Organ specific regulation of sterol 14-demethylase P450 expression relating to its organ specific functions

本课题是我们的研究项目的一部分，目的是研究与其器官特异性功能相关的固醇14-脱甲基酶P450(CyP51)表达的器官特异性调控机制。CYP51是一种独特的P450蛋白，在哺乳动物的器官中广泛表达。然而，其在不同器官中的表达水平存在较大差异，提示不同器官对其表达的调控方式可能不同。然后，观察几种激素对大鼠肝脏、小肠、肾上腺、脑和卵巢细胞色素P51表达水平的影响。最有趣的发现是促性腺激素(PMSG)对卵巢细胞色素P51的特异性诱导。由于羊毛甾醇的14-脱甲基衍生物已被鉴定为哺乳动物减数分裂激活甾醇(MAS)，因此，卵巢促性腺激素依赖性的细胞色素P51的表达可能与该基因的卵巢特异性功能有关。免疫组织化学观察表明促性腺激素依赖性细胞色素P5…的表达更多的1定位于肿块，靠近卵母细胞的颗粒细胞支持这种可能性。肝脏细胞色素P51的表达依赖于胰岛素。与其他脂代谢酶一样，胰岛素对SREBP-1c的诱导作用解释了胰岛素的增强作用。这一事实表明，肝脏细胞色素P51的表达可能是作为脂代谢酶的一员而被调控的。肝脏、小肠和肾上腺组织中细胞色素P51的表达依赖于甲状腺激素。地塞米松可抑制甲状腺激素依赖性的细胞色素P51的表达，降低肝脏、小肠和肾上腺的细胞色素P51含量。剂量反应实验提示糖皮质激素受体参与了地塞米松抑制细胞色素P51表达的作用。在脑和肝脏中，激素对细胞色素P51表达的调节没有显著差异。SER、Cre和GCAAT元件在细胞色素P51表达中的重要作用也被提出。较少

This subject consists of a part of our research project for examining organ specific regulatory mechanisms of sterol 14-demethylase P450(CYP51) expression relating to its organ specific functions. CYP51 is a unique P450 that expresses ubiquitously in mammalian organs. However, its expression level was considerably different among organs, suggesting that expression of CYP51 might be regulated differently by organ specific manners. Then, effects of several hormones on the CYP51 expression levels in liver, small intestine, adrenal gland, brain and ovary of rats were examined. The most interesting finding was specific induction of ovarian CYP51 by a gonadotropin(PMSG). Since 14-demethylated derivatives of lanosterol have been identified as mammalian meiosis activating sterols(MAS), the gonadotropin dependent expression of ovarian CYP51 might be related to this ovary specific function of CYP51. The immunohistochemical observation indicating that the gonadotropin-dependent expression of CYP5 … More 1 was localized at tumulus and granulosa cells close to oocyte supported this possibility. The expression of hepatic CYP51 was dependent on insulin. The enhancing effect of insulin was explained by its inducing effect on SREBP-1c, as in the case of other lipid metabolizing enzymes. This fact indicated that the expression of hepatic CYP51 might be regulated as a member of lipid-metabolizing enzymes. It was also shown that expression of CYP51 in liver, small intestine and adrenal gland was dependent on thyroid hormone. The thyroid hormone-dependent expression of CYP51 was repressed by dexamethazone(dex), and dex reduced the CYP51 contents in liver, small intestine and adrenal gland. Dose response experiments suggested the contribution of glucocorticoid receptor to the repressive effect of dex on CYP51 expression. No substantial difference was observed between the hormonal regulation of CYP51 expression in brain and liver. Essential role of SER,CRE and a GCAAT element on CYP51 expression was also suggested. Less