Ubiquitin-Specific Protease 4 Is an Endogenous Negative Regulator of Metabolic Dysfunctions in Nonalcoholic Fatty Liver Disease in Mice.
Hepatology
; 68(3): 897-917, 2018 09.
Article
em En
| MEDLINE
| ID: mdl-29573006
ABSTRACT
Nonalcoholic fatty liver disease (NAFLD), characterized by hepatic steatosis (HS), insulin resistance (IR), and inflammation, poses a high risk of cardiometabolic disorders. Ubiquitin specific protease 4 (USP4), a deubiquitinating enzyme, is pivotally involved in regulating multiple inflammatory pathways; however, the role of USP4 in NAFLD is unknown. Here, we report that USP4 expression was dramatically down-regulated in livers from NAFLD patients and different NAFLD mouse models induced by high-fat diet (HFD) or genetic deficiency (ob/ob) as well as in palmitate-treated hepatocytes. Hepatocyte-specific USP4 depletion exacerbated HS, IR, and inflammatory response in HFD-induced NAFLD mice. Conversely, hepatic USP4 overexpression notably alleviated the pathological alterations in two different NAFLD models. Mechanistically, hepatocyte USP4 directly bound to and deubiquitinated transforming growth factor-ß activated kinase 1 (TAK1), leading to a suppression of the activation of downstream nuclear factor kappa B (NF-κB) and c-Jun N-terminal kinase (JNK) cascades, which, in turn, reversed the disruption of insulin receptor substrate/protein kinase B/glycogen synthase kinase 3 beta (IRS-AKT-GSK3ß) signaling. In addition, USP4-TAK1 interaction and subsequent TAK1 deubiquitination were required for amelioration of metabolic dysfunctions. Conclusion:
Collectively, the present study provides evidence that USP4 functions as a pivotal suppressor in NAFLD and related metabolic disorders. (Hepatology 2018; 00000-000).
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Proteases Específicas de Ubiquitina
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Hepatopatia Gordurosa não Alcoólica
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Fígado
Tipo de estudo:
Etiology_studies
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Prognostic_studies
Limite:
Animals
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Humans
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Male
Idioma:
En
Revista:
Hepatology
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
China