Function and Regulation of GPIHBP1 in Lipid Metabolism

项目1(“GPIHBP1在脂质代谢中的功能和调节”)的主要目标是定义 糖基磷脂酰肌醇锚定高密度脂蛋白结合蛋白1在血管内皮细胞中的作用 血浆甘油三酯代谢和调节脂肪组织和肌肉的燃料输送。这 目标与本PPG的总体目标密切一致，目的是阐明基本的 甘油三酯代谢和脂肪形成的机制，重点是新发现的分子和 受PPARy调控的通路。 Gpihbpl缺陷小鼠有严重的乳糜体微粒血症，即使在低脂饮食中也是如此，并伴有血浆甘油三酯。 浓度高达5000毫克/分升。GPIHBP1位于心脏内皮细胞的管腔表面， 肌肉和脂肪，血浆甘油三酯在这些地方发生脂肪分解。GPIHBP1在培养细胞中的表达 赋予了结合脂蛋白脂肪酶(LPL)和乳糜粒的能力，表明GPIHBP1是一个关键 沿着毛细血管的管腔表面对乳糜粒进行脂解处理的平台。 尽管GPIHBP1显然对富含甘油三酯的脂蛋白的脂解作用很重要，但许多问题 关于GPIHBP1的生物学功能还没有被探索。我们还没有检查其影响 不同饮食对Gpihbpl缺陷小鼠脂和糖代谢的影响，也不知道为什么Gpihbpl- 缺乏营养的小鼠可以免受饮食引起的肥胖的影响。此外，乳胶粒和脂蛋白脂酶的分子基础 与GPIHBP1的结合尚不清楚，特别是GPIHBP1中的高负电荷结构域是否 与LPL中带正电荷的“肝素结合”结构域以及LPL中的各种载脂蛋白相互作用 乳糜粒(如apo-E、apo-B和apo-AV)。最后，Gpihbpl受到禁食和再喂养的高度调控。 和PPARy，但这一调控的分子基础尚未定义。 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。在……里面 特定目标2，我们将确定LPL和LPL结合所需的GPIHBP1的结构域 乳糜粒，并定义介导乳糜粒(和其他脂蛋白)结合的载脂蛋白 组分)转导Gpihbpl基因的细胞。在具体目标3中，我们将定义Gpihbpl的组织模式 PPARy激动剂和不同代谢条件对Gpihbpl表达的影响

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.