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.
