Identification of androgen response elements in the enhancer I of hepatitis B virus: A mechanism for sex disparity in chronic hepatitis B
Journal
Hepatology
Journal Volume
50
Journal Issue
5
Pages
1392-1402
Date Issued
2009
Author(s)
Abstract
Hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) occurs more often in men than in women. Male HBV carriers usually have higher viral loads, which is a well-known risk factor for HCC. Whether and how the male androgen axis regulates HBV transcription and replication is investigated here. We used HBV transgenic mice to evaluate any sex disparity of serum hepatitis B surface antigen and HBV titers as well as the castration effect on this disparity. Compared to females, HBV transgenic male mice showed higher hepatitis B surface antigen and viral titers, which were lessened by castration of the males. In a cell culture system, HepG2 cells transfected with HBV and androgen receptor (AR) constructs were used to study the effect of the androgen pathway on viral transcription and replication. We found the ligand-stimulated AR could increase the transcription of HBV RNAs through its transcription activation domain. A genomic region within HBV enhancer I was identified that is responsible for the transcriptional activation of AR. The results from chromatin immunoprecipitation and in vitro binding assays further demonstrated a direct binding of AR to this region, in a ligand-dependent manner. Two androgen-responsive element motifs in this region were identified, and their mutations can significantly abolish the AR effects. Conclusion: This study demonstrated that the androgen pathway can increase the transcription of HBV through direct binding to the androgen-responsive element sites in viral enhancer I. This may explain a higher HBV titer in male carriers and an increased risk of HCC. Copyright ? 2009 by the American Association for the Study of Liver Diseases.
SDGs
Other Subjects
androgen receptor; hepatitis B surface antigen; virus RNA; animal experiment; animal model; animal tissue; article; cancer risk; cell strain HepG2; controlled study; enhancer region; female; gene mutation; hepatitis B; Hepatitis B virus; hormone responsive element; human; human cell; in vitro study; liver cell carcinoma; male; mouse; nonhuman; priority journal; receptor binding; RNA transcription; sex difference; transcription initiation; transcription regulation; transgenic mouse; viral genetics; virus carrier; virus replication; virus transcription
Publisher
John Wiley and Sons Inc.
Type
journal article