STUB1 increases adiponectin expression by inducing ubiquitination and degradation of NR2F2, thereby reducing hepatic stellate cell activation and alleviating non-alcoholic fatty liver disease.
Tissue Cell
; 88: 102345, 2024 Jun.
Article
em En
| MEDLINE
| ID: mdl-38471267
ABSTRACT
BACKGROUND:
Adiponectin (APN) has exhibited ameliorating effects on non-alcoholic fatty liver disease (NAFLD). This study investigates the roles of APN and its regulatory molecules in hepatic stellate cell (HSC) activation and the progression of NAFLD.METHODS:
Mice were subjected to a high-fat diet (HFD) to establish NAFLD models. Liver tissue was examined for lipid metabolism, fibrosis, and inflammation. Mouse 3T3-L1 adipocytes were exposed to palmitic acid (PA) to mimic a high-fat environment. The conditioned medium (CM) from adipocytes was collected for the culture of isolated mouse HSCs. Gain- or loss-of-function studies of APN, nuclear receptor subfamily 2 group F member 2 (NR2F2), and STIP1 homology and U-box containing protein 1 (STUB1) were performed to analyze their roles in NAFLD and HSC activation in vivo and in vitro.RESULTS:
APN expression was poorly expressed in HFD-fed mice and PA-treated 3T3-L1 adipocytes, which was attributed to the transcription inhibition mediated by NR2F2. Silencing of NR2F2 restored the APN expression, ameliorating liver steatosis, fibrosis, and inflammatory cytokine infiltration in mouse livers and reducing HSC activation. Similarly, the NR2F2 silencing condition reduced HSC activation in vitro. However, these effects were counteracted by artificial APN silencing. STUB1 facilitated the ubiquitination and protein degradation of NR2F2, and its upregulation mitigated NAFLD-like symptoms in mice and HSC activation, effects reversed by the NR2F2 overexpression.CONCLUSION:
This study highlights the role of STUB1 in reducing HSC activation and alleviating NAFLD by attenuating NR2F2-mediated transcriptional repression of APN.Palavras-chave
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Células 3T3-L1
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Ubiquitina-Proteína Ligases
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Adiponectina
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Ubiquitinação
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Células Estreladas do Fígado
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Hepatopatia Gordurosa não Alcoólica
Limite:
Animals
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article