Lipoprotein Metabolism In Genetic Dyslipoproteinemias

遗传性异常脂蛋白血症的脂蛋白代谢

• 批准号: 7594390
• 负责人: Richard Cannon
• 金额: $ 12.6万
• 依托单位: NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7594390
• 关键词: Animal Model; Antiatherogenic; Apolipoprotein A-I; Apolipoproteins; Apolipoproteins C; Arterial Fatty Streak; Atherosclerosis; C-Peptide; Catabolism; Cells; Cholesterol Esters; Computers; Coronary heart disease; Cultured Cells; Data; Defect; Development; Diet; Epidemiologic Studies; Familial Hypercholesterolemia; Foundations; Gene Mutation; Genes; Genetic; Hereditary Disease; High Density Lipoprotein Cholesterol; High Density Lipoproteins; Human; In Vitro; Investigation; Kinetics; Lipids; Lipoproteins; Liver; Low-Density Lipoproteins; Metabolic Pathway; Metabolism; Methods; Mus; Pathologic; Pathway interactions; Patients; Peripheral; Personal Satisfaction; Pharmaceutical Preparations; Play; Prevalence; Process; Protein Overexpression; Research Design; Role; Structure; Techniques; Transgenic Organisms; Triglycerides; Very low density lipoprotein; base; dyslipoproteinemia; healthy volunteer; in vivo; insight; interest; lipid metabolism; novel; particle; protein metabolism; reverse cholesterol transport

Lipids and lipoproteins play an important role in the development of atherosclerotic cardiovascular disease. The structure, function, and metabolism of lipoproteins have been intensively investigated utilizing both in vivo and in vitro experimental methods. One of the most productive techniques utilized for the investigation of the function and metabolism of the proteins associated with lipoprotein particles, the apolipoproteins, has been in vivo kinetic studies. The maturation of high-density lipoprotein (HDL) is important for reverse cholesterol transport, a hypothesis that HDL transports cholesteryl ester (CE) from peripheral atherosclerotic lesions to the liver. This hypothesis is based on epidemiological studies that indicated an inverse correlation between the HDL cholesterol (HDL-C) levels and the prevalence of coronary heart disease (CHD) as an independent anti-atherogenic factor for CHD. It is therefore interesting to note that despite a markedly low level of HDL-C some people dont develop CHD while others with extremely high HDL can develop CHD. Little is known about the initiation of this process in humans Our aim was to elucidate the mechanism(s) responsible for the formation and maturation of HDL using in vitro cell cultures, animal models and correlating this in vivo in humans who are normal and have genetic mutations in specific lipid pathways. Studies are designed to formulate metabolic pathways in patients with defined genetic disorders of lipid metabolism as well as in healthy volunteers to provide new and novel insights into normal and pathologic metabolic pathways. All kinetic data is computer analyzed to provide quantitative data and facilitate direct comparison of multiple studies. The metabolism of very low density lipoproteins (VLDL), low density lipoproteins (LDL), high density lipoproteins (HDL), and their associated apolipoproteins has been studied in vitro in cells, in animal models lacking genes (KO mice) or overexpressing genes (transgenic) and in normal and dyslipoproteinemic subjects. Our early studies have laid the foundation for the understanding of many of the key metabolic pathways in lipid metabolism. It is well accepted that VLDL serves as a precursor for LDL, and during this conversion triglycerides and the apolipoprotein C peptides are selectively removed. It has also been shown that the major defect in type II hyperlipoproteinemia appears to be decreased LDL catabolism. We have shown that HDL concentrations are influenced by the apolipoprotein composition of the HDL particles. HDL particles containing only apolipoprotein A-I (LpA-I) are catabolized differently than HDL particles containing both apolipoprotein A-I and A-II (LpA-I:AII). Studying the effects of diet, drug, and genetic factors upon these different particles has permitted a better understanding of what modulates HDL levels.

脂质和脂蛋白在动脉粥样硬化心血管疾病的发展中起重要作用。 脂蛋白的结构，功能和代谢已通过体内和体外实验方法进行了深入研究。 用于研究与脂蛋白颗粒相关的蛋白质功能和代谢的最有生产力的技术之一，是载脂蛋白，是体内动力学研究。 高密度脂蛋白（HDL）的成熟对于反向胆固醇转运很重要，这是HDL将胆固醇酯（CE）从外周动脉粥样硬化病变转运到肝脏的假设。该假设基于流行病学研究，该研究表明HDL胆固醇（HDL-C）水平与冠状动脉疾病（CHD）的患病率是一种独立的抗动脉粥样硬化因子，这是CHD的独立抗动脉粥样硬化因素。因此，有趣的是，尽管HDL-C水平明显低，有些人没有发展CHD，而HDL极高的其他人则可以发展CHD。 关于在人类中这一过程的启动知之甚少 我们的目的是阐明使用体外细胞培养物，动物模型的HDL形成和成熟的机制，并将其在正常且在特定脂质途径中具有基因突变的体内相关。 研究旨在制定脂质代谢遗传疾病的患者以及健康志愿者的代谢途径，以提供对正常和病理代谢途径的新新见解。 所有动力学数据均经过计算机分析，以提供定量数据并促进多个研究的直接比较。 非常低密度脂蛋白（VLDL），低密度脂蛋白（LDL），高密度脂蛋白（HDL）及其相关的载脂蛋白的代谢，在细胞中已经研究了缺乏基因的动物模型（KO小鼠）或过度表达基因（Transgenic）和普通基因和dyssoptimoptimoptimoptimotigotigotigitigientimoptimoptimoptimotigotigion。 我们的早期研究为理解脂质代谢中许多关键代谢途径的理解奠定了基础。 VLDL充当LDL的前体众所周知，在此转化甘油三酸酯和载脂蛋白C肽中，VLDL被选择性地去除。 还已经表明，II型高脂蛋白血症的主要缺陷似乎降低了LDL分解代谢。我们已经表明，HDL浓度受HDL颗粒的载脂蛋白组成的影响。 仅包含载脂蛋白A-I（LPA-I）的HDL颗粒与含有载脂蛋白A-I和A-II（LPA-I：AII）的HDL颗粒的分解代谢不同。 研究饮食，药物和遗传因素对这些不同颗粒的影响使人们可以更好地了解哪种调节HDL水平。