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: 9191308
• 负责人: Ayon Ibrahim
• 金额: $ 4.36万
• 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 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9191308
• 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; Data; Deposition; Diabetes Mellitus; Diet; Disease; Endothelial Cells; Endothelium; Environment; Epidemiologic Studies; 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; 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; capillary; 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; research study; success; trafficking; uptake

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.

项目摘要 II型糖尿病（T2DM）的标志是脂质物种的异常分布，例如 骨骼肌中未完全氧化的非层化脂肪酸。但是，通过 哪种脂肪酸到达肌肉，尤其是它们如何横穿肌肉 内皮屏障在很大程度上是未知的。我们发现了研究不佳的代谢物 3-羟基异丁酸酯（3-HIB）在脂肪酸摄取中起着新的作用。在骨骼中产生 肌肉作为缬氨酸分解代谢的产物，3-HIB诱导经内端脂肪酸转运 体外和体内。 Valine是一种分支链氨基酸（BCAA），一类分子 最近在胰岛素抵抗中暗示的许多流行病学研究中显示。这 发现3-Hib在脂肪酸摄取中的作用为探索连接开辟了新的途径 在BCAA通量，脂质沉积和胰岛素抵抗之间。此外，脂肪酸转运 蛋白质（脂肪）已显示在众多组织中脂肪酸摄取中起主要作用， 而且，有趣的是，在内皮细胞中主要脂肪的FATP3和FATP4的敲低， 这些细胞中消除了3-HIB介导的脂肪酸摄取。这些观察结果一起导致 我们假设3-Hib是反流血FATP3/4-的主要旁分泌调节剂 介导的脂肪酸转运，超过BCAA分解代谢，3-HIB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，并辨别它们如何共同诱导脂肪酸 横穿内皮的运输。这些问题将通过各种方法来解决： 全基因组，高通量屏幕，以识别途径的关键成分；细胞培养 识别亚细胞定位的实验和酰基-COA合酶的相关性 FATP3/4的活动；以及新生成的内皮细胞特异性遗传模型的研究 FATP3/4淘汰小鼠。最终，我们希望使用这些投资来验证这些新的 预防非辅助时机中脂质积累的靶标，因此用于治疗 治疗T2DM患者的干预措施。