title: Steatotic liver allografts up-regulate UCP-2 expression and suffer necrosis in rats.
abstract: BACKGROUND
  Fatty split-liver and living-related liver transplantation is associated with massive hepatocellular necrosis during acute rejection. Uncoupling protein (UCP)-2 is a potential regulator of energy expenditure and ATP production. We investigated the role of UCP-2 and the effects of a metalloprotease inhibitor, Y-39083, on hepatocellular injury in fatty liver allografts in rats.
  
  
  METHODS
  Rats were treated for 6 weeks with high-ethanol or isocalic dextrose-containing liquid diets that caused characteristic pericentral lipid accumulation. Alcoholic or nonalcoholic fatty livers from ACI (RT1a) rats were transplanted into LEW (RT1l) rats orthotopically. Hepatic necrosis was determined histologically following liver transplantation. UCP-2 mRNA levels in the hepatic allograft and in primary cultured hepatocytes from fatty liver stimulated by tumor necrosis factor (TNF)-alpha were determined. Y-39083 was administered to recipient rats continuously at 5 mg/kg/day using an osmotic infusion mini-pump.
  
  
  RESULTS
  The acute rejection index on day 5 posttransplant in alcoholic and nonalcoholic fatty donor livers was higher than in lean grafts. Massive hepatocyte necrosis was more prominent in alcoholic than nonalcoholic fatty liver allografts and was not seen in lean allografts. UCP-2 transcripts in both alcoholic and nonalcoholic fatty liver allografts were higher than in lean allografts. Serum TNF-alpha concentrations in recipient rats with either fatty liver allograft were greater than in animals with lean allografts. In vitro UCP-2 mRNA levels in primary cultured hepatocytes from both alcoholic and nonalcoholic fatty livers increased more after stimulation with TNF-alpha than those from lean livers. In vitro TNF-alpha production by Kupffer cells isolated from alcohol-induced fatty liver allografts on day 3 posttransplant was greater than those from lean allografts. Y-39083 significantly reduced serum concentrations of TNF-alpha and prevented massive hepatocellular necrosis in rats with both alcoholic and nonalcoholic fatty liver allografts.
  
  
  CONCLUSIONS
  Liver grafts with steatosis up-regulated UCP-2. TNF-alpha further enhanced UCP-2 transcripts, inducing massive hepatocellular necrosis during acute rejection. Posttransplantation necrosis may be prevented by metalloprotease inhibitors.
authors.affiliation: Department of Surgery II, Kumamoto University Medical School, Kumamoto, Japan.
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Uchino
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Yamaguchi
authors.forename: Takashi
authors.initials: T
authors.lastname: Furuhashi
authors.forename: Feng-Shan
authors.initials: FS
authors.lastname: Wang
authors.forename: Jia-Lin
authors.initials: JL
authors.lastname: Zhang
authors.forename: Kazutoshi
authors.initials: K
authors.lastname: Okabe
authors.forename: Shinichi
authors.initials: S
authors.lastname: Kihara
authors.forename: Shinwa
authors.initials: S
authors.lastname: Yamada
authors.forename: Katsutaka
authors.initials: K
authors.lastname: Mori
authors.forename: Michio
authors.initials: M
authors.lastname: Ogawa
mesh_terms: D000818:Animals; D005234:Fatty Liver / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D006084:Graft Rejection / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects* / Q000473:pathology; D007473:Ion Channels; D007728:Kupffer Cells / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D016031:Liver Transplantation; D026901:Membrane Transport Proteins / Q000096:biosynthesis*; D024101:Mitochondrial Proteins / Q000096:biosynthesis*; D009336:Necrosis; D051381:Rats; D019714:Tissue Inhibitor of Metalloproteinases / Q000494:pharmacology; D014184:Transplantation, Homologous; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D000071246:Uncoupling Protein 2; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D007473:Ion Channels; D026901:Membrane Transport Proteins; D024101:Mitochondrial Proteins; D019714:Tissue Inhibitor of Metalloproteinases; D014409:Tumor Necrosis Factor-alpha; C000604391:Ucp2 protein, rat; D000071246:Uncoupling Protein 2