TM7SF3 controls TEAD1 splicing to prevent MASH-induced liver fibrosis.
Cell Metab
; 36(5): 1030-1043.e7, 2024 May 07.
Article
en En
| MEDLINE
| ID: mdl-38670107
ABSTRACT
The mechanisms of hepatic stellate cell (HSC) activation and the development of liver fibrosis are not fully understood. Here, we show that deletion of a nuclear seven transmembrane protein, TM7SF3, accelerates HSC activation in liver organoids, primary human HSCs, and in vivo in metabolic-dysfunction-associated steatohepatitis (MASH) mice, leading to activation of the fibrogenic program and HSC proliferation. Thus, TM7SF3 knockdown promotes alternative splicing of the Hippo pathway transcription factor, TEAD1, by inhibiting the splicing factor heterogeneous nuclear ribonucleoprotein U (hnRNPU). This results in the exclusion of the inhibitory exon 5, generating a more active form of TEAD1 and triggering HSC activation. Furthermore, inhibiting TEAD1 alternative splicing with a specific antisense oligomer (ASO) deactivates HSCs in vitro and reduces MASH diet-induced liver fibrosis. In conclusion, by inhibiting TEAD1 alternative splicing, TM7SF3 plays a pivotal role in mitigating HSC activation and the progression of MASH-related fibrosis.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Factores de Transcripción
/
Proteínas de Unión al ADN
/
Factores de Transcripción de Dominio TEA
/
Cirrosis Hepática
Límite:
Animals
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Humans
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Male
Idioma:
En
Revista:
Cell Metab
Asunto de la revista:
METABOLISMO
Año:
2024
Tipo del documento:
Article
País de afiliación:
Estados Unidos