Statin inhibits large hepatitis delta antigen-Smad3 -twist-mediated epithelial-to-mesenchymal transition and hepatitis D virus secretion.
J Biomed Sci
; 27(1): 65, 2020 May 21.
Article
em En
| MEDLINE
| ID: mdl-32434501
ABSTRACT
BACKGROUND:
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. 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-ß) and induces epithelial-mesenchymal transition (EMT), possibly leading to liver fibrosis. However, the mechanism is unclear.METHODS:
The 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-ß secretion, expression of EMT markers, and to evaluate efficacy of statins for HDV treatment.RESULTS:
We found that L-HDAg activated Twist expression, TGF-ß 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-ß expression, and EMT, and reduces the release of HDV virions into the culture medium.CONCLUSIONS:
We demonstrate that L-HDAg activates EMT via Twist and TGF-ß activation. Treatment with statins suppressed Twist expression, and TGF-ß 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.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Hepatite D
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Proteínas Nucleares
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Vírus Delta da Hepatite
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Antígenos da Hepatite delta
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Proteína Smad3
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Proteína 1 Relacionada a Twist
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Transição Epitelial-Mesenquimal
Limite:
Humans
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article