GPR116 alleviates acetaminophen-induced liver injury in mice by inhibiting endoplasmic reticulum stress.
Cell Mol Life Sci
; 81(1): 299, 2024 Jul 13.
Article
en En
| MEDLINE
| ID: mdl-39001944
ABSTRACT
BACKGROUND:
Acetaminophen (APAP) overdose is a significant contributor to drug-induced liver injury worldwide. G-protein-coupled receptor 116 (GPR116) is an important homeostatic maintenance molecule in the body, but little is known about its role in APAP-induced liver injury (AILI).METHODS:
GPR116 expression was determined in both human and mouse AILI models. Hepatic function and damage response were analyzed in hepatocyte-specific GPR116 deletion (GPR116â³HC) mice undergoing APAP challenge. RNA-sequencing, immunofluorescence confocal, and co-immunoprecipitation (CO-IP) were employed to elucidate the impact and underlying mechanisms of GPR116 in AILI.RESULTS:
Intrahepatic GPR116 was upregulated in human and mice with AILI. GPR116â³HC mice were vulnerable to AILI compared to wild-type mice. Overexpression of GPR116 effectively mitigated AILI in wild-type mice and counteracted the heightened susceptibility of GPR116â³HC mice to APAP. Mechanistically, GPR116 inhibits the binding immunoglobulin protein (BiP), a critical regulator of ER function, through its interaction with ß-arrestin1, thereby mitigating ER stress during the early stage of AILI. Additionally, the activation of GPR116 by ligand FNDC4 has been shown to confer a protective effect against early hepatotoxicity caused by APAP in murine model.CONCLUSIONS:
Upregulation of GPR116 on hepatocytes inhibits ER stress by binding to ß-arrestin1, protecting mice from APAP-induced hepatotoxicity. GPR116 may serve as a promising therapeutic target for AILI.Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Receptores Acoplados a Proteínas G
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Enfermedad Hepática Inducida por Sustancias y Drogas
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Estrés del Retículo Endoplásmico
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Acetaminofén
Límite:
Animals
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Humans
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Male
Idioma:
En
Revista:
Cell Mol Life Sci
Asunto de la revista:
BIOLOGIA MOLECULAR
Año:
2024
Tipo del documento:
Article
País de afiliación:
China