Metabolism: clinical and experimental · 2026
Macrophage-enriched GPR91 aggravates acute liver injury by inhibiting efferocytosis via the AC/cAMP/PPARγ pathway.
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Qiu Shaotian, Hu Jiaxuan, Guo Kefei, Shao Shuai, Zhang Qian, He Yifan, Zheng Lina, Shi Zhemin, Zhang Kun, Hong Wei, Han Tao
Аннотация
OBJECTIVE: Acute liver injury is a common precipitating factor in the progression of various liver diseases including liver failure, underscoring the urgent need to identify novel therapeutic targets. G-protein coupled receptors (GPCRs) are widely regarded as promising drug targets, however, the roles of non-chemokine GPCRs in acute liver injury remain poorly defined. In this study, we analyzed three GEO datasets related to acute liver injury and identified Sucnr1, encoding GPR91, as a key regulator. We aimed to reveal the role of GPR91 in acute liver injury and to elucidate the underlying mechanism.
METHODS: Sucnr1-knockout (Sucnr1-KO) mice were generated and treated by carbon tetrachloride (CCl4) with or without succinate co-administration. The role of GPR91 was investigated in the acute and resolution stages of liver injury at 24 h and 72 h after CCl4 injection, respectively. Confocal microscopy and flow cytometry were conducted to examine the involvement of GPR91 in regulating macrophage efferocytosis, in vitro.
RESULTS: Macrophage-enriched Sucnr1 decreased sharply in the acute phase but recovered gradually in the resolution phase. In contrast, succinate, the endogenous GPR91 ligand, surged acutely and, subsequently, exhibited a gradual decline. In vivo data from multiple models demonstrated that Sucnr1 deficiency significantly alleviated CCl4-induced inflammation and injury in the acute stage and promoted injury resolution in the resolution stage, while succinate administration itself had no significant effect. Moreover, in vitro data revealed that Sucnr1-knockout (Sucnr1-KO) macrophages manifested lower expression of pro-inflammatory cytokines and higher ability of efferocytosis, accompanied by higher expression of PPARγ. However, the enhanced efferocytosis in macrophages of Sucnr1-KO mice was decreased by in vitro treatment of GW9662, a specific inhibitor of PPARγ. In addition, adenylate cyclase inhibitor SQ22536 could decrease the over-expression of PPARγ, and the enhanced efferocytosis in Sucnr1-KO macrophages.
CONCLUSION: Our work has revealed that macrophage-enriched GPR91 plays a vital role in controlling the inflammation and efferocytosis of macrophage, providing a potential therapeutic target for acute liver injury and liver failure.
METHODS: Sucnr1-knockout (Sucnr1-KO) mice were generated and treated by carbon tetrachloride (CCl4) with or without succinate co-administration. The role of GPR91 was investigated in the acute and resolution stages of liver injury at 24 h and 72 h after CCl4 injection, respectively. Confocal microscopy and flow cytometry were conducted to examine the involvement of GPR91 in regulating macrophage efferocytosis, in vitro.
RESULTS: Macrophage-enriched Sucnr1 decreased sharply in the acute phase but recovered gradually in the resolution phase. In contrast, succinate, the endogenous GPR91 ligand, surged acutely and, subsequently, exhibited a gradual decline. In vivo data from multiple models demonstrated that Sucnr1 deficiency significantly alleviated CCl4-induced inflammation and injury in the acute stage and promoted injury resolution in the resolution stage, while succinate administration itself had no significant effect. Moreover, in vitro data revealed that Sucnr1-knockout (Sucnr1-KO) macrophages manifested lower expression of pro-inflammatory cytokines and higher ability of efferocytosis, accompanied by higher expression of PPARγ. However, the enhanced efferocytosis in macrophages of Sucnr1-KO mice was decreased by in vitro treatment of GW9662, a specific inhibitor of PPARγ. In addition, adenylate cyclase inhibitor SQ22536 could decrease the over-expression of PPARγ, and the enhanced efferocytosis in Sucnr1-KO macrophages.
CONCLUSION: Our work has revealed that macrophage-enriched GPR91 plays a vital role in controlling the inflammation and efferocytosis of macrophage, providing a potential therapeutic target for acute liver injury and liver failure.