Small heterodimer partner attenuates profibrogenic features of hepatitis C virus-infected cells.
Liver Int
; 35(10): 2233-45, 2015 Oct.
Article
em En
| MEDLINE
| ID: mdl-25976932
ABSTRACT
BACKGROUND & AIMS:
An atypical orphan nuclear receptor small heterodimer partner (SHP) is known to be regulated by AMP-activated protein kinase (AMPK). Both of them inhibit TGF-ß and Smad signalling and exhibit antifibrotic activity in the liver. However, little is known about the protective effects of SHP and AMPK against hepatitis c virus (HCV)-induced hepatic fibrosis.METHODS:
Levels of SHP, p-AMPK and fibrotic markers in HCV-infected human liver and in Huh-7.5 cells infected with HCV genotype 2a (JFH-1) were investigated. The effect of adenovirus-mediated overexpression of SHP (Ad-SHP) and AMPK activation via metformin and 5-amino-1-b-D-ribofuranosyl-imidazole-4-carboxamide (AICAR) on fibrotic gene expression was evaluated in HCV-infected cells. Finally, we examined the effect of Ad-SHP and AMPK activators on invasion and activation of LX2 human HSCs induced by conditioned media from HCV-infected hepatocyte (CM).RESULTS:
In HCV-infected human livers and Huh-7.5 cells infected with HCV, SHP mRNA and protein levels were diminished compared with controls, whereas profibrotic factors were increased. Pharmacological AMPK activation recovered SHP expression, and Ad-SHP inhibited HCV-induced fibrotic gene expression. This finding was accompanied by inhibition of HCV-stimulated nuclear factor-kappa B, an inducer of TGF-ß. Moreover, CytoSelect invasion assay revealed that enhanced activity and invasiveness of hepatic stellate cells induced by CM.CONCLUSION:
These results demonstrate that overexpression of SHP and activation of AMPK reverses profibrogenic features of HCV-infected cells by decreasing TGF-ß and fibrotic gene expression. These findings provide a rationale for SHP as a possible therapeutic target against HCV-induced hepatic fibrosis.Palavras-chave
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Fator de Crescimento Transformador beta
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Receptores Citoplasmáticos e Nucleares
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Proteínas Quinases Ativadas por AMP
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Cirrose Hepática
Limite:
Humans
Idioma:
En
Revista:
Liver Int
Assunto da revista:
GASTROENTEROLOGIA
Ano de publicação:
2015
Tipo de documento:
Article