Abstract
BackgroundHepatitis D virus (HDV) infection may induce fulminant hepatitis in chronic hepatitis B patients (CHB) or rapid progression of CHB to cirrhosis or hepatocellular carcinoma. There is no effective treatment for HDV infection. HDV encodes small delta antigens (S-HDAg) and large delta antigens (L-HDAg). S-HDAg is essential for HDV replication. Prenylated L-HDAg plays a key role in HDV assembly. Previous studies indicate that L-HDAg transactivates transforming growth factor beta (TGF-β) and induces epithelial-mesenchymal transition (EMT), possibly leading to liver fibrosis. However, the mechanism is unclear.MethodsThe mechanisms of the activation of Twist promoter by L-HDAg were investigated by luciferase reporter assay, chromatin immunoprecipitation, and co-immunoprecipitation analysis. ELISA and Western blotting were used to analyze L-HDAg prenylation, TGF-β secretion, expression of EMT markers, and to evaluate efficacy of statins for HDV treatment.ResultsWe found that L-HDAg activated Twist expression, TGF-β expression and consequently induced EMT, based on its interaction with Smad3 on Twist promoter. The treatment of statin, a prenylation inhibitor, resulted in reduction of Twist promoter activity, TGF-β expression, and EMT, and reduces the release of HDV virions into the culture medium.ConclusionsWe demonstrate that L-HDAg activates EMT via Twist and TGF-β activation. Treatment with statins suppressed Twist expression, and TGF-β secretion, leading to downregulation of EMT. Our findings clarify the mechanism of HDV-induced EMT, and provide a basis for possible novel therapeutic strategies against HDV infection.
Highlights
Hepatitis D virus (HDV) infection may induce fulminant hepatitis in chronic hepatitis B patients (CHB) or rapid progression of CHB to cirrhosis or hepatocellular carcinoma
Analysis of Twist promoter sequence using MatInspector [24] revealed two putative Smad3 sites clustered at the proximal promoter region with consensus Smad binding elements (SBEs) of CAG(AC)|(CC) (Fig. 1b)
Huh7 cells were transfected with either LHDAg- or S-HDV encodes delta antigens (HDAg)-expressing plasmid, and binding of L-HDAg to clustered SBE sites of Twist promoter were detected by chromatin immunoprecipitation (ChIP) assay using antiserum from delta antigen hepatitis patients
Summary
Hepatitis D virus (HDV) infection may induce fulminant hepatitis in chronic hepatitis B patients (CHB) or rapid progression of CHB to cirrhosis or hepatocellular carcinoma. HDV encodes small delta antigens (S-HDAg) and large delta antigens (L-HDAg). Prenylated L-HDAg plays a key role in HDV assembly. Hepatitis D virus (HDV) infection may induce fulminant hepatic failure or aggravate underlying chronic hepatitis B to liver cirrhosis, liver failure, or hepatocellular carcinoma (HCC); alternatively, it may display a slow, subclinical course [1,2,3]. S-HDAg is involved in transactivation of HDV RNA replication, while prenylated L-HDAg plays a key role in packaging of complete HDV virions through its interaction with SHDAg, HDV RNA, and HBsAg [4, 5]. HDV-1 is distributed worldwide, while HDV-2 and HDV-4 are restricted to certain Far Eastern regions such as Taiwan, Japan, and Yakutia [6,7,8,9]
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