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 While many have considered chylomicrons as non-atherogenic and too large to cross the EC barrier, this concept is now outdated with the understanding that lipoprotein entry into the artery is a receptor-mediated process.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.

抽象的 动脉粥样硬化的第一步是跨内皮运动和下皮的积累 脂蛋白脂质。 LDL的内皮细胞（EC）转胞胞病涉及两个受体清除受体-BI（SR-BI） 和激活素样激酶1（ALK1）。我们表明，EC还通过SR-BI和 用溶酶体加工它们，导致某些脂质作为脂质液滴的储存和小细胞外的释放 导致巨噬细胞中脂质积累的囊泡（SEV）。虽然许多人认为酪蛋白是 非动脉粥样硬化，太大而无法跨越EC的障碍，现在已经过时了，以至于 脂蛋白进入动脉是受体介导的过程。项目3（P3）的总体目标是确定 EC乳糜微粒的摄取如何影响EC生物学，向动脉提供脂质并加速动脉粥样硬化。在 AIM 1，我们建议确定肝脏和肠中富含甘油三酸酯的脂蛋白（TRL）是如何的 内部化并在EC中进行处理或经跨性别。为此，我们将使用小鼠和选择性淘汰 从侯赛因博士（P1）获得的肝脏和肠微粒体甘油三酸酯转移蛋白（MTP）的 脂蛋白特征决定了它们与SR-BI和ALK1的相互作用。我们还将确定如何 用肝脏Fit2敲除（P2）产生的脂蛋白影响EC炎症以及生产和组成 EC发布了Sevs。我们的初步数据表明，APOB的N末端区域具有单独的配体结合 ALK1和SR-BI的区域以及此目标将决定为什么和如何通过这些脂蛋白摄取摄取脂蛋白 受体会影响EC。在AIM 2中，我们提出了体内研究，以确定餐后脂肪血症是否导致 EC炎症以及这些TRL的起源部位是否决定了它们对动脉EC的影响。我们提供 初步数据表明，在脂蛋白脂肪酶（LPL）缺乏小鼠中积聚的酪蛋白增加 动脉粥样硬化。我们将使用APOB的N末端片段来减少脂蛋白的摄取，以确定 ALK1和SR-BI在EC炎症和动脉粥样硬化中的作用。拟议研究的完成承诺 为了改变我们对酪蛋白与血管疾病的关系的看法，请确定是否来自肝脏和 肠对ECS具有相似的影响，并定义了预防动脉粥样硬化的新方法。