Steatotic liver allografts up-regulate UCP-2 expression and suffer necrosis in rats

• Published in: The Journal of surgical research 2004-07, Vol.120 (1), p.73-82
• Main Authors: Uchino, Shinichiro, Yamaguchi, Yasuo, Furuhashi, Takashi, Wang, Feng-Shan, Zhang, Jia-Lin, Okabe, Kazutoshi, Kihara, Shinichi, Yamada, Shinwa, Mori, Katsutaka, Ogawa, Michio
• Format: Article
• Language: English
• Subjects: alcohol; Animals; Biological and medical sciences; fatty liver; Fatty Liver - metabolism; Fatty Liver - pathology; Fatty Liver - surgery; General aspects; Graft Rejection - metabolism; hepatocyte necrosis; Hepatocytes - drug effects; Hepatocytes - pathology; Ion Channels; Kupffer Cells - drug effects; Kupffer Cells - metabolism; Liver - drug effects; Liver - pathology; Liver Transplantation; Medical sciences; Membrane Transport Proteins - biosynthesis; Mitochondrial Proteins - biosynthesis; Necrosis; rat; Rats; Tissue Inhibitor of Metalloproteinases - pharmacology; Transplantation, Homologous; Tumor Necrosis Factor-alpha - biosynthesis; Uncoupling Protein 2; Up-Regulation - drug effects
• ISSN: 0022-4804; 1095-8673
• DOI: 10.1016/j.jss.2003.10.010

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. 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)-α were determined. Y-39083 was administered to recipient rats continuously at 5 mg/kg/day using an osmotic infusion mini-pump. 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-α 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-α than those from lean livers. In vitro TNF-α 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-α and prevented massive hepatocellular necrosis in rats with both alcoholic and nonalcoholic fatty liver allografts. Liver grafts with steatosis up-regulated UCP-2. TNF-α further enhanced UCP-2 transcripts, inducing massive hepatocellular necrosis during acute rejection. Posttransplantation necrosis may be prevented by metalloprotease inhibitors.