METABOLIC AND GENETIC BASIS OF RARE STEROL DISORDERS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. There is ample evidence showing a causal link between low-density lipoprotein (LDL) cholesterol metabolism and coronary heart disease. Clinical trials of LDL-lowering therapy with statins show a marked reduction of myocardial infarctions and other coronary end-points. For this reason, there is a growing interest in optimally reducing LDL levels. This lipoprotein is the end product of the metabolism of very-low and intermediate density lipoproteins. Collectively, these lipoproteins are known as non-HDL and they transport plasma sterols. The sterols are derived from endogenous synthesis of cholesterol by the liver and dietary absorption of sterols by the intestine. The main sterol in mammals is cholesterol and its metabolic products include bile acids, oxysterols, and steroid hormones. Sterols of dietary origin include cholesterol, phytosterols (sitosterol) and marine sterols (22-dehydrocholesterol, C-26 sterol, brassicasterol, and 24-methylene cholesterol). Normally, intestinal absorption of cholesterol is more efficient than the absorption of non-cholesterol sterols. But, both exogenous sterols and dietary fat influence significantly levels of plasma LDL. For this reason, the intestine and the liver have emerged as critical organs in the control of whole body sterol metabolism. Cholesterol metabolism in the liver responds to absorption, synthesis, and biliary secretion of cholesterol and the conversion of the sterol into bile acids. The mechanisms of cholesterol biosynthesis and its conversion into bile acids are much better understood than those of intestinal absorption and biliary secretion of cholesterol. However, in recent years three key proteins that significantly regulate intestinal sterol absorption have been identified. These include sterolin 1, and 2 and Niemann-Pick type C1 -like protein 1(NPC1-L1). These transporters apparently facilitate intestinal absorption of cholesterol and sterolin 1 and 2 also promote secretion of cholesterol and bile. This project will examine the influence of diet on cholesterol levels in subjects that have rare disorders of sterols or have unusual responses to dietary fats and sterols. This protocol is designed to carry out a number of metabolic tests that will provide information regarding abnormalities in sterol metabolism leading to hyper- or hypocholesterolemia. Metabolic studies will be carried out to measure cholesterol absorption, and LDL responsiveness to diet interventions. Subjects referred to the investigators because they have unusual responses to diet, hypolipidemic, drugs or other unusual sterol profiles will be recruited into the protocol. Members of the nuclear family also may be invited to undergo similar testing to serve as controls or if they have similar clinical phenotypes to the proband.