LXRα gene downregulation by lentiviral-based RNA interference enhances liver function after fatty liver transplantation in rats

BackgroundSteatotic liver grafts, although accepted, increase the risk of poor posttransplantation liver function. However, the growing demand for adequate donor organs has led to the increased use of so-called marginal grafts. Liver X receptor alpha (LXRα) is important in fatty acid metabolism and interrelated with the specific ischemia-reperfusion injury in fatty liver transplantation. This study aimed to investigate whether LXRα RNA interference (RNAi) could improve the organ function of liver transplant recipients.MethodsFifty Sprague-Dawley rats were fed with a high-fat diet and 56% alcohol. The livers of these animals had greater than 60% macrovesicular steatosis and were used as liver donors. The experimental donors were treated with 7×107 TU LXRα-RNAi-LV of a mixture injection and control donors with negative control-LV vector injection into the portal vein 72 hours before the operation. The effects of LXRα-RNAi-LV were assessed by serum aminotransferases, histology, immunostaining, and protein levels. The transcription of LXRα mRNA was assessed by reverse transcription-polymerase chain reaction.ResultsCompared with controls, LXRα RNAi inhibited the expression of LXRα at the mRNA (0.53±0.03 vs 0.94±0.02, P<0.05) and protein levels (0.51±0.08 vs 1.09±0.12, P<0.05). LXRα RNAi also decreased the expressions of sterol regulatory element-binding protein 1c (SREBP-1c) and CD36. LXRα RNAi consequently reduced fatty acid accumulation in hepatocytes. Compared with control animals, LXRα RNAi-treated group had lower serum alanine aminotransferase, aspartate aminotransferase, interleukin-1β, and tumor necrosis factor-alpha levels and milder pathologic damages. TUNEL analysis revealed a significant reduction of apoptosis in the livers of rats treated with LXRα-RNAi-LV, and overall survival as determined by the Kaplan-Meier method was improved among rats treated with LXRα-RNAi-LV (P<0.05).ConclusionLXRα-RNAi-LV treatment significantly downregulated LXRα expression and improve steatotic liver graft function and recipient survival after a fatty liver transplantation in rats.