Fatty Acid Transport in Eukaryotes

真核生物中的脂肪酸运输

• 批准号: 7735862
• 负责人: Paul N. Black
• 金额: $ 31.4万
• 依托单位: UNIVERSITY OF NEBRASKA LINCOLN
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-06 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7735862
• 关键词: Acyl Coenzyme A; Acylation; Address; Apoptosis; Arrhythmia; Automobile Driving; Binding; Biochemical; Cardiovascular Diseases; Cell Death; Cell Line; Cell membrane; Cells; Ceramides; Coenzyme A Ligases; Complex; Developed Countries; Developing Countries; Development; Diabetes Mellitus; Disease; Disease Progression; Eukaryota; Fatty Acids; Heart failure; Homeostasis; Hormonal; Hypertrophy; Insulin; Insulin Resistance; Kinetics; Label; Laboratories; Lead; Lipids; Malignant Neoplasms; Mammalian Cell; Mass Spectrum Analysis; Membrane; Membrane Protein Traffic; Metabolic; Metabolic Pathway; Metabolic syndrome; Methods; Monitor; Morbidity - disease rate; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Obesity; Pancreas; Pathology; Pharmaceutical Preparations; Physiologic pulse; Plasma; Process; Production; Protein Isoforms; Proteins; Reactive Oxygen Species; Resolution; Role; Saturated Fatty Acids; Site; Specificity; Stress; Testing; Tissues; Toxic effect; Triglycerides; United States; Work; Yeasts; combat; defined contribution; fatty acid oxidation; fatty acid transport; fatty acid-transport protein; high throughput screening; inhibitor/antagonist; lipid metabolism; mortality; novel; prevent; protein function; public health relevance; research study; trafficking; uptake

DESCRIPTION (provided by applicant): Lipid homeostasis is maintained through a complex network of hormonal, neuronal and environmental regulators. Inability to modulate lipid metabolism to maintain homeostasis is a hallmark of many disease states including metabolic syndrome, obesity, diabetes, cardiovascular disease and some cancers. Together, these diseases are the leading causes of morbidity and mortality in the United States and most other developed countries. Specific metabolic disturbances in lipid metabolism result in elevating the levels of circulating free fatty acids, which in turn lead to increased fatty acid internalization and ectopic accumulation of triglycerides. The correlation between chronically elevated plasma free fatty acids and triglycerides with the development of obesity, insulin resistance and cardiovascular disease has led to the hypothesis that decreases in pancreatic insulin production, cardiac failure, arrhythmias, and hypertrophy are due to aberrant accumulation of lipids in these tissues. The proposed work addresses how fatty acids traverse the plasma membrane and how they are trafficked into downstream metabolic pools. These are especially important questions as the underlying biochemical mechanisms, which govern the transport of fatty acids into the cell and trafficking into discrete metabolic compartments are poorly defined. An understanding of the mechanism(s) leading to cellular uptake of free fatty acids is essential to prevent and combat lipotoxicity leading to the pathologies listed above. Previous work has shown that one process driving fatty acid transport is vectorial acylation, where specific fatty acid transport (FATP) isoforms alone or in concert with specific long chain acyl CoA synthetase (Acsl) isoforms function in the concomitant transport and activation of fatty acids. It is hypothesized that specific isoforms of FATP and Acsl function in the vectorial acylation of different classes of fatty acids (saturated, monounsaturated, polyunsaturated and highly unsaturated) across the plasma membrane and direct their trafficking into discrete metabolic pools. This hypothesis will be tested by completing experiments detailed in the following Specific Aims: [1] Define the contribution of the different FATP and Acsl isoforms in the vectorial acylation of exogenous fatty acids in mammalian cells; [2] Establish whether the FATP and Acsl isoforms function in the selectivity and specificity of fatty acid trafficking; And [3] Distinguish and discriminate FATP-dependent fatty acid transport functions in studies employing compounds that inhibit transport identified in high throughput screens. These compounds are expected to provide mechanistic information useful to combat and prevent lipotoxicity. PUBLIC HEALTH RELEVANCE: Fatty acids are implicated in the development of obesity related illnesses including metabolic syndrome, type II diabetes and cardiovascular disease. The mechanisms causing the initiation and progression of these diseases are poorly understood. One method to prevent toxicity associated with fatty acid accumulation would be to inhibit fatty acid uptake and accumulation within cells. The planned studies will focus on the fatty acid transport proteins (FATP) and acyl-CoA synthetases (Acsl) to characterize their role in this process. This work will provide mechanistic details to understand how these proteins function in fatty acid uptake into a cell, will determine the specific roles of these proteins in the transport of specific classes of fatty acids, and will characterize small compound inhibitors that may be useful to develop drugs to combat fatty acid-related diseases.

描述（由申请人提供）：脂质稳态是通过激素、神经元和环境调节剂的复杂网络来维持的。无法调节脂质代谢以维持体内平衡是许多疾病状态的标志，包括代谢综合征、肥胖、糖尿病、心血管疾病和一些癌症。这些疾病加在一起是美国和大多数其他发达国家发病和死亡的主要原因。脂质代谢中的特定代谢紊乱导致循环游离脂肪酸水平升高，进而导致脂肪酸内化增加和甘油三酯的异位积累。血浆游离脂肪酸和甘油三酯长期升高与肥胖、胰岛素抵抗和心血管疾病的发展之间的相关性导致了这样的假设：胰腺胰岛素产生减少、心力衰竭、心律失常和肥厚是由于这些部位脂质的异常积累造成的。组织。拟议的工作解决了脂肪酸如何穿过质膜以及它们如何被运输到下游代谢池。这些都是特别重要的问题，因为控制脂肪酸运输到细胞中以及运输到离散代谢区室的潜在生化机制尚不清楚。了解导致细胞摄取游离脂肪酸的机制对于预防和对抗导致上述病理的脂毒性至关重要。先前的工作表明，驱动脂肪酸转运的一个过程是矢量酰化，其中特定脂肪酸转运（FATP）亚型单独或与特定长链酰基辅酶A合成酶（Acsl）亚型协同作用，在脂肪酸的伴随转运和激活中发挥作用。据推测，FATP 和 Acsl 的特定亚型在跨质膜的不同类别脂肪酸（饱和、单不饱和、多不饱和和高度不饱和）的矢量酰化中起作用，并引导它们运输到离散的代谢池中。该假设将通过完成以下具体目标中详述的实验来检验： [1] 定义不同 FATP 和 Acsl 亚型在哺乳动物细胞中外源脂肪酸矢量酰化中的贡献； [2] 确定FATP和Acsl亚型是否在脂肪酸运输的选择性和特异性中发挥作用； [3] 在使用抑制高通量筛选中鉴定的转运的化合物的研究中区分和区分 FATP 依赖性脂肪酸转运功能。这些化合物有望提供可用于对抗和预防脂毒性的机制信息。公共卫生相关性：脂肪酸与肥胖相关疾病的发生有关，包括代谢综合征、II 型糖尿病和心血管疾病。人们对导致这些疾病发生和进展的机制知之甚少。防止与脂肪酸积累相关的毒性的一种方法是抑制细胞内脂肪酸的摄取和积累。计划的研究将集中在脂肪酸转运蛋白 (FATP) 和酰基辅酶 A 合成酶 (Acsl) 上，以表征它们在此过程中的作用。这项工作将提供机制细节，以了解这些蛋白质如何在脂肪酸摄取到细胞中发挥作用，将确定这些蛋白质在特定类别脂肪酸运输中的具体作用，并将表征可能有助于开发的小化合物抑制剂对抗脂肪酸相关疾病的药物。