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 (GPR116△HC) 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△HC 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△HC 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.
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△HC) 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△HC 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△HC 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.
摘要：
背景：对乙酰氨基酚（APAP）过量是全球药物性肝损伤的重要原因。G蛋白偶联受体116(GPR116)是体内重要的稳态维持分子,但对其在APAP诱导的肝损伤（AILI）中的作用知之甚少。
方法:在人和小鼠AILI模型中测定GPR116表达。在进行APAP攻击的肝细胞特异性GPR116缺失（GPR116△HC）小鼠中分析了肝功能和损伤反应。RNA测序，免疫荧光共聚焦，和免疫共沉淀（CO-IP）用于阐明GPR116在AILI中的影响和潜在机制。
结果：肝内GPR116在患有AILI的人和小鼠中上调。与野生型小鼠相比，GPR116△HC小鼠易受AILI的影响。GPR116的过表达有效减轻了野生型小鼠的AILI，并抵消了GPR116△HC小鼠对APAP的敏感性。机械上,GPR116抑制结合免疫球蛋白（BiP），ER功能的关键调节器，通过其与β-arrestin1的相互作用，从而减轻AILI早期的内质网应激。此外,在小鼠模型中,配体FNDC4激活GPR116对APAP引起的早期肝毒性具有保护作用.
结论：GPR116上调肝细胞通过与β-arrestin1结合抑制内质网应激，保护小鼠免受APAP诱导的肝毒性。GPR116可以作为AILI的有希望的治疗靶标。
方法:在人和小鼠AILI模型中测定GPR116表达。在进行APAP攻击的肝细胞特异性GPR116缺失（GPR116△HC）小鼠中分析了肝功能和损伤反应。RNA测序，免疫荧光共聚焦，和免疫共沉淀（CO-IP）用于阐明GPR116在AILI中的影响和潜在机制。
结果：肝内GPR116在患有AILI的人和小鼠中上调。与野生型小鼠相比，GPR116△HC小鼠易受AILI的影响。GPR116的过表达有效减轻了野生型小鼠的AILI，并抵消了GPR116△HC小鼠对APAP的敏感性。机械上,GPR116抑制结合免疫球蛋白（BiP），ER功能的关键调节器，通过其与β-arrestin1的相互作用，从而减轻AILI早期的内质网应激。此外,在小鼠模型中,配体FNDC4激活GPR116对APAP引起的早期肝毒性具有保护作用.
结论：GPR116上调肝细胞通过与β-arrestin1结合抑制内质网应激，保护小鼠免受APAP诱导的肝毒性。GPR116可以作为AILI的有希望的治疗靶标。
