Background: FXR is a ligand-dependent transcription factor belonging to the nuclear hormone receptor superfamily, which plays important roles in lipid metabolism, glucose homeostasis, inflammatory responses and cell apoptosis . It has been reported that FXR contributes to myocardial IRI via regulating apoptosis. We hypothesized that FXR may play an important role in the hepatic IRI. Methods&Results: The murine IRI model was performed with liver warm ischemia (60min) and reperfusion (0-6h). In WT control, the expression of FXR was significantly upregulated at 2h after hepatic IR. Pretreatment with FXR Agonist,GW4064(i.v. 1h prior ischemia ),could protect liver against IRI, as shown by ALT levels(5997±1758U/L vs. 10904±1413U/L in WT controls, p<0.05). The HE staining showed that GW4064+ IR group had a lower degree of necrosis compared with the IR group. In addition, hepatic IRI in FXR-KO mice were markedly aggravated as compared to WT littermates, evidenced by ALT levels (13515±556U/L vs. 10376±1291U/L in controls, p<0.05), and the hepatoprotection by GW4064 was not observed in FXR-KO mice(11104±973U/L). We hepothesized that FXR plays its protective role during hepatic I/R via the activation of PI 3-kinase/Akt (PI3K/Akt) pathway. We then investigated the effect of GW4064 and IR on Akt phosphorylation. IR and GW4064 had no effect on total AKT expression. In WT livers subjected to IR without GW4064, a significant time-dependent increase of Akt phosphorylation was observed at 2 hours after the beginning of reperfusion. In GW4064 pretreated group, Akt phosphorylation was observed much earlier, starting at 30 min after reperfusion. Strikingly, Akt phosphorylation was diminished in FXR-KO IR-livers with and without GW4064 pretreatment. The GW4064 and IR induced Akt phosphorylation was attenuated by PI3K inhibitors, wortmaning ( i.v. 75min prior to 60min ischemia ). In parallel , the protective effect of GW4064 on hepatic IRI was completely abolished by the treatment with PI3K inhibitors.

Conclusion: Activation of FXR may provide a new therapeutic strategies against hepatic IRI in clinical settings. Additionally, the PI3K/Akt pathway plays an essential role in the protective effects of FXR in hepatic IRI.

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