GHIHBP1 and the Metabolism of Triglyceride-Rich Lipoproteins

GHIHBP1 和富含甘油三酯的脂蛋白的代谢

• 批准号: 7578979
• 负责人: Stephen G. Young
• 金额: $ 34.73万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-01 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7578979
• 关键词: Adipocytes; Adipose tissue; Affect; Agonist; Alleles; Amino Acids; Animals; Apolipoproteins; Attention; Binding; Binding Proteins; Biochemistry; Biological Assay; Blood capillaries; Body Weight; Cell Line; Cell surface; Cells; Cellular biology; Charge; Cholesterol; Chylomicrons; Cleaved cell; Cultured Cells; Defect; Development; Diet; Diving; Emulsions; Endothelium; Excision; Exons; Fasting; Fat-Restricted Diet; Fatty Acids; Fatty acid glycerol esters; Female; Fibroblasts; GPI Membrane Anchors; Galactosidase; Glucose; Goals; Hand; Heart; Heparin; High Density Lipoproteins; Hyperlipidemia; Hypertriglyceridemia; Injection of therapeutic agent; Insulin; Intravenous; Investigation; Knock-in Mouse; Knockout Mice; Laboratories; LacZ Genes; Lead; Leptin; Link; Lipids; Lipolysis; Lipoprotein Binding; Lipoproteins; Literature; Liver; Measures; Mediating; Membrane Microdomains; Metabolic; Metabolism; Molecular Biology; Mus; Muscle Cells; Nonesterified Fatty Acids; Northern Blotting; Pattern; Peptides; Peroxisome Proliferator-Activated Receptors; Phase; Phenotype; Phospholipase C; Physiological; Plasma; Play; Production; Proteins; Public Health; RNA Splicing; Radiolabeled; Recruitment Activity; Reporter; Role; Site; Staging; Stretching; Testing; Time; Tissue Stains; Tissues; Transcript; Triglyceride Metabolism; Triglycerides; Triton; Very low density lipoprotein; Weight Gain; Western Blotting; Work; capillary; improved; in vivo; lipoprotein lipase; lipoprotein lipase inhibitor; male; mutant; radiotracer

DESCRIPTION (provided by applicant): Hyperlipidemia is a major public health problem. The objective of this proposal is to define the role of glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein 1 (GPIHBP1) in plasma triglyceride metabolism. During the past few months, we have made a stunning observation-that GPIHBP1 plays a major role in the metabolism of triglyceride-rich lipoproteins in the plasma. Remarkably, the sole phenotype of male and female Gpihbpl-deficient mice on a chow diet is chylomicronemia, with plasma triglycerides of -10,000 mg/ dl. GPIHBP1 is expressed on the surface of cells, mainly in adipose tissue and heart, the principal tissue sites of lipolysis of triglyceride-rich lipoproteins. Because the expression pattern of GPIHBP1 faithfully mirrors that of lipoprotein lipase (LPL), it is overwhelmingly likely that the hypertriglyceridemia in Gpihbpl - deficient mice is due to impaired lipolysis of chylomicrons and very low density lipoproteins (VLDL). Only one description of GPIHBP1 exists in the literature. That study that showed that GPIHBP1 can bind to high density lipoproteins in cultured cells. However, no link was made to triglyceride-rich lipoproteins, and the in vivo physiologic importance of the molecule was not explored. We propose that GPIHBP1 plays a major role in the lipolysis of triglyceride-rich lipoproteins. We hypothesize that GPIHBP1 is involved in "capturing" lipoproteins as they flow through capillaries and recruiting LPL (from a reservoir on the surface of cells) so that lipolysis can begin. However, at this stage, there are more questions than answers about the functions of GPIHBPL in Specific Aim 1 of this proposal; we will further characterize the hyperlipidemia in Gpihbpl-deficient mice and to test the hypothesis that the severe chylomicronemia is related to defective LPL-mediated lipolysis along the capillary endothelium. In Specific Aim 2, we will define the pattern of Gpihbpl expression in various mouse tissues and determine if Gpihbpl expression is regulated according to different metabolic states (e.g., fasting, refeeding). Defining the Gpihbpl expression will be facilitated by the fact that the Gpihbpl knockout mice have a lacZ reporter. In Specific Aim 3, we will test the idea that GPIHBP1 binds directly to triglyceride-rich lipoproteins and/or to LPL, thereby facilitating lipolysis.

描述（由申请人提供）：高脂血症是一个主要的公共卫生问题。该提案的目的是定义糖基磷脂酰肌醇的高密度脂蛋白结合蛋白1（GPIHBP1）在血浆甘油三酸酯代谢中的作用。在过去的几个月中，我们进行了令人惊叹的观察 - GPIHBP1在血浆中富含甘油三酸酯的脂蛋白代谢中起着重要作用。值得注意的是，在食物饮食上，男性和雌性GPIHBPL缺乏小鼠的唯一表型是乳糜症，血浆甘油三酸酯为-10,000 mg/ dl。 GPIHBP1在细胞表面表达，主要是脂肪组织和心脏，这是富含甘油三酸酯的脂蛋白脂解的主要组织部位。由于GPIHBP1的表达模式忠实地反映了脂蛋白脂肪酶（LPL）的表达模式，因此绝大部分可能是GPIHBPL中的高甘油三酸酯血症 - 缺乏小鼠造成的脂肪受损，这是由于脂肪的脂肪受损而导致的乳清细胞脂解和密度非常低的脂蛋白（VLDL）。文献中只有一个GPIHBP1的描述。该研究表明，GPIHBP1可以与培养细胞中的高密度脂蛋白结合。但是，没有与富含甘油三酸酯的脂蛋白建立联系，并且没有探索分子的体内生理重要性。我们建议GPIHBP1在富含甘油三酸酯的脂蛋白的脂解中起主要作用。我们假设GPIHBP1参与“捕获”脂蛋白流经毛细血管并募集LPL（从细胞表面的储层）中，以便可以开始脂肪分解。但是，在此阶段，关于GPIHBPL在本提案的特定目的1中功能的答案多得多。我们将进一步表征GPIHBPL缺陷小鼠中的高脂血症，并检验以下假设：严重的乳糜症与沿毛细血管内皮沿着毛细血管内皮的有缺陷的LPL介导的脂肪有关。在特定的目标2中，我们将定义各种小鼠组织中GPIHBPL表达的模式，并根据不同的代谢状态（例如，禁食，再进度）确定GPIHBPL表达是否受到调节。通过GPIHBPL敲除小鼠具有LACZ记者的事实，将促进定义GPIHBPL表达的情况。在特定目标3中，我们将测试GPIHBP1直接与富含甘油三酸酯的脂蛋白和/或LPL结合的想法，从而促进脂肪分解。