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Author: [email protected]
Date: 2012-01-17 01:44 +100
Subject: Estrogen Receptor-a Represses Transcription of HBV Genes via Interaction with Hepatocyte Nuclear Factor 4a
Gastroenterology. 2012 Jan 9. [Epub ahead of print]
Estrogen Receptor-? Represses Transcription of HBV Genes via Interaction with Hepatocyte Nuclear Factor 4?
Wang SH, Yeh SH, Lin WH, Yeh KH, Yuan Q, Xia NS, Chen DS, Chen PJ.
Department of Microbiology, National Taiwan University College of Medicine, Taipei, Taiwan.
BACKGROUND & AIMS: Women with hepatitis B virus (HBV) infection usually have lower viral loads than men, reducing their risk for liver cancer. There are two androgen-responsive elements in the HBV enhancer I, which contribute to higher viral titers in men. We investigated whether and how estrogen signaling interacts 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)? was increased by estrogen exposure. In HepG2 cells, upregulation of ER? reduced HBV transcription, which required a specific region within enhancer I. Direct DNA-binding of ER? and histone deacetylase activity were not required for ERa-mediated repression of HBV genes. Overexpression of hepatocyte nuclear factor (HNF)4?, which binds to this region, overcame the repressive effect of ER?. ER? did not repress transcription of an HBV replicon with a mutant HNF4a-binding site within enhancer I. Co-immunoprecipitation assays demonstrated an interaction between ERa and HNF4?; this interaction prevented HNF4a binding to enhancer I and activation of HBV transcription.
CONCLUSIONS: Estrogen can repress transcription of HBV genes by upregulating ER?, which interacts with and alters binding of HNF4? 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.