Transcriptional Regulation of Hepatitis B Virus Biosynthesis by Bile Acids and FoxA Factors

HBV is a major human pathogen that currently chronically infects approximately 400 million individuals worldwide and is responsible for about one million deaths annually. New modalities of therapy are urgently needed to address this major public health issue. The results presented show multiple nuclear receptors are capable of activating HBV biosynthesis in non-hepatoma cells, including RXRα/FXRα, and both SHP and PGC1α can modulate RXRα/FXRα-dependent HBV biosynthesis in non-hepatoma cells. However, bile acids have only a modest effect in vivo. Based on the cell culture analysis, it is possible that in vivo even the activation of FXR by bile acids is not sufficient to further enhance HBV transcription and replication, which is being directed by other constitutively active nuclear receptors. Of great interest, the results presented suggest that FoxA transcription factor deficiency in vivo can selectively prevent HBV biosynthesis without greatly altering hepatocyte physiology. However significant fibrosis, a common consequence of HBV infection, is apparent in the FoxA-deficient mice. It remains to be determined what the relative contributions from direct transcriptional regulation by FoxA and indirect effects mediated by nonparanchymal cells are to HBV biosynthesis in this system. Although findings presented in this study suggest FoxA deficiency itself can result in inhibition of HBV biosynthesis, it is quite possible both modes of regulation contribute to the observed effects on HBV biosynthesis.