ATHEROGENICITY OF POSTPRANDIAL TG-RICH LIPOPROTEINS

大多数心脏病患者的血脂正常。人们对此知之甚少 脂蛋白介导的正常人动脉粥样硬化的细胞机制 受试者，甚至是高胆固醇血症受试者，因为自然禁食 这类受试者的脂蛋白在体外似乎不会导致动脉粥样硬化。 [不会导致人类单核巨噬细胞(HMM)中的脂质堆积]。 人类经常处于餐后状态，认为动脉粥样硬化 是一种被广泛接受的餐后现象。人们对此知之甚少 特异餐后富含甘油三酯的脂蛋白的相互作用 然而，亚种(PpTGRLP)与HMM的相互作用可能会 有助于动脉粥样硬化的形成。 这项提案的总体目标是确定 短暂出现的ppTGRLP亚种的致动脉粥样硬化作用 某些正常和高脂蛋白血症患者的餐后反应 动脉粥样硬化的风险增加(低高密度脂蛋白水平；小而致密的低密度脂蛋白 模式；低密度脂蛋白升高；高载脂蛋白B；空腹甘油三酯水平升高；男性；载脂蛋白 E4表型)。代谢稳定的受试者会吃一顿饭 含有维生素A以标记肠道衍生颗粒；TGRLP将 在餐前和餐后的特定时间被分离，由 累积浮选成均匀大小的子类。禁食和 PpTGRLP子类将测试快速胆固醇酯和 人THP-1单核巨噬细胞甘油三酯负荷的体外实验 对于潜在的致动脉粥样硬化；选定的致动脉粥样硬化ppTGRLP将是 免疫亲和层析纯化apoB-100与B-48 颗粒来确定致动脉粥样硬化物种的起源。机制： 摄取将被确定(通过低密度脂蛋白受体，独特的巨噬细胞 TGRLP异常的受体，或其他机制)。结构性决定因素 每个致动脉粥样硬化的ppTGRLP亚类的功能异常将是 确定、跟踪餐后时间，并与已知的 风险因素。这些研究应该确定基本的细胞机制 参与人类动脉粥样硬化(巨噬细胞转化为泡沫 细胞)和导致动脉粥样硬化的因素。 对潜在致动脉粥样硬化的基本生化决定因素的认识 PpTGRLP/细胞相互作用可能导致合理饮食的发展 以及减少致动脉粥样硬化的ppTGRLP表达的治疗措施 而且，可能是为了更好地确定在其他情况下的风险 血脂正常的受试者。

Most subjects with heart disease are normolipemic. Little is known about lipoprotein-mediated cellular mechanisms of atherogenicity in normal subjects or even in hypercholesterolemic subjects, since native fasting lipoproteins from such subjects do not appear to be atherogenic in vitro [do not cause lipid accumulation in human monocyte-macrophages (HMM)]. Humans are often in a postprandial state and the idea that atherosclerosis is a postprandial phenomenon is widely accepted. Little is known about the interactions of specific postprandial triglyceride-rich lipoprotein subspecies (ppTGRLP) with HMM, however, interactions that are likely to contribute to atherogenesis. The overall goal of this proposal is to determine cellular mechanisms of atherogenicity of ppTGRLP subspecies that appear transiently during the postprandial response in certain normal and hyperlipoproteinemic subjects at increased risk for atherosclerosis (low HDL levels; small, dense LDL pattern; elevated LDL; hyperapoB; higher fasting TG levels; maleness; apo E4 phenotype). Metabolically stabilized subjects will consume a meal containing vitamin A to label intestinally-derived particles; TGRLP will be isolated before and at specific times postprandially, subfractionated by cumulative flotation into homogeneously sized subclasses. Fasting and ppTGRLP subclasses will be tested for rapid cholesteryl ester and triglyceride loading of human THP-1 monocyte-macrophages as in vitro tests for potential atherogenicity; selected atherogenic ppTGRLP will be subfractionated by immunoaffinity chromatography into apoB-100 vs B-48 particles to determine the origin of atherogenic species. Mechanisms of uptake will be determined (via the LDL receptor, the distinct macrophage receptor for abnormal TGRLP, or other mechanisms). Structural determinants of functional abnormalities of each atherogenic ppTGRLP subclass will be identified, tracked with time postprandially, and correlated with known risk factors. These studies should identify basic cellular mechanisms involved in human atherosclerosis (conversion of macrophages into foam cells) and factors responsible for the occurrence of atherogenic ppTGRLP. Knowledge of the basic biochemical determinants of potentially atherogenic ppTGRLP/cellular interactions may lead to development of rational dietary and therapeutic measures to minimize the expression of atherogenic ppTGRLP and, possibly, to better means of determining risk in otherwise normolipemic subjects.