title: LXRalpha gene downregulation by lentiviral-based RNA interference enhances liver function after fatty liver transplantation in rats.
abstract: 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 (RNAi) 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 LXRalpha-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 LXRalpha-RNAi-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 RNAi 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 RNAi also decreased the expressions of sterol regulatory element-binding protein 1c (SREBP-1c) and CD36. LXRalpha RNAi consequently reduced fatty acid accumulation in hepatocytes. Compared with control animals, LXRalpha RNAi-treated 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 LXRalpha-RNAi-LV, and overall survival as determined by the Kaplan-Meier method was improved among rats treated with LXRalpha-RNAi-LV (P<0.05).
  
  
  CONCLUSIONS
  LXRalpha-RNAi-LV treatment significantly downregulated LXRalpha expression and improve steatotic liver graft function and recipient survival after a fatty liver transplantation in rats.
authors.affiliation: Department of Hepatobiliary and Transplantation Surgery, Ganmei Affiliated Hospital, Kunming Medical University, Kunming 650011, China. ynkmlili62@hotmail.com.
authors.forename: Ying-Peng
authors.initials: YP
authors.lastname: Zhao
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Jing-Pan
authors.initials: JP
authors.lastname: Ma
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.forename: Jian-Hua
authors.initials: JH
authors.lastname: Bai
mesh_terms: D000818:Animals; D017209:Apoptosis; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D015536:Down-Regulation; D005234:Fatty Liver / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000601:surgery*; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006085:Graft Survival; D016086:Lentivirus / Q000235:genetics*; D008099:Liver / Q000378:metabolism / Q000473:pathology / Q000601:surgery*; D016031:Liver Transplantation / Q000379:methods*; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics* / Q000378:metabolism; D000067492:RNAi Therapeutics / Q000379:methods*; D017207:Rats, Sprague-Dawley; D013997:Time Factors
chemical_list: D000071518:Liver X Receptors; C000605215:Nr1h3 protein, rat; D057093:Orphan Nuclear Receptors; D012333:RNA, Messenger; D034741:RNA, Small Interfering