Ischemia/reperfusion (I/R) injury is responsible for liver injury during hepatic resection and liver transplantation. The plasma membrane-bound G protein-coupled bile acid receptor (TGR5) could regulate immune response in multiple liver diseases. Nevertheless, the underlying role of TGR5 in hepatic I/R injury remains largely unknown. This study aimed to investigate the potential mechanism of TGR5 in hepatic I/R injury. Wild-type (WT) and TGR5 knockout (TGR5KO) mice were used to perform hepatic I/R, and macrophages were isolated from mice for in vitro experiments. The results demonstrated that knockout of TGR5 in mice significantly exacerbated liver injury and inflammatory response. TGR5KO mice infused with WT macrophages showed relieved liver injury. Further study revealed that TGR5 knockout inhibited sirtuin 3 (SIRT3) and forkhead box O3 (FOXO3) expression. In vitro experiments indicated that SIRT3 inhibited acetylation, ubiquitination and degradation of FOXO3. FOXO3 inhibited HIF-1α transcription by binding to its promoter. TGR5 knockout inhibited SIRT3 expression, thus promoted the acetylation, ubiquitination, and degradation of FOXO3, which resulted in increased HIF-1α transcription and macrophages proinflammatory response. Collectively, TGR5 plays a critical protective role in hepatic I/R injury. FOXO3 deacetylation mediated by SIRT3 can attenuate hepatic I/R injury. TGR5 deficiency aggravates hepatic I/R injury via inhibiting SIRT3/FOXO3/HIF-1α pathway.

缺血/再灌注（I / R）损伤是肝切除和肝移植期间肝损伤的原因。质膜结合的G蛋白偶联胆汁酸受体（TGR5）可以调节多种肝脏疾病的免疫反应。然而，TGR5在肝I / R损伤中的潜在作用仍然未知。这项研究旨在调查TGR5在肝脏I / R损伤中的潜在机制。使用野生型（WT）和TGR5敲除（TGR5KO）小鼠进行肝I / R，并从小鼠中分离出巨噬细胞用于体外实验。结果表明，敲除小鼠中的TGR5会显着加剧肝损伤和炎症反应。输注WT巨噬细胞的TGR5KO小鼠表现出减轻的肝损伤。进一步的研究表明，TGR5敲除可抑制sirtuin 3（SIRT3）和叉头盒O3（FOXO3）的表达。体外实验表明，SIRT3抑制FOXO3的乙酰化，泛素化和降解。FOXO3通过与其启动子结合来抑制HIF-1α转录。TGR5基因敲除抑制SIRT3表达，从而促进FOXO3的乙酰化，泛素化和降解，从而导致HIF-1α转录增加和巨噬细胞促炎反应。总的来说，TGR5在肝I / R损伤中起着至关重要的保护作用。SIRT3介导的FOXO3脱乙酰基作用可以减轻肝脏I / R损伤。TGR5缺乏症通过抑制SIRT3 / FOXO3 /HIF-1α途径加重了肝I / R损伤。FOXO3通过与其启动子结合来抑制HIF-1α转录。TGR5基因敲除抑制SIRT3表达，从而促进FOXO3的乙酰化，泛素化和降解，从而导致HIF-1α转录增加和巨噬细胞促炎反应。总的来说，TGR5在肝I / R损伤中起着至关重要的保护作用。SIRT3介导的FOXO3脱乙酰基作用可以减轻肝脏I / R损伤。TGR5缺乏症通过抑制SIRT3 / FOXO3 /HIF-1α途径加重了肝I / R损伤。FOXO3通过与其启动子结合来抑制HIF-1α转录。TGR5基因敲除抑制SIRT3表达，从而促进FOXO3的乙酰化，泛素化和降解，从而导致HIF-1α转录增加和巨噬细胞促炎反应。总的来说，TGR5在肝I / R损伤中起着至关重要的保护作用。SIRT3介导的FOXO3脱乙酰基作用可以减轻肝脏I / R损伤。TGR5缺乏症通过抑制SIRT3 / FOXO3 /HIF-1α途径加重了肝I / R损伤。SIRT3介导的FOXO3脱乙酰基作用可以减轻肝脏I / R损伤。TGR5缺乏症通过抑制SIRT3 / FOXO3 /HIF-1α途径加重了肝I / R损伤。SIRT3介导的FOXO3脱乙酰基作用可以减轻肝脏I / R损伤。TGR5缺乏症通过抑制SIRT3 / FOXO3 /HIF-1α途径加重了肝I / R损伤。