Liver disorders in mice lacking transcription factors

基因中断研究已经产生了一些转录因子缺陷的小鼠，其中一些可以用作人类疾病的模型动物。最近，缺乏CCAAT/增强子结合蛋白(C/EBP)转录因子家族成员的小鼠被证明表现出各种肝脏疾病。为了研究这些疾病的病理生理学并开发针对这些疾病的治疗方法，我们检测了肝脏中用于解毒氨的鸟氨酸循环酶基因的异常表达。C/eBPα缺陷小鼠的病理生理学-据报道，C/eBPα缺陷小鼠出生后几个小时内死亡，原因是肝脏中糖异生酶基因表达不足导致低血糖。我们发现，由于鸟氨酸循环酶基因的不足，小鼠也出现了高氨血症。现在我们正在研究用糖皮质激素和cAMP诱导其他成员，如C/EBPβ是否可以弥补C/EBPα缺乏。此外，我们正在通过检查精氨酸酶基因在唾液腺中的表达是否受到影响来研究这种缺陷的器官特异性。C/eBPβ缺陷小鼠的鸟氨酸循环酶基因的激素反应缺陷-我们表明，在来自C/eBPβ缺陷小鼠的原代培养的肝细胞中，糖皮质激素和胰高血糖素诱导的两种酶的基因几乎完全丢失。现在，我们正在研究禁食是否会影响体内酶基因的诱导，从而增强糖皮质激素和胰高血糖素的作用。

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.