C/EBP homologous protein modulates liraglutide-mediated attenuation of non-alcoholic steatohepatitis.
Lab Invest
; 96(8): 895-908, 2016 08.
Article
em En
| MEDLINE
| ID: mdl-27239734
ABSTRACT
The CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP), a major transcriptional regulator of endoplasmic reticulum (ER) stress-mediated apoptosis, is implicated in lipotoxicity-induced ER stress and hepatocyte apoptosis in non-alcoholic fatty liver disease (NAFLD). We have previously demonstrated that the glucagon-like peptide-1 (GLP-1) agonist, liraglutide, protects steatotic hepatocytes from lipotoxicity-induced apoptosis by improved handling of free fatty acid (FFA)-induced ER stress. In the present study, we investigated whether CHOP is critical for GLP-1-mediated restoration of ER homeostasis and mitigation of hepatocyte apoptosis in a murine model of NASH (non-alcoholic steatohepatitis). Our data show that despite similar caloric intake, CHOP KO (CHOP(-/-)) mice fed a diet high in fat, fructose, and cholesterol (HFCD) for 16 weeks developed more severe histological features of NASH compared with wild-type (WT) controls. Severity of NASH in HFCD-fed CHOP(-/-) mice correlated with significant decrease in peroxisomal ß-oxidation, and increased de novo lipogenesis and ER stress-mediated hepatocyte apoptosis. Four weeks of liraglutide treatment markedly attenuated steatohepatitis in HFCD-fed WT mice by improving insulin sensitivity, and suppressing de novo lipogenesis and ER stress-mediated hepatocyte apoptosis. However, in the absence of CHOP, liraglutide did not improve insulin sensitivity, nor suppress peroxisomal ß-oxidation or ER stress-mediated hepatocyte apoptosis. Taken together, these data indicate that CHOP protects hepatocytes from HFCD-induced ER stress, and has a significant role in the mechanism of liraglutide-mediated protection against NASH pathogenesis.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fator de Transcrição CHOP
/
Hepatopatia Gordurosa não Alcoólica
/
Liraglutida
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Lab Invest
Ano de publicação:
2016
Tipo de documento:
Article
País de afiliação:
Gabão