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

Abstract

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.

Hepatitis B virus molecular biology and pathogenesis

“…For example, multiple transcription factors associated with hepatic metabolic processes, including HNFs, [244, 245] peroxisome proliferator-activated receptors (PPARs), [245–247] and FXR [248–250] can all be recruited to the HBV genome. [33] Moreover, studies in vitro have shown that exogenous addition of bile acids to HBV-expressing cells can increase HBV replication.…”

The Hepatitis B Virus Receptor

“…HBV transcription is regulated by a complex network composed of cellular nuclear receptors and transcription factors, including hepatocyte nuclear factor 4α (HNF4α) (Curtil et al 2014, Quasdorff & Protzer 2010. FXR is a liver-enriched nuclear receptor activated by its natural ligands, bile acids.…”

Synthesis and biological evaluations of chalcones, flavones and chromenes as farnesoid x receptor (FXR) antagonists

“…Apart from its crucial role in maintaining bile acids and cholesterol homeostasis, FXR also regulates the metabolism of lipid and glucose [7–9]. It has been shown that FXR is involved in various diseases such as metabolic disorders, hepatitis, arteriosclerosis and cancer [10–14]. Thus, FXR has been considered as an important drug target after the deorphanization of FXR in 1999 [15].…”