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Regulation of c-met expression in rats with acute hepatic failure
T Mizuguchi1, Y Kamohara, T Hui
1Liver Support Research Laboratory, UCLA School of Medicine, Los Angeles, CA 90048, USA.
Background:
Earlier we described a model of fulminant hepatic failure (FHF) in the rat where partial hepatectomy is combined with induction of right liver lobe necrosis. In FHF rats, lack of hepatocyte proliferation was associated with delayed expression of HGF and HGF receptor c-met. Since the c-met promoter region has Sp1 binding sites, we decided to examine whether in FHF rats down-regulation of c-met is associated with decreased Sp1 function and whether changes in blood HGF, IL-6, and TGFbeta1 levels might be responsible for these effects.
Materials And Methods:
Induction of FHF, partial (2/3) hepatectomy (PH), and sham hepatectomy (SH) was performed in adult Sprague-Dawley rats. The levels of c-met mRNA and Sp1 DNA binding activity were studied in rat liver remnants at different time points after surgery. Blood levels of HGF, IL-6, and TGFbeta1 were also measured in these rats. Additionally, the effects of treatment with TGF-beta1, IL-6, or a combination of both on c-met expression and Sp1 DNA binding were studied in HGF-induced rat hepatocyte cultures.
Results:
Compared to SH rats, in PH rat livers c-met was up-regulated after 6 h and Sp1 DNA binding was at or only slightly lower than levels at all time points studied. In FHF rat livers, c-met expression was markedly reduced after 2 and 6 h, moderate after 12 h, and undetectable after 24 h. At the same time, Sp1 DNA binding was detected at 2 h postinduction only. In FHF rats, blood levels of all three cytokines showed early and sustained elevation. In vitro, IL-6 had no effect on c-met expression, whereas TGFbeta1 up-regulated c-met. When used alone, none of the cytokines affected Sp1 DNA binding activity. In contrast, a combination of IL-6 and TGFbeta1 down-regulated c-met expression as well as Sp1 DNA binding activity. These effects were dependent on the IL-6 concentration used. This study suggests that following massive loss of hepatocyte mass in rats, early increase in blood IL-6 and TGFbeta1 levels may weaken the expression of HGF receptor c-met in surviving hepatocytes through suppression of Sp1 DNA binding.