Journal
FASEB JOURNAL
Volume 28, Issue 3, Pages 1454-1463Publisher
WILEY
DOI: 10.1096/fj.13-236372
Keywords
HBV; epigenetic; metabolism; nuclear receptors
Categories
Funding
- Agence Nationale de Recherche sur le Sida et les Hepatites Virales (ANRS)
- Natheb program (French Fond Unique Interministeriel)
- Sectorial Operational Programme Human Resources Development (SOP HRD)
- European Social Fund
- Romanian government [POSDRU 6/1.5/17]
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Hepatitis B virus (HBV) genome transcription is highly dependent on liver-enriched, metabolic nuclear receptors (NRs). Among others, NR farnesoid X receptor (FXR) enhances HBV core promoter activity and pregenomic RNA synthesis. Interestingly, two food-withdrawal-induced FXR modulators, peroxisome proliferator-activated receptor- coactivator 1 (PGC-1) and deacetylase SIRT1, have been found to be associated with HBV genomes ex vivo. Whereas PGC-1 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 FXR 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 FXR in overexpression and silencing experiments, we demonstrated that SIRT1 activated the core promoter in an FXR- and PGC-1-dependent manner. Maximal activation (>150-fold) was observed in FXR- and PGC-1-overexpressing Huh-7 cells treated with FXR 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., Scholtes, C., Deloire, A., Roche, D., Lotteau, V., Andre, P., and Ramiere, C. The metabolic sensors FXR, PGC-1, and SIRT1 cooperatively regulate hepatitis B virus transcription.
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