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

BACKGROUND:Steatotic 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 (LXRalpha) is important in fatty acid metabolism and interrelated with the specific ischemia-reperfusion injury in fatty liver transplantation. This study aimed to investigate whether LXRalpha RNA interference could improve the organ function of liver transplant recipients. METHODS:Fifty 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 7X107 TU 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 LXRalpha-duanyu1615-LV were assessed by serum aminotransferases, histology, immunostaining, and protein levels. The transcription of LXRalpha mRNA was assessed by reverse transcription-polymerase chain reaction. RESULTS:Compared with controls, LXRalpha inhibited the expression of LXRalpha 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). LXRalpha duanyu1615 also decreased the expressions of sterol regulatory element-binding protein 1c (SREBP-1c) and CD36. LXRalpha duanyu1615 consequently reduced fatty acid accumulation in hepatocytes. Compared with control animals, LXRalpha group had lower serum alanine aminotransferase, aspartate aminotransferase, interleukin-1beta, 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 and overall survival as determined by the Kaplan-Meier method was improved among rats treated with LXRalpha-duanyu1615-LV treatment significantly downregulated LXRalpha expression and improve steatotic liver graft function and recipient survival after a fatty liver transplantation in rats.

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