ATHEROGENICITY OF POSTPRANDIAL TG-RICH LIPOPROTEINS

大多数心脏病患者的血脂正常。 知之甚少 脂蛋白介导的正常人动脉粥样硬化形成的细胞机制 受试者或甚至高胆固醇血症受试者，因为自然禁食 来自这些受试者的脂蛋白在体外似乎不具有致动脉粥样硬化性 [do不会引起人单核细胞-巨噬细胞（HMM）中的脂质蓄积]。 人类通常处于餐后状态， 是一种普遍接受的餐后现象。 很少有人知道的 特异性餐后富含磷脂酰肌醇脂蛋白的相互作用 亚种（ppTGRLP）与HMM，但是，相互作用，可能 有助于动脉粥样硬化形成。 这项提案的总体目标是确定细胞机制， ppTGRLP亚种的致动脉粥样硬化性，这些亚种在动脉粥样硬化过程中短暂出现。 某些正常和高脂蛋白血症受试者的餐后反应 动脉粥样硬化的风险增加（低HDL水平;小而密的LDL 模式;高LDL;高载脂蛋白B;高空腹甘油三酯水平;男性;载脂蛋白 E4表型）。 代谢稳定的受试者将进食 含有维生素A，以标记脑源性颗粒; TGRLP将 在餐前和餐后特定时间分离，通过 累积浮选成均匀大小的亚类。 禁食和 将检测ppTGRLP亚类的快速胆固醇酯， 作为体外试验的人THP-1单核-巨噬细胞的甘油三酯负荷 对于潜在的致动脉粥样硬化性;选择的致动脉粥样硬化ppTGRLP将是 通过免疫亲和色谱法细分为apo B-100与B-48 颗粒来确定致动脉粥样硬化物质的来源。 机制 将测定摄取（通过LDL受体，不同的巨噬细胞 异常TGRLP受体或其他机制）。 结构性决定因素 每种致动脉粥样硬化ppTGRLP亚类的功能异常将被 确定，餐后随时间跟踪，并与已知的 危险因素 这些研究应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ppTGRLP发生的因子。 潜在致动脉粥样硬化的基本生化决定因素的知识 ppTGRLP/细胞相互作用可能导致合理膳食的发展 以及最小化致动脉粥样硬化ppTGRLP表达的治疗措施 而且，可能的话，还可以找到更好的方法来确定 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.