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.

PI 的实验室重点研究导致组织吸收脂质的途径及其代谢影响，我们发现 FA 转运蛋白 CD36 介导 VLDL 来源的 FA 的吸收，但不介导乳糜微粒 (CM) 来源的 FA 的吸收，并在体内证实了这一点。我们最近对 CD36 基因进行了修饰，并在多个组织中进行了敲除，这与该提议最密切相关，我们发现内皮细胞 (EC) 具有特异性。 CD36 缺失再现了全局 CD36 缺失的许多体内效应，包括减少肌肉和脂肪组织中的长链 FA 摄取。这些发现证明了内皮细胞在调节脂质摄取中的重要性，并与新的初步数据一起构成了当前应用的基础。 ，其重点是了解 EC 在摄取非酯化 FA 以及源自 CM 和 VLDL 的 FA 方面如何发挥作用。我们的初步数据表明，外源 FA 与复合物。 EC-CD36 与 Caveolin 1 (Cav1) 一起被内化到囊泡中，并从外泌体样小细胞外囊泡或 sEV 内的 EC 中释放出来。在目标 1 中，我们将剖析与 FA-CD36-Cav1 相互作用相关的细胞事件和EC 的 FA 转胞吞作用并定义了 sEV 分泌所需的过程。此外，我们建议在高 FA 水平下，例如，在 CM 脂肪分解过程中，FA 转移的非 CD36 旁细胞途径被激活，我们将确定介导 FA 诱导的 EC 连接和屏障功能变化的机制。脂蛋白脂肪酶和非 CD36 需要的过程似乎涉及清道夫受体 B1 在目标 2 中，我们将研究 EC 如何从 CM 传递 FA。我们将确定 CM 与 EC 表面相互作用的分子要求、内化的细胞过程以及 CM 脂质是否跨 EC 转胞吞并在 EV 中释放。我们将比较 CM 摄取途径和 VLDL 的摄取途径。我们还将研究 FA、CM、VLDL 和 EV 产品的内化如何改变 EC 和巨噬细胞生物学。器官之间的关系，并将定义组织中脂质的生理和病理吸收和储存的基本过程，这些信息将提出新的方法来破坏代谢综合征和2型糖尿病引起的过量热量摄入的病理后果。