The G-Protein-Coupled Bile Acid Receptor (TGR5), also called Gpbar1 or GPBA, is a G-protein coupled plasma membrane receptor for Bile acids (BAs) which is expressed by various liver cells. TGR5 has been implicated in the control of glucose homeostasis, inflammation and liver functions. However, there are few reports on the effects of TGR5 on liver ischemia/reperfusion injury (IRI). Here we have used a mouse liver ischemia/reperfusion model to analyze the effects of TGR5 on liver IRI and underlying mechenisms. We have found: 1. Expression of TGR5 was obviously increased in ischemic liver after reperfusion. 2. TGR5 knockout (KO) significantly increased liver IRI compared with wide type (WT) mice, as evidenced by increased serum ALT, histological liver damage, and hepatocellular apoptosis. In addtion, TGR5 agonist (Oleanolic Acid) effectively attenuated liver IRI in WT mice. 3. TGR5KO significantly promoted TLR4 innate immune responses in vivo based on cytokines expression (TNF-α, IL-6 and IL-10) and TLR4/NF-κB signaling. Oleanolic Acid (OA) markedly inhibited these TLR4 innate immune responses during liver IRI; 4. Interestingly, TGR5KO significantly inhibited NRF2/HO-1 signaling expression compared with WT mice. Furthermore, OA significantly activated NRF2/HO-1 signaling in ischemic liver in WT mice. Importantly, NRF2 activator, oltipraz (M2), effectively rescued TGR5KO-mediated TLR4 innate responses and liver IRI. These findings indicate TGR5 attenuate liver IRI by inhibiting TLR4 innate immune resposes through Nrf2/HO-1 signaling pathway. Our study documents a potential immune regulatory role of TGR5 in the mechanism of liver IRI and a rationale for a novel therapeutic strategy to manage liver IRI.

« Back to 2015 American Transplant Congress