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.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 有足够的证据表明低密度脂蛋白（LDL）胆固醇代谢与冠状动脉疾病之间存在因果关系。 他汀类药物降低LDL疗法的临床试验表明，心肌梗死和其他冠状动脉终点显着减少。 因此，对最佳降低LDL水平的兴趣越来越大。该脂蛋白是非常低和中间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，它们运输血浆固醇。 这些固醇是由肝脏对胆固醇的内源性合成的，肠子通过肠子吸收固醇。 哺乳动物中的主要固醇是胆固醇，其代谢产物包括胆汁酸，氧甲醇和类固醇激素。饮食起源的固醇包括胆固醇，植物固醇（羟基苯酚）和海洋固醇（22-脱氢胆固醇，C-26固醇，甘蓝甲醇和24-甲基胆固醇）。 通常，胆固醇的肠吸收比非胆固醇固醇的吸收更有效。 但是，外源固醇和饮食脂肪都显着影响血浆LDL水平。 因此，肠道和肝脏已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，合成和胆道分泌有何反应，以及将固醇转化为胆汁酸。 胆固醇生物合成的机制及其转化为胆汁酸比胆固醇的肠道吸收和胆汁分泌的方法要多得多。但是，近年来，已经确定了明显调节肠固醇吸收的三种关键蛋白质。 其中包括固醇1和2和Niemann-Pick型C1样蛋白1（NPC1-L1）。 这些转运蛋白显然促进了胆固醇和固醇1和2的肠道吸收，也促进了胆固醇和胆汁的分泌。 该项目将检查饮食对稀有固醇疾病或对饮食脂肪和固醇的异常反应的受试者中胆固醇水平的影响。 该方案旨在进行许多代谢检测，这些测试将提供有关固醇代谢异常的信息，导致高降脂酯血症。 将进行代谢研究以测量胆固醇的吸收和对饮食干预措施的反应。 受试者称研究人员对饮食，低脂，药物或其他不寻常的固醇概况的反应异常，将招募到该方案中。 还可以邀请核家族的成员进行类似的测试，以作为对照，或者是否具有与概率类似的临床表型。