title: Estrogen receptor α represses transcription of HBV genes via interaction with hepatocyte nuclear factor 4α.
abstract: OBJECTIVE
  Women with hepatitis B virus (HBV) infection usually have lower viral loads than men, reducing their risk of liver cancer. There are 2 androgen-responsive elements in the HBV enhancer I that contribute to higher viral titers in men. We investigated whether and how estrogen signaling affects progression of HBV infection.
  
  
  METHODS
  Ovariectomy and estrogen supplementation were used to evaluate the effect of estrogen on HBV titers in transgenic mice with replicating HBV in hepatocytes. The effect of estrogen signaling on transcription of HBV genes, and the mechanisms of regulation, were studied in HepG2 cells.
  
  
  RESULTS
  HBV titers increased in female mice after ovariectomy and decreased in male mice supplemented with estrogen. Hepatic expression of estrogen receptor (ER)-α was increased by estrogen exposure. In HepG2 cells, up-regulation of ER-α reduced HBV transcription, which required a specific region within enhancer I. Direct DNA binding of ER-α and histone deacetylase activity were not required for ER-α-mediated repression of HBV genes. Overexpression of hepatocyte nuclear factor (HNF)-4α, which binds to this region, overcame the repressive effect of ER-α. ER-α did not repress transcription of an HBV replicon with a mutant HNF-4α binding site within enhancer I. Coimmunoprecipitation assays showed an interaction between ER-α and HNF-4α; this interaction prevented HNF-4α binding to enhancer I and activation of HBV transcription.
  
  
  CONCLUSIONS
  Estrogen can repress transcription of HBV genes by up-regulating ER-α, which interacts with and alters binding of HNF-4α to the HBV enhancer I. These findings might account for the lower viral load and reduced incidence of liver cancer in HBV-infected women than men.
authors.affiliation: Department of Microbiology, National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Sheng-Han
authors.initials: SH
authors.lastname: Wang
authors.forename: Shiou-Hwei
authors.initials: SH
authors.lastname: Yeh
authors.forename: Wei-Hsiang
authors.initials: WH
authors.lastname: Lin
authors.forename: Kun-Huei
authors.initials: KH
authors.lastname: Yeh
authors.forename: Quan
authors.initials: Q
authors.lastname: Yuan
authors.forename: Ning-Shao
authors.initials: NS
authors.lastname: Xia
authors.forename: Ding-Shinn
authors.initials: DS
authors.lastname: Chen
authors.forename: Pei-Jer
authors.initials: PJ
authors.lastname: Chen
mesh_terms: D000818:Animals; D001665:Binding Sites; D004279:DNA, Viral / Q000378:metabolism; D004343:Drug Implants; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D015914:Estrogen Replacement Therapy; D004967:Estrogens / Q000008:administration & dosage; D005260:Female; D015967:Gene Expression Regulation, Viral; D056945:Hep G2 Cells; D006515:Hepatitis B virus / Q000235:genetics* / Q000254:growth & development; D051557:Hepatocyte Nuclear Factor 4 / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism* / Q000821:virology*; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010052:Ovariectomy; D012333:RNA, Messenger / Q000378:metabolism; D012737:Sex Factors; D015398:Signal Transduction; D014158:Transcription, Genetic; D014162:Transfection; D019562:Viral Load; D014779:Virus Replication
chemical_list: D004279:DNA, Viral; D004343:Drug Implants; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D004967:Estrogens; C496592:HNF4A protein, human; D051557:Hepatocyte Nuclear Factor 4; C496593:Hnf4a protein, mouse; D012333:RNA, Messenger; D006655:Histone Deacetylases