The metabolic sensors FXRα, PGC‐1 α, and SIRT1 cooperatively regulate hepatitis B virus transcription. Issue 3 (2nd December 2013)

• Record Type: Journal Article
• Authors: Curtil, Claire; Enache, Liviu S.; Radreau, Pauline; Dron, Anne‐Gaëlle; Scholtès, Caroline; Deloire, Alexandre; Roche, Didier; Lotteau, Vincent; André, Patrice; Ramière, Christophe
• Is Part Of: FASEB journal. Volume 28:Issue 3(2014)
• Page Start: 1454
• Page End: 1463
• Publication Date: 2013-12-02
• Subjects: HBV -- epigenetic -- metabolism -- nuclear receptors; Biology -- Periodicals; Biology, Experimental -- Periodicals; 570
• DOI: 10.1096/fj.13-236372
• Languages: English
• ISSNs: 0892-6638

Abstract

Abstract : Hepatitis B virus (HBV) genome transcription is highly dependent on liver‐enriched, metabolic nuclear receptors (NRs). Among others, NR farnesoid X receptor a (FXRa) 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 hepatocar‐cinoma‐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‐1 α‐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.—Curtil, C., Enache, L. S., Radreau, P., Dron, A.‐G., Scholtès, C., Deloire, A., Roche, D., Lotteau, V., André, P., and Ramière, C. The metabolic sensors FXRα, PGC‐1 α, and SIRT1 cooperatively regulate hepatitis B virus transcription. FASEB J. 28, 1454–1463 (2014). www.fasebj.org