METABOLIC AND GENETIC BASIS OF BARE STEROL DISORDERS

裸甾醇疾病的代谢和遗传基础

• 批准号: 7606347
• 负责人: Helen Haskell Hobbs
• 金额: $ 0.21万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2007-09-16
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7606347
• 关键词: Bile Acids; Bile fluid; Biliary; Cholesterol; Cholesterol Homeostasis; Clinical Trials; Complement component C1s; Computer Retrieval of Information on Scientific Projects Database; Coronary; Coronary heart disease; Dehydrocholesterols; Diet; Dietary Fats; Dietary Sterol; Disease; End Point; Funding; Genetic; Grant; IDL lipoproteins; Institution; Intervention; Intestinal Absorption; Intestines; LDL Cholesterol Lipoproteins; Link; Lipoproteins; Liver; Low-Density Lipoproteins; Mammals; Marines; Measures; Metabolic; Metabolism; Myocardial Infarction; Nuclear Family; Numbers; Organ; Pharmaceutical Preparations; Phytosterols; Plasma; Proteins; Protocols documentation; Rare Diseases; Recruitment Activity; Research; Research Personnel; Resources; Sitosterol; Sitosterols; Source; Sterols; Testing; United States National Institutes of Health; absorption; base; brassicasterol; carbene; cholesterol absorption; cholesterol biosynthesis; clinical phenotype; design; hypercholesterolemia; hypocholesterolemia; interest; member; metabolic abnormality assessment; proband; response; steroid hormone

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.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 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关系。 他汀类药物降低 LDL 治疗的临床试验显示，心肌梗塞和其他冠状动脉终点事件显着减少。 因此，人们越来越关注如何以最佳方式降低低密度脂蛋白水平。这种脂蛋白是极低和中密度脂蛋白代谢的最终产物。 总的来说，这些脂蛋白被称为非 HDL，它们运输血浆甾醇。 甾醇来源于肝脏内源性合成胆固醇和肠道对甾醇的饮食吸收。 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、氧甾醇和类固醇激素。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、菜子甾醇和24-亚甲基胆固醇）。 通常，肠道对胆固醇的吸收比非胆固醇甾醇的吸收更有效。 但是，外源性甾醇和膳食脂肪都会显着影响血浆低密度脂蛋白水平。 因此，肠道和肝脏已成为控制全身甾醇代谢的关键器官。 肝脏中的胆固醇代谢响应胆固醇的吸收、合成和胆汁分泌以及甾醇转化为胆汁酸。 胆固醇生物合成及其转化为胆汁酸的机制比肠道吸收和胆汁分泌胆固醇的机制更容易理解。然而，近年来，已经确定了三种显着调节肠道甾醇吸收的关键蛋白质。 其中包括甾醇 1 和 2 以及 Niemann-Pick 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，甾醇1和甾醇2也促进了胆固醇和胆汁的分泌。 该项目将研究饮食对患有罕见甾醇疾病或对膳食脂肪和甾醇有异常反应的受试者胆固醇水平的影响。 该方案旨在进行许多代谢测试，这些测试将提供有关导致高胆固醇血症或低胆固醇血症的甾醇代谢异常的信息。 将进行代谢研究来测量胆固醇吸收以及低密度脂蛋白对饮食干预的反应。 由于受试者对饮食、降血脂、药物或其他不寻常的甾醇谱有不寻常的反应，因此向研究人员推荐的受试者将被招募到方案中。 核心家庭的成员也可能被邀请接受类似的测试作为对照，或者如果他们与先证者具有相似的临床表型。