Increased cytoprotective function in the liver of transgenic mice expressing osteopontin in hepatocytes

Osteopontin is a crucial factor for initiation of Th1 immune reaction. Previously, we established transgenic mice expressing osteopontin in hepatocytes, in which lymphocyte infiltration occurred spontaneously at 12 weeks of age and liver necrosis at 24 weeks of age. This liver necrosis may develop through provocation by excessive Th1 immune reaction, but it is also possible that hepatocytes become fragile under abundant osteopontin in the cytoplasm. Thus, gene expression profiles in the liver were evaluated to seek such contributing factors in the transgenic mice. On DNA microarray analysis of 3774 mouse genes, 16 genes were selected as hepatic genes significantly up-regulated in the transgenic mice aged 8 weeks than in the negative littermate, which included mRNAs of cytoprotective metallothionein and glutathione S-transferase (GST). Hepatic up-regulations of both genes were also seen by Western blotting. Liver necrosis in the centrilobular areas developed after carbon tetrachloride treatment, but its histological extent and plasma ALT activities were significantly smaller in the transgenic mice aged 8 weeks than in the wild-type C57BL/6 control mice. We conclude that cytoprotective function of the liver is increased through up-regulated expressions of metallothionein and GST, and thereby susceptibility of hepatocytes to the stress may be less possible, if any, in the development of spontaneous liver necrosis in transgenic mice expressing osteopontin in hepatocytes.