Liver disorders in mice lacking transcription factors

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Gene disruption studies have produced a number of transcription factor-deficient mice, some of which are useful as model animals for human disorders. Recently, mice lacking members of the CCAAT/enhancer-binding protein (C/EBP) family of transcription factors were shown to exhibit a variety of liver disorders. To investigate pathophysiology and to develop therapy for these disorders, we examined abnormalities in expression of genes for ornithine cycle enzymes which detoxify ammonia in the liver.Pathophysiology of C/EBPα-deficient mice- It has been reported that C/EBPα-deficient mice die within several hours after birth because of hypoglycemia resulting from insufficiency of expression of genes for gluconeogenic enzymes in the liver. We showed that the mice also exhibit hyperammonemia resulting from insufficiency of genes for ornithine cycle enzymes. Now we are examining whether induction of other members such as C/EBPβ by administration of glucocorticoids and cAMP can compensate C/EBPα-deficiency or not. In addition, we are investigating organ-specificity of the defficiency by examining whether expression of the gene for arginase, the last enzyme of the ornithine cycle, in salivary glands is affected or not.Defects in hormone responsiveness of genes for ornithine cycle enzymes in C/EBPβ-deficient mice- We showed that in primary-cultured hepatocytes derived from C/EBPβ-deficient mice induction of genes for two enzymes of the cycle by glucocorticoids and glucagon are almost completely lost. Now we are examining whether the induction of genes for the enzymes in vivo is affected or not in fasting which augments effects of glucocorticoids and glucagon.