Blood TG clearance and vascular biology

血液 TG 清除率和血管生物学

• 批准号: 10628992
• 负责人: Ira J Goldberg
• 金额: $ 63.42万
• 依托单位: NYU LONG ISLAND 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: 2023-05-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10628992
• 关键词: Acceleration; Activins; Adipocytes; Affect; Apolipoproteins B; Arteries; Atherosclerosis; Binding; Biogenesis; Biology; Blood; Blood Vessels; Cardiovascular Diseases; Catabolism; Cells; Cellular Metabolic Process; Cellular biology; Characteristics; Cholesterol; Chronic; Chylomicrons; Data; Development; Endothelial Cells; Endothelium; Enterocytes; Event; Fasting; Fatty acid glycerol esters; Gene Expression; Genes; Goals; Hepatic; Hepatocyte; Human; In Vitro; Inflammation; Inflammatory; Intestines; Knock-out; Knockout Mice; Ligand Binding; Link; Lipids; Lipolysis; Lipoproteins; Liver; Low Density Lipoprotein Receptor; Low-Density Lipoproteins; Lysosomes; Macrophage; Mediating; Movement; Mus; N-terminal; Pathway interactions; Peptides; Phosphotransferases; Postprandial Period; Prevention; Process; Production; Protein Deficiency; Proteomics; RNA; Reporting; Research Personnel; Role; SR-BI receptor; Site; Source; Testing; Tissues; Triglycerides; Vascular Diseases; Very low density lipoprotein; bafilomycin A; endothelial cell scavenger receptor; extracellular vesicles; feeding; impression; in vivo; lipidomics; lipoprotein lipase; microsomal triglyceride transfer protein; novel; novel strategies; receptor; single cell analysis; transcytosis; uptake; vascular inflammation; western diet

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 While many have considered chylomicrons as non-atherogenic and too large to cross the EC barrier, this concept is now outdated with the understanding that lipoprotein entry into the artery is a receptor-mediated process.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 Project 3 (P3) 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 (TRLs) from the liver and intestines are internalized and either processed within ECs or transcytosed. To do this, we will use mice with selective knockout of liver and intestinal microsomal triglyceride transfer protein (MTP) obtained from Dr. Hussain (P1) to determine lipoprotein characteristics that determine their interaction with SR-BI and ALK1. We will also determine how lipoproteins created with liver FIT2 knockout (P2) affect EC inflammation and the production and composition of EC released sEVs. Our preliminary data show that the N-terminal region of apoB has separate ligand binding regions for ALK1 and SR-BI and this aim will determine why and how lipoprotein uptake via each of these receptors affects ECs. In Aim 2, we propose in vivo studies to determine whether postprandial lipemia leads to EC inflammation and whether the site of origin of these TRLs determines their effects on arterial ECs. We provide preliminary data suggesting that chylomicrons that accumulate in lipoprotein lipase (LpL) deficient mice increase atherosclerosis. We will use N-terminal fragments of apoB to reduce lipoprotein uptake into ECs to determine role(s) of ALK1 and SR-BI in EC inflammation and atherosclerosis. Completion of the proposed studies promises to alter our view of the relationship of chylomicrons to vascular disease, determine whether TRLs from liver and intestine have similar effects on ECs, and define a novel approach to atherosclerosis prevention.

摘要 动脉粥样硬化的第一步是血管内皮细胞的跨内皮细胞运动和内皮下堆积。 脂蛋白脂质。低密度脂蛋白的内皮细胞转胞作用涉及清道夫受体-BI(SR-BI)两种受体 和激活素样激酶1(ALK1)。我们发现内皮细胞还通过SR-BI和 在溶酶体中处理它们，导致一些脂肪以脂滴的形式储存，并释放出细胞外的小分子 导致巨噬细胞脂质堆积的囊泡(SEV)。虽然许多人认为乳糜龙是 这个概念不会导致动脉粥样硬化，而且太大，无法越过EC屏障，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。项目3(P3)的总体目标是确定 EC乳胶粒摄取如何影响EC生物学，将脂质输送到动脉，并加速动脉粥样硬化。在……里面 目的1，我们建议确定来自肝脏和肠道的富含甘油三酯的脂蛋白(TRL)是如何 内化，或者在ECs内处理，或者通过细胞转运。为此，我们将使用具有选择性基因敲除的小鼠 从Hussain博士(P1)获得的肝脏和肠道微粒体甘油三酯转移蛋白(MTP)以确定 决定其与SR-BI和ALK1相互作用的脂蛋白特性。我们还将确定如何 肝脏FIT2基因敲除后产生的脂蛋白(P2)影响EC炎症和血管内皮生长因子的产生和组成 欧共体发布了SEV。我们的初步数据表明，apoB的N-末端区域有单独的配体结合 ALK1和SR-BI的区域，这一目标将确定为什么以及如何通过这些区域摄取脂蛋白 受体影响内皮细胞。在目标2中，我们建议进行体内研究，以确定餐后血脂是否会导致 血管内皮细胞炎症以及这些TRL的来源是否决定了它们对动脉内皮细胞的影响。我们提供 初步数据表明，脂蛋白脂肪酶(LPL)缺陷小鼠体内积累的乳糜粒增加 动脉硬化。我们将使用apoB的N末端片段来减少内皮细胞对脂蛋白的摄取，以确定 ALK1和SR-BI在EC炎症和动脉粥样硬化中的作用(S)。完成拟议研究的承诺 为了改变我们对乳糜粒与血管疾病关系的看法，确定来自肝脏和肝脏的TRL 肠道对内皮细胞也有类似的作用，为动脉粥样硬化的预防提供了一种新的途径。