Ischemic preconditioning (IP) has been shown to protect hepatic tissue from liver ischemia-reperfusion injury (IRI). TGR5, as a new-type bile acid receptor, has been shown protective roles in several liver diseases. However, the relationship between TGR5 and IP is still unknown. This study investigated effects of IP on TGR5 as well as the roles of TGR5 on hepatic tissue lesions and apoptosis in liver IRI. We showed that TGR5 was significantly upregulated in liver tissues after IP. To further analyzed effects of the TGR5 on liver IRI, wild type and TGR5 knockout mice were used to establish the liver IRI model. IP effectively alleviated liver IRI, but TGR5 deficiency significantly neutralized IP-related liver protection, as evidenced by serum alanine aminotransferase levels, histological liver damage, hepatocellular apoptosis and cytokines expressions. In addition, molecules related to apoptosis were detected by Western Blot, which showed that activation of TGR5 by IP increased expression of Bcl-2, and inhibited expressions of IRAK4 and cleaved caspase-3, but TGR5 deficiency abolished IP-induced expressions of anti-apoptosis molecule. In vitro, effects of TGR5 on hepatocytes were further analyzed by TGR5 agonist (INT-777) and hypoxia/reoxygenation (H/R), which displayed that INT-777 markedly attenuated H/R-induced hepatocellular apoptosis. In conclusion, our study indicates that IP alleviates hepatocellular apoptosis, and reduces liver IRI through TGR5-mediated anti-apoptosis functions. (C) 2016 Elsevier Inc. All rights reserved.