Estrogen Receptor α Represses Transcription of HBV Genes via Interaction With Hepatocyte Nuclear Factor 4α

BACKGROUND & AIMS: 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)-alpha was increased by estrogen exposure. In HepG2 cells, up-regulation of ER-alpha reduced HBV transcription, which required a specific region within enhancer I. Direct DNA binding of ER-alpha and histone deacetylase activity were not required for ER-alpha mediated repression of HBV genes. Overexpression of hepatocyte nuclear factor (HNF)-4 alpha, which binds to this region, overcame the repressive effect of ER-alpha. ER-alpha did not repress transcription of an HBV replicon with a mutant HNF-4 alpha binding site within enhancer I. Coimmunoprecipitation assays showed an interaction between ER-alpha and HNF-4 alpha; this interaction prevented HNF-4 alpha binding to enhancer I and activation of HBV transcription. CONCLUSIONS: Estrogen can repress transcription of HBV genes by up-regulating ER-alpha, which interacts with and alters binding of HNF-4 alpha 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.