Arrb2 in hepatocytes promotes M2 macrophage polarization, ameliorates hepatic ischemia–reperfusion injury through upregulating metabolite 6-ketoLCA

BACKGROUND: Hepatic ischemia-reperfusion injury (IRI) is an important factor affecting the prognosis of liver transplantation patients. The role of Arrb2 in liver injury is unclear. Our study aimed to determine the role of Arrb2 in hepatic IRI and to identify its underlying mechanisms. METHODS: An analysis of clinical samples was conducted to assess the association between Arrb2 expression and the prognosis of liver transplantation. A 70% hepatic ischemia/reperfusion model in mice was established to verify the mechanism of Arrb2 in hepatocytes promoting M2 macrophage polarization in attenuating hepatic IRI by regulating 6-ketoLCA. A model of hypoxia/reoxygenation in vitro was established to investigate the molecular mechanism of 6-ketoLCA in promoting M2 macrophage polarization and pharmacological screening. RESULTS: Arrb2 in hepatocytes has been shown to provide significant liver protection against hepatic IRI, primarily through promoting the polarization of liver macrophages to M2. Arrb2 remodels bile acids and upregulates 6-ketoLCA through Cyp7a1 in hepatocytes, promoting M2 polarization of macrophages, thereby alleviating hepatic IRI. Mechanistically, TGR5 plays a crucial role in promoting the induction of M2 polarization in macrophages by 6-ketoLCA. Pharmacological screening indicates that dutasteride enhances the activity of the Arrb2 promoter and upregulates Arrb2 expression in hepatocytes, thereby mitigating hepatic IRI. CONCLUSIONS: Arrb2 in hepatocytes attenuates hepatic IRI by promoting macrophages toward the M2 phenotype through bile acid. Moreover, dutasteride, a selective agonist of Arrb2, emerges as a promising targeted therapeutic agent for the clinical management of liver injury.