Tyrosine kinase receptor B attenuates liver fibrosis by inhibiting TGF-ß/SMAD signaling.
Hepatology
; 78(5): 1433-1447, 2023 11 01.
Article
em En
| MEDLINE
| ID: mdl-36800849
ABSTRACT
BACKGROUND AND AIMS:
Liver fibrosis is a leading indicator for increased mortality and long-term comorbidity in NASH. Activation of HSCs and excessive extracellular matrix production are the hallmarks of liver fibrogenesis. Tyrosine kinase receptor (TrkB) is a multifunctional receptor that participates in neurodegenerative disorders. However, paucity of literature is available about TrkB function in liver fibrosis. Herein, the regulatory network and therapeutic potential of TrkB were explored in the progression of hepatic fibrosis. METHODS ANDRESULTS:
The protein level of TrkB was decreased in mouse models of CDAHFD feeding or carbon tetrachloride-induced hepatic fibrosis. TrkB suppressed TGF-ß-stimulated proliferation and activation of HSCs in 3-dimensional liver spheroids and significantly repressed TGF-ß/SMAD signaling pathway either in HSCs or in hepatocytes. The cytokine, TGF-ß, boosted Nedd4 family interacting protein-1 (Ndfip1) expression, promoting the ubiquitination and degradation of TrkB through E3 ligase Nedd4-2. Moreover, carbon tetrachloride intoxication-induced hepatic fibrosis in mouse models was reduced by adeno-associated virus vector serotype 6 (AAV6)-mediated TrkB overexpression in HSCs. In addition, in murine models of CDAHFD feeding and Gubra-Amylin NASH (GAN), fibrogenesis was reduced by adeno-associated virus vector serotype 8 (AAV8)-mediated TrkB overexpression in hepatocytes.CONCLUSION:
TGF-ß stimulated TrkB degradation through E3 ligase Nedd4-2 in HSCs. TrkB overexpression inhibited the activation of TGF-ß/SMAD signaling and alleviated the hepatic fibrosis both in vitro and in vivo . These findings demonstrate that TrkB could be a significant suppressor of hepatic fibrosis and confer a potential therapeutic target in hepatic fibrosis.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fator de Crescimento Transformador beta
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Hepatopatia Gordurosa não Alcoólica
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Cirrose Hepática
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Hepatology
Ano de publicação:
2023
Tipo de documento:
Article
País de afiliação:
China