The metabolic sensors FXRα, PGC-1α, and SIRT1 cooperatively regulate hepatitis B virus transcription.

Hepatitis B virus (HBV) genome transcription is highly dependent on liver-enriched, metabolic nuclear receptors (NRs). Among others, NR farnesoid X receptor α (FXRα) enhances HBV core promoter activity and pregenomic RNA synthesis. Interestingly, two food-withdrawal-induced FXRα modulators, peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) and deacetylase SIRT1, have been found to be associated with HBV genomes ex vivo. Whereas PGC-1α induction was shown to increase HBV replication, the effect of SIRT1 on HBV transcription remains unknown. Here, we showed that, in hepatocarcinoma-derived Huh-7 cells, combined activation of FXRα by GW4064 and SIRT1 by activator 3 increased HBV core promoter-controlled luciferase expression by 25-fold, compared with a 10-fold increase with GW4064 alone. Using cell lines differentially expressing FXRα in overexpression and silencing experiments, we demonstrated that SIRT1 activated the core promoter in an FXRα- and PGC-1α-dependent manner. Maximal activation (>150-fold) was observed in FXRα- and PGC-1α-overexpressing Huh-7 cells treated with FXRα and SIRT1 activators. Similarly, in cells transfected with full-length HBV genomes, maximal induction (3.5-fold) of core promoter-controlled synthesis of 3.5-kb RNA was observed in the same conditions of transfection and treatments. Thus, we identified a subnetwork of metabolic factors regulating HBV replication, strengthening the hypothesis that transcription of HBV and metabolic genes is similarly controlled.

Role of nuclear receptors in hepatitis B and C infections.

Nuclear receptors are key regulators of many cellular functions including energy supply by the direct control of the expression of target genes. They constitute a super-family of transcription factors activated by ligands, hormones or metabolites, and therefore, sensible to host metabolic stimuli. Viral replication and production requires energy and elementary building blocks from the infected cells. Hepatitis B and C virus replication is modulated in part by liver nuclear receptors that regulate the glucose and lipid metabolism. However, nuclear receptors control the two viruses' replication by different mechanisms. The expression of hepatitis B virus genes is directly under the control of nuclear receptors, which bind to the viral genome regulatory regions. Viral replication and production may, therefore, be optimal when cells receive the correct metabolic signals. Hepatitis C virus replication and production depend to a large extent on lipidogenesis and lipoprotein secretion. The role of nuclear receptors in controlling hepatitis C replication may be to turn on the cellular mode that would provide the appropriate metabolic environment for viral replication.