Background: Liver X Receptor Alpha (LXRα) is a transcription factor crucial for cholesterol, fatty acid, and glucose homeostasis. We hypothesize that LXRαKO may promote hepatocellular survival by promoting the hepatic antioxidant stress via the LXRα-fibroblast growth factor 21 (FGF21) pathway. Methods&Results: In our murine model of liver warm ischemia (90min) and reperfusion (0-12h), LXRαexpression peaked at 2h of reperfusion. Indeed, LXRα KO mice were resistant against liver IRI, as shown by sALT levels (3903±743U/L vs.7401±1080U/L in controls, p<0.0001) and liver histology, compared with WT controls. In parallel, intrahepatic expression of TNF-α, IL-1β, IL-6 and CXCL-10 were decreased in LXRαKO. We then assessed LXRαoverexpression (Adenovirus vector with LXRαgene) vs. WT livers (Adenovirus vector only) subjected to IR insult. Interestingly, hepatic LXRαoverexpression enhanced local injury, evidenced by increased sALT levels (14078±802U/Lvs.10220±877U/L in controls, p<0.01). Bone marrow transplantation was performed between the LXRαKO and WT mice.The LXRαKO recipients (WT⇒LXRαKO) have no significance with the other group of recipients (LXRαKO⇒LXRαKO), indicating that the LXRαKO plays an important role in the hepatocytes. We then focused on FGF21, the antioxidant stress downstream factor.The serum FGF21 was measured by ELISA,at 1h of reperfusion,the serum FGF21 was higher in LXRαKO IR-livers, as compared with WT controls (654±50U/Lvs.436±33U/L,p<0.001). To mimic in vivo settings, we used hydrogen peroxide (H2O2)-necrotic hepatocytes. Consistently, LXRαKO prevented H2O2-mediated hepatocyte necrosis in primary hepatocyte cultures in vitro. The cytoprotective effects of LXRαKO on hepatocytes were confirmed by decreased cytoplasmic LDH release, increased of FGF21. In contrast, addition of FGF21 SiRNA reversed LXRαKO-induced hepatocellular protection in vitro.Finally,intravenous of recombinant mouse FGF21 reversed LXRαoverexpression -induced hepatic injury in vivo.

Conclusion: This is the first study to provide evidence that LXRαKO may: 1) attenuate hepatocellular damage in pathophysiology of liver IRI; 2) enhance FGF21 expression; 3) exert cytoprotrotection via integrated LXRα-FGF21 signaling network in hepatocyte. These findings identify LXRα as a novel regulator of hepatocyte survival in a therapeutic regimen against organ IRI in transplant recipients.

« Back to 2015 American Transplant Congress