Negative regulation of pro-apoptotic AMPK/JNK pathway by itaconate in mice with fulminant liver injury.
Cell Death Dis
; 14(7): 486, 2023 07 31.
Article
em En
| MEDLINE
| ID: mdl-37524706
ABSTRACT
Accumulating evidence indicates that metabolic responses are deeply integrated into signal transduction, which provides novel opportunities for the metabolic control of various disorders. Recent studies suggest that itaconate, a highly concerned bioactive metabolite catalyzed by immune responsive gene 1 (IRG1), is profoundly involved in the regulation of apoptosis, but the underlying mechanisms have not been fully understood. In the present study, the molecular mechanisms responsible for the apoptosis-modulatory activities of IRG1/itaconate have been investigated in mice with lipopolysaccharide (LPS)/D-galactosamine (D-Gal)-induced apoptotic liver injury. The results indicated that LPS/D-Gal exposure upregulated the level of IRG1 and itaconate. Deletion of IRG1 resulted in exacerbated hepatocytes apoptosis and liver injury. The phospho-antibody microarray analysis and immunoblot analysis indicated that IRG1 deletion enhanced the activation of AMP-activated protein kinase (AMPK)/c-jun-N-terminal kinase (JNK) pathway in LPS/D-Gal exposed mice. Mechanistically, IRG1 deficiency impaired the anti-oxidative nuclear factor erythroid-2 related factor 2 (Nrf2) signaling and then enhanced the activation of the redox-sensitive AMPK/JNK pathway that promotes hepatocytes apoptosis. Importantly, post-insult supplementation with 4-octyl itaconate (4-OI), a cell-permeable derivate of itaconate, resulted in beneficial outcomes in fulminant liver injury. Therefore, IRG1/itaconate might function as a negative regulator that controls AMPK-induced hepatocyte apoptosis in LPS/D-Gal-induced fulminant liver injury.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Sistema de Sinalização das MAP Quinases
/
Proteínas Quinases Ativadas por AMP
Limite:
Animals
Idioma:
En
Revista:
Cell Death Dis
Ano de publicação:
2023
Tipo de documento:
Article
País de afiliação:
China