Steatotic liver allografts up-regulate UCP-2 expression and suffer necrosis in rats.
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.
Uchino
Shinichiro
S
Department of Surgery II, Kumamoto University Medical School, Kumamoto, Japan.
Yamaguchi
Yasuo
Y
Furuhashi
Takashi
T
Wang
Feng-Shan
FS
Zhang
Jia-Lin
JL
Okabe
Kazutoshi
K
Kihara
Shinichi
S
Yamada
Shinwa
S
Mori
Katsutaka
K
Ogawa
Michio
M
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
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