title: The metabolic sensors FXRα, PGC-1α, 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.
authors.affiliation: 2Centre International de Recherche en Infectiologie, INSERM U1111, 21 Ave. Tony Garnier, 69365 Lyon Cedex 07, France. patrice.andre@inserm.fr.
authors.forename: Claire
authors.initials: C
authors.lastname: Curtil
authors.forename: Liviu S
authors.initials: LS
authors.lastname: Enache
authors.forename: Pauline
authors.initials: P
authors.lastname: Radreau
authors.forename: Anne-Gaëlle
authors.initials: AG
authors.lastname: Dron
authors.forename: Caroline
authors.initials: C
authors.lastname: Scholtès
authors.forename: Alexandre
authors.initials: A
authors.lastname: Deloire
authors.forename: Didier
authors.initials: D
authors.lastname: Roche
authors.forename: Vincent
authors.initials: V
authors.lastname: Lotteau
authors.forename: Patrice
authors.initials: P
authors.lastname: André
authors.forename: Christophe
authors.initials: C
authors.lastname: Ramière
mesh_terms: D001483:Base Sequence; D015152:Blotting, Northern; D015153:Blotting, Western; D045744:Cell Line, Tumor; D017931:DNA Primers; D006515:Hepatitis B virus / Q000235:genetics*; D006801:Humans; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D056564:Sirtuin 1 / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology*; D014158:Transcription, Genetic / Q000502:physiology*; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D017931:DNA Primers; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D034741:RNA, Small Interfering; D018160:Receptors, Cytoplasmic and Nuclear; D056564:Sirtuin 1; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated; C486497:PPARGC1A protein, human; C447939:SIRT1 protein, human
keywords: HBV; epigenetic; metabolism; nuclear receptors