Estrogen receptor α represses transcription of HBV genes via interaction with hepatocyte nuclear factor 4α
Journal
Gastroenterology
Journal Volume
142
Journal Issue
4
Pages
989-998.e4
Date Issued
2012
Author(s)
Abstract
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)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-αmediated 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. ? 2012 AGA Institute.
SDGs
Other Subjects
estrogen; estrogen receptor alpha; hepatocyte nuclear factor 4alpha; histone deacetylase; messenger RNA; animal experiment; animal model; article; binding site; cancer risk; controlled study; disease course; DNA binding; down regulation; enzyme activity; female; gene control; gene repression; genetic transcription; hepatitis B; Hepatitis B virus; human; human cell; immunoprecipitation; life cycle; liver cell; male; mouse; nonhuman; ovariectomy; priority journal; receptor upregulation; replicon; virus gene; virus load; virus replication; virus transcription
Publisher
W.B. Saunders
Type
journal article