Role of trans-endothelial fatty acid transport in insulin resistance

跨内皮脂肪酸转运在胰岛素抵抗中的作用

• 批准号: 9764352
• 负责人: Ayon Ibrahim
• 金额: $ 4.34万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2020-08-07
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9764352
• 关键词: Acyl Coenzyme A; Acylation; Address; Amino Acids; Blood; Blood Glucose; Blood Vessels; Blood capillaries; Branched-Chain Amino Acids; Catabolism; Cell Culture Techniques; Cells; Clinical; Closure by clamp; Data; Deposition; Diabetes Mellitus; Diet; Disease; Endothelial Cells; Endothelium; Environment; Fatty Acids; Fatty acid glycerol esters; Genes; Genetic Models; Glucose; Goals; Human; In Vitro; Insulin; Insulin Resistance; Investigation; Knockout Mice; Lead; Lipids; Lysosomes; Measures; Mediating; Mediator of activation protein; Mentorship; Metabolic Diseases; Methodology; Methods; Molecular; Morbidity - disease rate; Mus; Muscle; Nature; Non-Insulin-Dependent Diabetes Mellitus; Oxides; Pathogenesis; Pathway interactions; Patients; Pennsylvania; Peripheral; Physiological; Play; Prevention; Process; Regulation; Research; Role; Running; Signal Transduction; Skeletal Muscle; Small Interfering RNA; Testing; Therapeutic; Therapeutic Intervention; Tissues; Universities; Valine; Western Blotting; Work; epidemiology study; experimental study; fatty acid transport; fatty acid-transport protein; gain of function; genome-wide; glucose tolerance; high throughput screening; in vivo; insulin signaling; insulin tolerance; interest; knock-down; late endosome; loss of function; notch protein; novel; paracrine; prevent; success; uptake; vector

Project Summary Type II diabetes mellitus (T2DM) is marked by aberrant distribution of lipid species, such as incompletely oxidized non-esterified fatty acids in skeletal muscle. However, the mechanism by which fatty acids reach the muscle, and in particular how they transverse across the endothelium barrier, is largely unknown. We have uncovered that the poorly-studied metabolite 3-hydroxyisobutyrate (3-HIB) plays a novel role in fatty acid uptake. Produced in the skeletal muscle as a product of valine catabolism, 3-HIB induces trans-endothelial fatty acid transport both in vitro and in vivo. Valine is a branched-chain amino acid (BCAA), a class of molecules recently shown in a number of epidemiological studies to be implicated in insulin resistance. The discovery of 3-HIB’s role in fatty acid uptake opens a new avenue for exploring the connection between BCAA flux, lipid deposition, and insulin resistance. Moreover, fatty acid transport proteins (FATPs) have been shown to play a major role in fatty acid uptake in numerous tissues, and, intriguingly, knockdown of FATP3 and FATP4, the predominant FATPs in endothelial cells, abrogate 3-HIB mediated fatty acid uptake in these cells. Together, these observations lead to us to hypothesize that 3-HIB is a dominant paracrine modulator of trans-vascular FATP3/4- mediated fatty acid transport, and that excess BCAA catabolism and 3-HIB leads to inappropriate lipid accumulation and insulin resistance. We propose to examine the molecular nature of 3-HIB, FATP3 and FATP4, and discern how they work in concert to induce fatty acid transport across the endothelium. These questions will be addressed by various methods: a genome-wide, high-throughput screen to identify critical components of the pathway; cell culture experiments identifying the subcellular localization and the relevance of the acyl-CoA synthase activity of FATP3/4; and studies in newly generated genetic models of endothelial cell specific FATP3/4 knockout mice. Ultimately, we hope to use these investigations to validate these new targets for the prevention of lipid accumulation in non-adipose tissues, and thus for therapeutic intervention for treating patients with T2DM.

项目概要 II 型糖尿病 (T2DM) 的特点是脂质种类分布异常，例如 骨骼肌中不完全氧化的非酯化脂肪酸。然而，该机制通过 哪些脂肪酸到达肌肉，特别是它们如何横穿肌肉 内皮屏障，很大程度上是未知的。我们发现，研究不足的代谢物 3-羟基异丁酸酯 (3-HIB) 在脂肪酸吸收中发挥着新的作用。产生于骨骼 肌肉作为缬氨酸分解代谢的产物，3-HIB 诱导跨内皮脂肪酸转运 体外和体内。缬氨酸是一种支链氨基酸（BCAA），一类分子 最近的一些流行病学研究表明，与胰岛素抵抗有关。这 3-HIB 在脂肪酸摄取中的作用的发现为探索这种联系开辟了新途径 支链氨基酸流动、脂质沉积和胰岛素抵抗之间的关系。此外，脂肪酸运输 蛋白质（FATP）已被证明在许多组织的脂肪酸摄取中发挥着重要作用， 有趣的是，FATP3 和 FATP4（内皮细胞中主要的 FATP）被敲低， 消除这些细胞中 3-HIB 介导的脂肪酸摄取。这些观察结果共同导致 我们假设 3-HIB 是跨血管 FATP3/4- 的主要旁分泌调节剂 介导的脂肪酸转运，过量的 BCAA 分解代谢和 3-HIB 会导致 不适当的脂质积累和胰岛素抵抗。我们建议检查分子 3-HIB、FATP3 和 FATP4 的性质，并了解它们如何协同作用以诱导脂肪酸 穿过内皮的运输。这些问题将通过多种方法来解决： 全基因组、高通量筛选，以确定该途径的关键组成部分；细胞培养 鉴定酰基辅酶A合酶的亚细胞定位和相关性的实验 FATP3/4 的活性；以及新生成的内皮细胞特异性遗传模型的研究 FATP3/4 基因敲除小鼠。最终，我们希望利用这些调查来验证这些新的 预防非脂肪组织中脂质积累的目标，从而用于治疗 治疗 T2DM 患者的干预措施。