Function and Regulation of GPIHBP1 in Lipid Metabolism

GPIHBP1在脂质代谢中的功能和调控

• 批准号: 7898771
• 负责人: Stephen G. Young
• 金额: $ 47.24万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7898771
• 关键词: A Mouse; Adipocytes; Adipose tissue; Affect; Agonist; Alleles; Apolipoprotein E; Apolipoproteins; Apolipoproteins B; Area; Aspartate; Binding; Binding Proteins; Biological Process; Biology; Blood capillaries; Breeding; Cardiac Myocytes; Cell Culture Techniques; Cell surface; Cells; Centrifugation; Charge; Chinese Hamster Ovary Cell; Chylomicrons; Complementary DNA; Cultured Cells; Data; Diet; Electrostatics; Employee Strikes; Endothelial Cells; Epitope Mapping; Eye; Face; Fasting; Fat-Restricted Diet; Fatty acid glycerol esters; Figs - dietary; GPI Membrane Anchors; Glucose; Glutamates; Heart; Heparan Sulfate Proteoglycan; Heparin Binding; High Density Lipoproteins; Human; Hydrolysis; Hyperlipidemia; Hypertriglyceridemia; Immunoassay; Insulin; LacZ Genes; Left; Ligands; Lipids; Lipolysis; Lipoprotein Binding; Lipoproteins; Liver; Mediating; Messenger RNA; Metabolic; Metabolism; Molecular; Monoclonal Antibodies; Mus; Muscle Cells; Myocardium; Nutrient; Obesity; Paracrine Communication; Pathway interactions; Pattern; Peroxisome Proliferator-Activated Receptors; Phenotype; Plasma; Play; Principal Investigator; Process; Program Research Project Grants; Proteins; Publishing; Regulation; Reporter; Research Personnel; Reverse Transcriptase Polymerase Chain Reaction; Right-On; Role; Sampling; Skeletal Muscle; Surface; Testing; Time; Tissues; Triglyceride Metabolism; Triglycerides; Update; Work; base; capillary; dimer; energy balance; expression cloning; glucose metabolism; lipid biosynthesis; lipid metabolism; lipid transport; lipoprotein lipase; member; novel; prevent; programs; receptor; research study; response; reverse cholesterol transport; vascular bed

The main objective of Project 1 ("Function and Regulation of GPIHBP1 in Lipid Metabolism") is to define the function of glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein 1 (GPIHBP1) in plasma triglyceride metabolism and in the regulation of fuel delivery to adipose tissue and muscle. This objective is closely aligned with the overall objectives of this PPG, which are to elucidate the basic mechanisms of triglyceride metabolism and adipogenesis, focusing on newly discovered molecules and pathways that are regulated by PPARy. Gpihbpl-deficient mice have severe chylomicronemia, even on a low-fat diet, with plasma triglyceride levels as high as 5000 mg/dl. GPIHBP1 is located on the luminal surface of endothelial cells of heart, muscle, and fat, where lipolysis of plasma triglycerides occurs. Expression of GPIHBP1 in cultured cells confers the ability to bind both lipoprotein lipase (LpL) and chylomicrons, suggesting that GPIHBP1 is a key platform for the lipolytic processing of chylomicrons along the luminal face of capillaries. Although GPIHBP1 is clearly important for the lipolysis of triglyceride-rich lipoproteins, many issues regarding the biological function of GPIHBP1 have not been explored. We have not yet examined the impact of different diets on lipid and glucose metabolism in Gpihbpl-deficient mice, nor do we know why Gpihbpl - deficient mice are protected from diet-induced obesity. Also, the molecular basis for chylomicron and LpL binding to GPIHBP1 is unknown¿in particular whether the highly negatively charged domain in GPIHBP1 interacts with positively charged "heparin-binding" domains in LpL and various apolipoproteins within chylomicrons (e.g., apo-E, apo-B, and apo-AV). Finally, Gpihbpl is highly regulated by fasting and refeeding and by PPARy, but the molecular basis for this regulation has not been defined. In Specific Aim 1, we will further define the metabolic abnormalities in Gpihbpl-deficient mice. In Specific Aim 2, we will identify the structural domains of GPIHBP1 required for the binding of LpL and chylomicrons and define the apolipoproteins that mediate the binding of chylomicrons (and other lipoprotein fractions) to Gpihbpl-transfected cells. In Specific Aim 3, we will define the tissue pattern of Gpihbpl expression and changes in Gpihbpl expression with PPARy agonists and different metabolic conditions.

项目1的主要目标（“脂质代谢中GPIHBP1的功能和调节”）是定义 糖基磷脂酰肌醇的高密度脂蛋白结合蛋白1（GPIHBP1）的功能 血浆甘油三酸酯代谢以及调节脂肪组织和肌肉的燃料递送。这 目标与该PPG的整体目标紧密相符，这些目标旨在阐明基本 甘油三酸酯代谢和脂肪形成的机制，重点是新发现的分子和 由PPARY调节的途径。 GPIHBPL缺陷小鼠即使在低脂饮食中，血浆甘油三酸酯也患有严重的乳糜激积 高达5000 mg/dl的水平。 GPIHBP1位于心脏内皮细胞的腔表面， 肌肉和脂肪，血浆甘油三酸酯的脂解。 GPIHBP1在培养细胞中的表达 赋予结合脂蛋白脂肪酶（LPL）和乳糜微粒的能力，这表明GPIHBP1是钥匙 沿毛细血管的腔脸的乳糜微粒的脂溶性加工的平台。 尽管GPIHBP1显然对于富含甘油三酸酯的脂肪蛋白的脂解显着重要，但许多问题 考虑到GPIHBP1的生物学功能尚未探索。我们尚未检查影响 GPIHBPL缺乏小鼠的脂质和葡萄糖代谢的不同饮食的不同，我们也不知道为什么GPIHBPL- 不足的小鼠免受饮食诱导的肥胖症的保护。同样，乳糜微粒和LPL的分子基础 与GPIHBP1的结合尤其是GPIHBP1中高负电荷的域是否未知 与LPL中带正电的“肝素结合”结构域相互作用，以及各种载脂蛋白 乳糜微粒（例如Apo-E，Apo-B和Apo-AV）。最后，GPIHBPL受禁食和参考高度调节 并且通过PPARY，但尚未定义该调节的分子基础。 在特定的目标1中，我们将进一步定义GPIHBPL缺陷小鼠的代谢异常。 具体目标2，我们将确定LPL和LPL结合所需的GPIHBP1的结构域 乳糜微粒并定义介导乳糜微粒结合（和其他脂蛋白的结合）的载脂蛋白 分数）至GPIHBPL转染的细胞。在特定的目标3中，我们将定义GPIHBPL的组织模式 与PPARY激动剂和不同的代谢条件的表达和GPIHBPL表达的变化。