Pathways of Tissue Lipid Uptake

组织脂质摄取途径

• 批准号: 10318196
• 负责人: Nada A. Abumrad
• 金额: $ 77.17万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-04-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10318196
• 关键词: Adipose tissue; Affect; Albumins; Alkynes; Animal Model; Apolipoproteins B; Apoproteins; Atherosclerosis; Biochemistry; Biogenesis; Biology; Blood Circulation; Calories; Capillary Permeability; Cell physiology; Cell surface; Cells; Cellular biology; Cholesterol; Cholesterol Esters; Chylomicrons; Collaborations; Complex; Confocal Microscopy; Data; Development; Disease; Electron Microscopy; Endothelial Cells; Endothelium; Esters; Event; Fasting; Fatty Acids; Foam Cells; Funding; Gene Expression; Genes; Grant; Heart; Heart failure; Human; In Vitro; Insulin Receptor; Intake; Intercellular Junctions; Investigation; Knock-out; Knockout Mice; Laboratories; Lipids; Lipolysis; Lipoproteins; LoxP-flanked allele; Mediating; Metabolic; Metabolic syndrome; Metabolism; Molecular; Movement; Mus; Muscle; Muscle Cells; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Organ; Particle Size; Pathologic; Pathway interactions; Phospholipids; Physiological; Population; Process; Proteins; Receptor Signaling; Regulation; Reporter; Reporting; Retinoids; Role; SR-BI receptor; Skeletal Muscle; Source; Testing; Tissues; Triglycerides; Very low density lipoprotein; base; caveolin 1; exosome; extracellular vesicles; fatty acid metabolism; fatty acid transport; gene function; in vivo; lipoprotein lipase; long chain fatty acid; macrophage; nanoGold; non-alcoholic fatty liver disease; novel; operation; prevent; receptor; receptor internalization; src-Family Kinases; synergism; transcytosis; uptake; very low density lipoprotein triglyceride; vesicular release

The PIs’ laboratories focus on the pathways leading to lipid uptake by tissues and their metabolic implications. We showed that the FA transporter, CD36, mediates uptake of VLDL- but not chylomicron (CM)-derived FAs and established in vivo that there are at least two pathways for FA uptake into tissues. We recently floxed the CD36 gene and created knockouts in multiple tissues. Most germane to this proposal, we showed that endothelial cell (EC) specific CD36 deletion reproduces many of the in vivo effects of global CD36 deletion including reduced long-chain FA uptake into muscle and adipose tissues. These findings documented importance of the endothelium in regulating tissue lipid uptake and together with novel preliminary data form the basis for the current application, which is focused on understanding how ECs function in uptake of non-esterified FAs and of FAs derived from CMs and VLDL. Our preliminary data show that exogenous FAs in complex with EC-CD36 and in conjunction with Caveolin 1 (Cav1) are internalized into vesicles and are released from ECs within exosome- like small extracellular vesicles or sEVs. In Aim 1 we will dissect the cellular events associated with the FA- CD36-Cav1 interaction and FA transcytosis by ECs and define the processes required for sEV secretion. In addition, we propose that at high FA levels, e.g. during CM lipolysis, a non-CD36 paracellular pathway of FA transfer is activated and we will determine the mechanisms that mediate FA-induced changes in EC junctions and barrier function. Other preliminary data show that ECs internalize and metabolize nascent CMs via a non- lipoprotein lipase and non-CD36 requiring process that appears to involve scavenger receptor-B1. In Aim 2 we will examine how EC delivery of FAs from CMs and VLDL differs. We will determine the molecular requirements for CM interaction with the EC surface, the cellular processes for internalization and whether CM lipids are transcytosed across ECs and released in EVs. The CM uptake pathway will be compared to that for VLDL where we will define the role of CD36. We will also examine how internalization of FAs, CMs, VLDL and EV products changes EC and macrophage biology. These studies will illustrate the pathways by which the body distributes calories between organs and will define basic processes that underlie the physiologic and pathological uptake and storage of lipids in tissues. Such information will suggest novel ways to disrupt the pathological consequences of excess calorie intake that occur with metabolic syndrome and type 2 diabetes.

PIS的实验室专注于导致组织脂肪摄取及其代谢意义的途径。我们表明，FA转运蛋白CD36介导了VLDL-的摄取，但不介导乳糜微粒（CM）衍生的FAS，并在体内确定，至少有两种摄入FA进入组织的途径。最近，我们在CD36基因中发挥了作用，并在多个组织中产生了敲除。该提案的大多数人都表明，内皮细胞（EC）特定的CD36缺失再现了全球CD36缺失的许多体内效应，包括减少长链FA对肌肉和脂肪时间的吸收。这些发现记录了内皮菌在确定组织脂质摄取的重要性，并与新的初步数据一起构成了当前应用的基础，该数据侧重于理解ECS在摄取非层化FAS和源自CMS和VLDL的FAS中的功能。我们的初步数据表明，与EC-CD36复合物以及与Caveolin 1（Cav1）结合使用的外源性FA被内部化为蔬菜，并从外部体内的EC中释放为小细胞外蔬菜或SEV。在AIM 1中，我们将通过ECS解剖与FA-CD36-CAV1相互作用和FA跨胞菌病有关的细胞事件，并定义SEV分泌所需的过程。此外，我们建议在高FA水平上，例如在CM脂解过程中，激活FA转移的非CD36旁细胞途径，我们将确定介导FA诱导的EC连接和屏障功能变化的机制。其他初步数据表明，ECS通过非脂蛋白脂肪酶和非CD36的NASCENT CM进行了内化和代谢，而非CD36则需要似乎涉及清道夫受体B1的过程。在AIM 2中，我们将研究EC从CMS和VLDL差异的EC传递。我们将确定与EC表面相互作用的分子需求，内部化的细胞过程以及CM脂质是否在EC跨EC跨性别并在EV中释放。将CM摄取途径与VLDL进行比较，我们将定义CD36的作用。我们还将研究FAS，CMS，VLDL和EV产品的内在化如何改变EC和巨噬细胞生物学。这些研究将说明身体在器官之间分配卡路里的途径，并定义基本过程，这些过程是组织中脂质的生理和病理摄取和储存的基础。这些信息将提出破坏代谢综合征和2型糖尿病的过量卡路里摄入量的病理后果的新方法。