Defective regulation of serum cholesterol levels plays a critical role in the development of atherosclerosis, the leading cause of mortality in the United States. Regulation of cellular and organismic cholesterol homeostasis has been hypothesized to involve one or more oxygenated sterols which act as a signal regulating a number of aspects of cholesterol metabolism including synthesis and receptor mediated clearance. In this proposal, we describe experiments utilizing a combination of molecular and somatic cell genetic techniques designed to further elucidate the mechanisms of action of oxygenated sterols on sterol metabolism in cultured mammalian cells. Experiments are also proposed to determine mechanisms of synthesis and function of epoxysterols unrelated to regulation of sterol metabolism. These latter compounds have been found to be naturally occurring in human liver and have been demonstrated to perform a vital cellular function. Finally, a series of experiments are proposed to examine the mechanisms of action of oxysterols in the regulation of hepatic cholesterol metabolism. It is anticipated that these studies will aid in the development of chemotherapeutic methods towards management of atherosclerosis as well as shedding new light on the possible function of epoxysterols.
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