Fatty Acid Transport in Eukaryotes

真核生物中的脂肪酸运输

• 批准号: 7943079
• 负责人: Paul N. Black
• 金额: $ 31.38万
• 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 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7943079
• 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; 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）：通过复杂的激素，神经元和环境调节剂的网络来维持脂质稳态。无法调节脂质代谢以维持稳态是许多疾病国家的标志，包括代谢综合征，肥胖，糖尿病，心血管疾病和一些癌症。总之，这些疾病是美国和大多数发达国家发病和死亡率的主要原因。脂质代谢中的特定代谢紊乱导致循环游离脂肪酸的水平升高，这又导致脂肪酸内在化增加和甘油三酸酯的异位积累。慢性血浆无脂肪酸和甘油三酸酯与肥胖，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，即胰腺胰岛素产生，心脏失败，心律失常，心律失常和肥肥的降低是由于这些脂肪在这些组织中的异常积累。拟议的工作解决了脂肪酸如何穿越质膜以及如何将其运输到下游代谢池中。这些是特别重要的问题，因为基本的生化机制控制了脂肪酸向细胞的运输并运输到离散代谢室中的运输较差。对导致游离脂肪酸细胞摄取的机制的理解对于预防和打击脂肪毒性至关重要，导致上述病理。先前的工作表明，一种驱动脂肪酸传输的过程是载酰化，其中特定的脂肪酸转运（FATP）同工型单独或与特定的长链酰基酰基酰基COA合成酶（ACSL）同工型在同一转运和脂肪酸的激活中的功能。假设FATP和ACSL的特异性同工型在不同类别的脂肪酸（饱和，单不饱和，多不饱和且高度不饱和）的矢量酰化中，并将其运输转移到离散的代谢池中。该假设将通过在以下特定目的中详细列出的实验进行检验：[1]定义了不同FATP和ACSL同工型在哺乳动物细胞中外源性脂肪酸的矢量酰化中的贡献； [2]确定FATP和ACSL同工型在脂肪酸运输的选择性和特异性中是否功能； [3]在使用抑制高吞吐量筛选中鉴定的化合物的研究中，区分和区分脂肪依赖性脂肪酸转运功能。这些化合物有望提供机械信息，可用于对抗和防止脂肪毒性。公共卫生相关性：脂肪酸与肥胖相关疾病的发展有关，包括代谢综合征，II型糖尿病和心血管疾病。引起这些疾病起步和进展的机制知之甚少。预防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。计划的研究将集中于脂肪酸转运蛋白（FATP）和酰基-COA合成酶（ACSL），以表征其在此过程中的作用。这项工作将提供机械细节，以了解这些蛋白质在脂肪酸摄取中的作用如何，将确定这些蛋白质在特定脂肪酸类别的运输中的特定作用，并将表征可能有用的小型复合抑制剂，这些抑制剂可能有助于开发药物以打击脂肪酸相关疾病。

项目成果

Targeting the fatty acid transport proteins (FATP) to understand the mechanisms linking fatty acid transport to metabolism.

以脂肪酸转运蛋白 (FATP) 为目标，了解脂肪酸转运与代谢之间的联系机制。

• DOI: 10.2174/187152209788009850
• 发表时间: 2009
• 期刊: Immunology, endocrine & metabolic agents in medicinal chemistry
• 作者: Black,PaulN;Sandoval,Angel;Arias-Barrau,Elsa;DiRusso,ConcettaC
• 通讯作者: DiRusso,ConcettaC

Fatty Acid Transport Proteins: Targeting FATP2 as a Gatekeeper Involved in the Transport of Exogenous Fatty Acids.

• DOI: 10.1039/c6md00043f
• 发表时间: 2016-04-01
• 期刊: MedChemComm
• 作者: Black PN;Ahowesso C;Montefusco D;Saini N;DiRusso CC
• 通讯作者: DiRusso CC

Vectorial acylation: linking fatty acid transport and activation to metabolic trafficking.

矢量酰化：将脂肪酸运输和激活与代谢运输联系起来。

• DOI: 10.1002/9780470985571.ch11
• 发表时间: 2007
• 期刊: Novartis Foundation symposium
• 作者: Black,PaulN;DiRusso,ConcettaC
• 通讯作者: DiRusso,ConcettaC

Chemical inhibition of fatty acid absorption and cellular uptake limits lipotoxic cell death.

• DOI: 10.1016/j.bcp.2015.09.004
• 发表时间: 2015-11-01
• 期刊: Biochemical pharmacology
• 影响因子: 5.8
• 作者: Ahowesso C;Black PN;Saini N;Montefusco D;Chekal J;Malosh C;Lindsley CW;Stauffer SR;DiRusso CC
• 通讯作者: DiRusso CC