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.