Chylomicrons and endothelial biology

乳糜微粒和内皮生物学

• 批准号: 10595225
• 负责人: Ira J Goldberg
• 金额: $ 82.79万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10595225
• 关键词: Acceleration; Activins; Affect; Albumins; Apolipoproteins B; Arterial Fatty Streak; Arteries; Atherosclerosis; Binding Sites; Biological; Biology; Blood Vessels; Body part; CD36 Antigens; Cardiovascular Diseases; Cells; Cellular biology; Cholesterol; Cholesterol Esters; Chylomicrons; Data; Deposition; Dietary Fats; Endothelial Cells; Endothelium; Event; Fatty acid glycerol esters; Filtration; Gene Expression; Goals; Heart; Hypertriglyceridemia; In Vitro; Inflammation; Intestines; LDL Cholesterol Lipoproteins; Label; Length; Leukocytes; Ligand Binding; Link; Lipids; Lipoproteins; Low Density Lipoprotein Receptor; Low-Density Lipoproteins; Lysosomes; Macrophage; Mediating; Movement; Mus; N-terminal; Nonesterified Fatty Acids; Pathway interactions; Peptide Fragments; Phenotype; Phosphotransferases; Process; Production; Proteins; RNA; Reporting; Research Personnel; Role; SR-BI receptor; Side; Site; Source; Specificity; Surface; Testing; Thinness; Tissues; Travel; Triglycerides; Vascular Diseases; Vascular Endothelium; Work; apolipoprotein B-48; atherogenesis; endothelial cell scavenger receptor; extracellular vesicles; impression; in vivo; knock-down; lipoprotein lipase; novel; novel strategies; overexpression; prevent; receptor; transcytosis; uptake; vesicular release

ABSTRACT The first steps in atherosclerosis are the transendothelial movement and subendothelial accumulation of lipoprotein lipid. Endothelial cell (EC) transcytosis of LDL involves two receptors, scavenger receptor-BI (SR-BI) and activin-like kinase 1 (ALK1). We showed that ECs also internalize undigested chylomicrons via SR-BI and process them in lysosomes, leading to storage of some lipid as lipid droplets and the release of small extracellular vesicles (sEVs) that cause lipid accumulation in macrophages. While many have considered chylomicrons as non-atherogenic and too large to cross the EC barrier, this concept is now outdated with the understanding that lipoprotein entry into the artery is a receptor-mediated process. The overall goal of this project is to determine how EC chylomicron uptake affects EC biology, delivers lipids to the artery, and accelerates atherosclerosis. In Aim 1, we propose to determine how triglyceride-rich lipoproteins affect lipid transfer across the vascular endothelium. We provide preliminary data suggesting that N-terminal apoB18 has separate ligand binding regions for ALK1 and SR-BI. We will determine whether lipoprotein size or apoB length determines exposure of these two different regions. We also will determine how sEVs from chylomicron-conditioned ECs cause lipid accumulation in macrophages and determine the differences between sEVs released from control and chylomicron-treated ECs. In Aim 2, we propose in vivo studies to determine the role of the EC-chylomicron uptake pathway in tissue lipid delivery and atherosclerosis. We provide preliminary data suggesting that chylomicrons that accumulate in lipoprotein lipase (LpL) deficient mice increase atherosclerosis. We will use genetically modified mice and knockdown strategies to assess the uptake of LDL and chylomicron lipids into arteries and will assess whether more extensive atherosclerosis in mice with combined deficiency of LpL and the LDL receptor is due to hyperchylomicronemia. Finally, we will determine whether AAV-mediated overexpression of apoB18 reduces EC uptake of apoB lipoproteins in vivo and alters atherosclerosis. Completion of the proposed studies promises to alter our view of the relationship of chylomicrons to vascular disease, define a novel pathway for arterial accumulation of atherogenic lipids, and illustrate a possible approach to prevent these lipids from entering the artery.

抽象的 动脉粥样硬化的第一步是跨内皮运动和内皮下积累 脂蛋白脂质。 LDL 的内皮细胞 (EC) 转胞吞作用涉及两种受体：清道夫受体-BI (SR-BI) 和激活素样激酶 1 (ALK1)。我们发现 EC 还通过 SR-BI 内化未消化的乳糜微粒 在溶酶体中处理它们，导致一些脂质以脂滴的形式储存并释放出小的细胞外 导致巨噬细胞脂质积累的囊泡（sEV）。虽然许多人认为乳糜微粒是 非动脉粥样硬化且太大而无法穿过 EC 屏障，这个概念现在已经过时了，因为人们认识到 脂蛋白进入动脉是一个受体介导的过程。该项目的总体目标是确定 EC 乳糜微粒摄取如何影响 EC 生物学、向动脉输送脂质并加速动脉粥样硬化。在 目标 1，我们建议确定富含甘油三酯的脂蛋白如何影响脂质跨血管转运 内皮细胞。我们提供的初步数据表明 N 端 apoB18 具有单独的配体结合 ALK1 和 SR-BI 区域。我们将确定脂蛋白大小或 apoB 长度是否决定了暴露 这两个不同的地区。我们还将确定来自乳糜微粒条件 EC 的 sEV 如何导致脂质 巨噬细胞中的积累并确定对照和对照释放的 sEV 之间的差异 乳糜微粒处理的 EC。在目标 2 中，我们提出体内研究以确定 EC-乳糜微粒的作用 组织脂质输送和动脉粥样硬化中的摄取途径。我们提供的初步数据表明 脂蛋白脂肪酶（LpL）缺陷小鼠体内积聚的乳糜微粒会加剧动脉粥样硬化。我们将使用 转基因小鼠和敲除策略来评估 LDL 和乳糜微粒脂质的摄取 动脉，并将评估 LpL 和 LpL 联合缺乏的小鼠是否出现更广泛的动脉粥样硬化 LDL 受体是由于高乳糜微粒血症所致。最后，我们将确定 AAV 是否​​介导 apoB18 的过度表达会减少体内 EC 对 apoB 脂蛋白的摄取并改变动脉粥样硬化。完成 拟议的研究有望改变我们对乳糜微粒与血管疾病关系的看法，定义 动脉粥样硬化脂质积聚的新途径，并说明了预防的可能方法 这些脂质进入动脉。