GPR116 alleviates acetaminophen-induced liver injury in mice by inhibiting endoplasmic reticulum stress.

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 (GPR116) 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. GPR116 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 GPR116 mice to APAP. Mechanistically, GPR116 inhibits the binding immunoglobulin protein (BiP), a critical regulator of ER function, through its interaction with β-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 β-arrestin1, protecting mice from APAP-induced hepatotoxicity. GPR116 may serve as a promising therapeutic target for AILI.