The deubiquitinating enzyme cylindromatosis mitigates nonalcoholic steatohepatitis.
Nat Med
; 24(2): 213-223, 2018 02.
Article
em En
| MEDLINE
| ID: mdl-29291351
ABSTRACT
Nonalcoholic steatohepatitis (NASH) is a common clinical condition that can lead to advanced liver diseases. Lack of effective pharmacotherapies for NASH is largely attributable to an incomplete understanding of its pathogenesis. The deubiquitinase cylindromatosis (CYLD) plays key roles in inflammation and cancer. Here we identified CYLD as a suppressor of NASH in mice and in monkeys. CYLD is progressively degraded upon interaction with the E3 ligase TRIM47 in proportion to NASH severity. We observed that overexpression of Cyld in hepatocytes concomitantly inhibits lipid accumulation, insulin resistance, inflammation and fibrosis in mice with NASH induced in an experimental setting. Mechanistically, CYLD interacts directly with the kinase TAK1 and removes its K63-linked polyubiquitin chain, which blocks downstream activation of the JNK-p38 cascades. Notably, reconstitution of hepatic CYLD expression effectively reverses disease progression in mice with dietary or genetically induced NASH and in high-fat diet-fed monkeys predisposed to metabolic syndrome. Collectively, our findings demonstrate that CYLD mitigates NASH severity and identify the CYLD-TAK1 axis as a promising therapeutic target for management of the disease.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Cisteína Endopeptidases
/
MAP Quinase Quinase Quinases
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Hepatopatia Gordurosa não Alcoólica
/
Inflamação
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Nat Med
Assunto da revista:
BIOLOGIA MOLECULAR
/
MEDICINA
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
China