METABOLIC AND GENETIC BASIS OF BARE STEROL DISORDERS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 有充分的证据表明低密度脂蛋白(LDL)胆固醇代谢与冠心病之间存在因果联系。他汀类药物降低低密度脂蛋白的临床试验显示，心肌梗死和其他冠状动脉终点显著减少。因此，人们对以最佳方式降低低密度脂蛋白水平的兴趣与日俱增。这种脂蛋白是极低密度和中等密度脂蛋白代谢的最终产物。总而言之，这些脂蛋白被称为非高密度脂蛋白，它们运输血浆类固醇。甾醇来自肝脏内源性合成胆固醇和肠道对胆固醇的饮食吸收。哺乳动物体内的主要甾醇是胆固醇，其代谢产物包括胆汁酸、氧化甾醇和类固醇激素。膳食来源的类固醇包括胆固醇、植物类固醇(谷甾醇)和海洋类固醇(22-脱氢胆固醇、C-26类固醇、油菜籽甾醇和24-亚甲基胆固醇)。正常情况下，肠道对胆固醇的吸收比非胆固醇类固醇的吸收更有效。但是，外源性类固醇和膳食脂肪都对血浆低密度脂蛋白水平有显著影响。正因为如此，肠道和肝脏已成为控制全身类固醇代谢的关键器官。肝脏中的胆固醇新陈代谢反应于胆固醇的吸收、合成和胆汁分泌，以及将甾醇转化为胆汁酸。胆固醇的生物合成及其转化为胆汁酸的机制比胆固醇的肠道吸收和胆汁分泌机制了解得更好。然而，近年来发现了三种显著调节肠道类固醇吸收的关键蛋白质。其中包括甾体素1、2和尼曼-匹克型C1样蛋白1(NPC1-L1)。这些转运蛋白显然促进了肠道对胆固醇的吸收，而固醇1和2也促进了胆固醇和胆汁的分泌。 这个项目将考察饮食对胆固醇水平的影响，这些受试者患有罕见的类固醇紊乱或对饮食脂肪和类固醇有不寻常的反应。该方案旨在进行一系列代谢测试，提供有关导致高胆固醇血症或低胆固醇血症的类固醇代谢异常的信息。将进行代谢研究，以衡量胆固醇吸收和低密度脂蛋白对饮食干预的反应。被转介给调查人员的受试者，因为他们对饮食、降血脂、药物或其他不寻常的类固醇特征有异常反应，将被招募到该方案中。核心家庭的成员也可能被邀请接受类似的测试作为对照，或者如果他们的临床表型与先证者相似。

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.