METABOLIC AND GENETIC BASIS OF RARE STEROL DISORDERS

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心机构，不一定为研究者机构。有充分的证据表明，低密度脂蛋白（LDL）胆固醇代谢和冠心病之间的因果关系。他汀类药物降低LDL治疗的临床试验显示心肌梗死和其他冠状动脉终点显著减少。出于这个原因，人们对最佳降低LDL水平越来越感兴趣。这种脂蛋白是极低和中密度脂蛋白代谢的终产物。总的来说，这些脂蛋白被称为非HDL，它们转运血浆固醇。甾醇来源于肝脏对胆固醇的内源性合成和肠道对甾醇的膳食吸收。哺乳动物中的主要固醇是胆固醇，其代谢产物包括胆汁酸、氧化固醇和类固醇激素。膳食来源的甾醇包括胆固醇、植物甾醇（谷甾醇）和海洋甾醇（22-脱氢胆固醇、C-26甾醇、油菜甾醇和24-亚甲基胆固醇）。通常，肠道对胆固醇的吸收比非胆固醇固醇的吸收更有效。但是，外源性固醇和膳食脂肪都显著影响血浆LDL水平。由于这个原因，肠和肝脏已经成为控制全身固醇代谢的关键器官。肝脏中的胆固醇代谢对胆固醇的吸收、合成和胆汁分泌以及固醇转化为胆汁酸作出反应。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的机制更容易理解。然而，近年来，已经确定了三种显著调节肠道固醇吸收的关键蛋白质。这些包括固醇1和2和尼曼-匹克型C1样蛋白1（NPC 1-L1）。这些转运蛋白明显促进胆固醇的肠吸收，并且固醇1和固醇2也促进胆固醇和胆汁的分泌。 这个项目将研究饮食对胆固醇水平的影响，这些受试者患有罕见的固醇紊乱或对膳食脂肪和固醇有不寻常的反应。本方案旨在进行大量代谢试验，以提供有关导致高胆固醇血症或低胆固醇血症的固醇代谢异常的信息。将进行代谢研究，以测量胆固醇吸收和低密度脂蛋白对饮食干预的反应。由于对饮食、降血脂、药物或其他异常固醇特征有异常反应而转介给研究者的受试者将被招募到方案中。核心家族的成员也可以被邀请接受类似的测试，作为对照，或者如果他们有类似的临床表型的先证者。

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.