Tripartite motif-containing protein 31 confers protection against nonalcoholic steatohepatitis by deactivating mitogen-activated protein kinase kinase kinase 7.
Hepatology
; 77(1): 124-143, 2023 01 01.
Article
em En
| MEDLINE
| ID: mdl-35429173
ABSTRACT
BACKGROUND AIMS:
As a global health threat, NASH has been confirmed to be a chronic progressive liver disease that is strongly associated with obesity. However, no approved drugs or efficient therapeutic strategies are valid, mainly because its complicated pathological processes is underestimated. APPROACHRESULTS:
We identified the RING-type E3 ubiquitin transferase-tripartite motif-containing protein 31 (TRIM31), a member of the E3 ubiquitin ligases family, as an efficient endogenous inhibitor of transforming growth factor-beta-activated kinase 1 (mitogen-activated protein kinase kinase kinase 7; MAP3K7), and we further confirmed that TRIM31 is an MAP3K7-interacting protein and promotes MAP3K7 degradation by enhancing ubiquitination of K48 linkage in hepatocytes. Hepatocyte-specific Trim31 deletion blocks hepatic metabolism homeostasis, concomitant with glucose metabolic syndrome, lipid accumulation, up-regulated inflammation, and dramatically facilitates NASH progression. Inversely, transgenic overexpression, lentivirus, or adeno-associated virus-mediated Trim31 gene therapy restrain NASH in three dietary mice models. Mechanistically, in response to metabolic insults, TRIM31 interacts with MAP3K7 and conjugates K48-linked ubiquitination chains to promote MAP3K7 degradation, thus blocking MAP3K7 abundance and its downstream signaling cascade activation in hepatocytes.CONCLUSIONS:
TRIM31 may serve as a promising therapeutic target for NASH treatment and associated metabolic disorders.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Ubiquitina-Proteína Ligases
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Hepatopatia Gordurosa não Alcoólica
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Proteínas com Motivo Tripartido
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article