TRANSLATIONAL CONTROL OF HMG-COA REDUCTASE

血清胆固醇水平升高与 动脉粥样硬化的发展使得调节动脉粥样硬化的机制 胆固醇在哺乳动物组织中的合成速率。 许多关于胆固醇合成调节机制的研究仍在继续 专注于决定酶活性的过程 3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶--关键酶 胆固醇生物合成途径中的调节酶。 在这 建议，我们提出的初步数据，强烈表明，一个主要的 HMG-CoA还原酶的调节机制是翻译控制 通过非甾醇甲羟戊酸衍生产物合成。 其他 初步数据表明，25-羟基胆固醇也可能作为一种 HMG-CoA还原酶在翻译水平上的合成调节剂， 培养成纤维细胞。 在该建议中，描述了实验， 有望进一步阐明 CHO细胞中HMG-CoA还原酶的翻译控制。 研究也 建议在CHO细胞和原代大鼠肝细胞中进一步测试 假设25-羟基胆固醇也可以作为一种调节剂， HMG-CoA还原酶mRNA的翻译。

The high correlation between elevated serum cholesterol levels and the development of atherosclerosis have made the mechanisms regulating the rates of synthesis of cholesterol in mammalian tissue of great interest. Much of the effort on mechanisms regulating cholesterol synthesis continues to focus on processes which determine the activity of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase-the critical regulatory enzyme in the cholesterol biosynthetic pathway. In this proposal, we present preliminary data that strongly suggest that a major mechanism of regulation of HMG-CoA reductase is the translational control of its synthesis by a non-sterol mevalonate derived product. Other preliminary data suggest that 25-hydroxycholesterol may also act as a regulator of HMG-CoA reductase synthesis at the translational level in cultured fibroblasts. In this proposal, experiments are described which are expected to lead to a further elucidation of the mechanism of translational control of HMG-CoA reductase in CHO cells. Studies are also proposed in both CHO cells and primary rat hepatocytes to further test the hypothesis that 25-hydroxycholesterol can also act as a regulator of translation of HMG-CoA reductase mRNA.