TRANSLATIONAL CONTROL OF HMG-COA REDUCTASE

血清胆固醇水平升高与高血压之间的高度相关性 动脉粥样硬化的发展使调节动脉粥样硬化的机制 哺乳动物组织中胆固醇的合成速度是人们非常感兴趣的。 关于胆固醇合成调控机制的大部分工作仍在继续。 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 胆固醇生物合成途径中的调节酶。在这 我们提供的初步数据强烈表明，一个主要的 HMG-CoA还原酶的调控机制是翻译调控 它的合成由非甾醇甲氧戊酸酯衍生产品。其他 初步数据表明，25-羟基胆固醇也可能是一种 HMG-CoA还原酶合成在翻译水平的调节 培养的成纤维细胞。在这个提案中，描述了一些实验，这些实验 有望进一步阐明其作用机制 HMG-CoA还原酶在CHO细胞中的转录调控。研究也在进行 建议在CHO细胞和原代大鼠肝细胞中进一步测试 25-羟基胆固醇也可以作为一种调节的假说 HMG-CoA还原酶基因的翻译。

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.