Inhibition of SIRT2 suppresses hepatic fibrosis.
Am J Physiol Gastrointest Liver Physiol
; 310(11): G1155-68, 2016 06 01.
Article
em En
| MEDLINE
| ID: mdl-27125275
ABSTRACT
Liver fibrosis can progress to cirrhosis and result in serious complications of liver disease. The pathogenesis of liver fibrosis involves the activation of hepatic stellate cells (HSCs), the underlying mechanisms of which are not fully known. Emerging evidence suggests that the classic histone deacetylases play a role in liver fibrosis, but the role of another subfamily of histone deacetylases, the sirtuins, in the development of hepatic fibrosis remains unknown. In this study, we found that blocking the activity of sirtuin 2 (SIRT2) by using inhibitors or shRNAs significantly suppressed fibrogenic gene expression in HSCs. We further demonstrated that inhibition of SIRT2 results in the degradation of c-MYC, which is important for HSC activation. In addition, we discovered that inhibition of SIRT2 suppresses the phosphorylation of ERK, which is critical for the stabilization of c-MYC. Moreover, we found that Sirt2 deficiency attenuates the hepatic fibrosis induced by carbon tetrachloride (CCl4) and thioacetamide (TAA). Furthermore, we showed that SIRT2, p-ERK, and c-MYC proteins are all overexpressed in human hepatic fibrotic tissues. These data suggest a critical role for the SIRT2/ERK/c-MYC axis in promoting hepatic fibrogenesis. Inhibition of the SIRT2/ERK/c-MYC axis represents a novel strategy to prevent and to potentially treat liver fibrosis and cirrhosis.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Sirtuína 2
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Cirrose Hepática
Tipo de estudo:
Etiology_studies
/
Observational_studies
Limite:
Adult
/
Aged
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Animals
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Revista:
Am J Physiol Gastrointest Liver Physiol
Assunto da revista:
FISIOLOGIA
/
GASTROENTEROLOGIA
Ano de publicação:
2016
Tipo de documento:
Article