In terms of regulation and the response to nutritional stimuli, HBV is quite reminiscent of metabolic genes; thus, one can attribute certain dynamic changes in the natural history of HBV not only to certain mutations or the genotypic diversity of the virus, but also to alterations in environmental nutritional conditions, or alternatively, to preexisting pathologic states that influence the host metabolism . According to previous studies, liver-enriched NRs play a pivotal role in the regulation of the HBV transcriptional program by binding to both EnhI and EnhII via the NR-response element [6,26,36]. Interestingly, liver-enriched NRs are central mediators of metabolic processes in the liver. A prominent example of such a process is gluconeogenesis, which is required for the maintenance of a normal blood glucose level during starvation. NRs, including glucocorticoid receptor, HNF4α and PPARs, bind to and activate the promoter of the phosphoenolpyruvate carboxykinase gene, a key gluconeogenic enzyme. In particular, HNF4α, retinoid X receptor α and PPARα mainly bind to the HBV NR-response elements. The essential function of liver-enriched NRs in HBV gene expression led us to investigate a possible association between major metabolic processes occurring in the liver and HBV gene expression. NRs are also involved in fatty acid β-oxidation, ketogenesis and bile acid homeostasis, which comprise other essential metabolic events occurring in the liver [35,37]. Cholesterol homeostasis is maintained by de novo synthesis, dietary absorption, and catabolism to bile acids and other steroids, as well as excretion into the bile . Cholestasis is a medical condition characterized by an impairment of normal bile flow; this impairment results either from a functional defect of bile secretion, or from an obstruction of the bile duct . Under cholestatic conditions, hepatocytes are exposed to increased bile acid concentrations, resulting in cytopathic effects [14,39]. Recent studies have demonstrated that bile acids not only serve as physiological detergents that facilitate the absorption, transport and distribution of lipid soluble vitamins and dietary fats, but also as signaling molecules that activate NRs and regulate bile acid and cholesterol metabolism [14,19]. Additionally, it has been demonstrated that bile acids inhibit the induction of proteins involved in the antiviral activity of the interferons IFNs . One of the classes of anti-HBV IFNs comprises secreted proteins that are involved in many biological activities, including antiviral defense [15,40]. Under cholestatic conditions in several environments, and because hepatocytes are exposed to high concentrations of bile acids in the liver , we hypothesized that the bile acid-mediated pathway demonstrates regulatory capacities with regard to HBV gene expression and the anti-HBV effects of IFN-α. In the present study, we demonstrate that bile acids, including an unconjugated CDCA, robustly induce HBV transcription and gene expression in human hepatoma cell lines. In addition, we tested whether the bile acid-mediated FXRα pathway is important in bile acid-mediated HBV gene expression using siFXR and the bile acid antagonist FXR, z-guggulsterone. This suggests that the FXRα pathway is important for bile acid-mediated HBV gene expression. In recent study, it was reported that two putative FXRE were identified in the EnhII of HBV genome, with homology to the typical inverted repeat sequence recognized by FXRα . These results indicate that the therapeutic inhibition of FXRα with the appropriate antagonist may represent a potential approach for inhibiting HBV gene expression in chronic carriers. Interestingly, the activity of EnhII depends on a functional EnhI. EnhI is located upstream of the X promoter and is targeted by multiple activators, including C/EBPs, AP-1 complex and ATFs. In the present study, we suggest that the CDCA-induced JNK/c-Jun pathway cooperated with the FXRα pathway in the promotion of HBV gene expression. According to previously obtained results [2,4,6,9], we can assume that bile acid-induced HBV gene expression is mediated by the FXRα pathway on EhnII in cooperation with the JNK/c-Jun pathway on Ehn1 of the HBV genome. On the other hand, it has been demonstrated that SHP, an orphan nuclear hormone receptor lacking a DNA binding domain, inhibits NR-mediated transcription and gene expression. The inhibition of HBV replication by SHP is dependent on the presence of NRs . SHP is present abundantly in the liver and performs a crucial function in cholesterol metabolism by modulating the transcription of enzymes involved in the pathway by which cholesterol is converted into bile acids . In the present study, we demonstrate that bile acids, including unconjugated CDCA, which activates the bile acid-mediated FXRα pathway, robustly induce HBV gene expression, whereas increased SHP levels reduce FXRα-induced HBV gene expression in human hepatoma cell lines. The conditions associated with elevated bile acid levels within the liver include choleostatic liver diseases or increased dietary cholesterol uptake . Under these conditions, it was shown that the FXRα and JNK/c-Jun pathways may be elevated. and not only might HBV gene expression consequently be increased, but also the anti-HBV effects of IFNs might be reduced. These observations indicate that the physiological regulation of HBV biosynthesis by bile acids in the liver will depend on both FXRα/JNK-c-Jun pathway levels and the relative inhibition of SHP in the context of HBV gene expression and gene expression. Furthermore, our findings may facilitate the development of novel and superior regimens for the treatment of chronic HBV infections, ostensibly by including agents that alter the bile acid-mediated FXRα and JNK/c-Jun pathways.