Coronary heart disease remains the leading cause of death in the United states, claiming approximately 800,000 lives each year. It has long been recognized that one of the major risk factors in this disease is the exponential relationship between the concentration of cholesterol in the serum (associated with the low density lipoprotein (LDL)) and the incidence of atherosclerotic coronary disease. This finding highlights the importance of a basic understanding of the regulation of isoprenoid biosynthesis in general and cholesterol biosynthesis in particular. Our lack of understanding about the regulation of sterol and isoprenoid biosynthesis is real and profound, notwithstanding the accumulation of primary sequence data at the genomic, mRNA, and protein level for the regulated HMG-CoA and mevalonate synthesis enzymes. Recent experimental findings from this laboratory indicate that certain oxysterols, e.g., sterol-24-epoxides, are formed endogenously by rats at early time intervals following the administration of a single cholesterol meal. Furthermore, these compounds can suppress HMG-CoA reductase activity in the intact animal. We propose to study the relationship between the formation of oxysterols, following an acute cholesterol challenge, and the suppression of rat liver HMG-CoA reductase.
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