007, France,1 Hospices Civils de Lyon, Lyon F-69002, France2

Received 26 April 2008/ Accepted 22 August 2008

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 (FXR{alpha}) in modulating transcription from the HBV core promoter. FXR{alpha} is a liver-enriched nuclear receptor activated by bile acids recognizing hormone response elements by forming heterodimers with retinoid X receptor alpha (RXR{alpha}). Electrophoretic mobility shift assays demonstrated that FXR{alpha}-RXR{alpha} heterodimers can bind two motifs on the HBV enhancer II and core promoter regions, presenting high homology to the consensus (AGGTCA) inverted repeat FXR{alpha} 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{alpha}. Moreover, using a greater-than-genome-length HBV construct, we showed that FXR{alpha} also increased synthesis of the viral pregenomic RNA and DNA replication intermediates. The data strongly suggest that FXR{alpha} 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.

* Corresponding author. Mailing address: INSERM U851, 21 avenue Tony Garnier, Lyon F-69007, France. Phone: 33 4 37 28 23 27. Fax: 33 4 37 28 23 41. E-mail: patrice.andre{at}inserm.fr

{triangledown} Published ahead of print on 3 September 2008.

Journal of Virology, November 2008, p. 10832-10840, Vol. 82, No. 21
0022-538X/08/$08.00+0     doi:10.1128/JVI.00883-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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