Acyl-CoA Synthetase: Structure, Function and Regulation

酰基辅酶 A 合成酶：结构、功能和调节

基本信息

批准号：
8474746
负责人：
Rosalind Anne Coleman
金额：
$ 30.14万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-04-15 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8474746
关键词：
ASCL1 gene Acyl Coenzyme A Acyltransferase Address Adipose tissue Atherosclerosis Carbohydrates Carnitine Carnitine Acyltransferases Cells Coenzyme A Ligases Complex Cultured Cells Data Development Diabetes Mellitus Dietary intake Eicosanoid Production Eicosanoids Endoplasmic Reticulum Energy-Generating Resources Enzymes Fatty Acids Fatty Liver Fatty acid glycerol esters Funding Gene Expression Gluconeogenesis Glucose Hand Heart Heart Hypertrophy Hepatocyte Hypertrophy Hypoglycemia Inflammation Inflammatory Insulin Insulin Resistance Knockout Mice Knowledge Learning Ligands Lipids Liver Location Mediating Membrane Messenger RNA Metabolic Metabolic Pathway Metabolic syndrome Metabolism Mitochondria Mus Myocardium Myopathy Nuclear Nutrition Disorders Obesity Organ Outer Mitochondrial Membrane Pathway interactions Peripheral Phospholipids Phosphorylation Polyunsaturated Fatty Acids Production Protein Isoforms Proteins Regulation Signal Transduction Skeletal Muscle Source Structure Thermogenesis Tissues Triglycerides adipocyte differentiation arachidonate base cost human FRAP1 protein insulin signaling lipid biosynthesis lipid metabolism long chain fatty acid oxidation preference response skeletal transcription factor

项目摘要

DESCRIPTION (provided by applicant): Dietary intake of excess fat or carbohydrate results in increased synthesis and storage of triacylglycerol (TAG). The long-chain fatty acids (FA) that contribute to TAG synthesis must be first converted to acyl-CoAs by long-chain acyl-CoA synthetase (ACSL). Because acyl-CoAs lie at a branch-point of storage and mitochondrial ¿-oxidation, the fate of the acyl-CoAs formed may contribute to, or counteract, nutritional disorders related to increased TAG storage like obesity, fatty liver, atherosclerosis, and diabetes. We hypothesize that 1) ACSL1 is able to direct FA towards ¿-oxidation in highly oxidative tissues because the enzyme interacts with carnitine acyltranferase to hand off its acyl-CoA product; 2) that the function of ACSL1 differs in liver because at least 50% of the protein is present on the endoplasmic reticulum where it interacts with glycerolipid acyltransferases; and 3) that the mechanism for these differences lies both in the membrane association and phosphorylation status of ACSL1. Further, we propose that tissue use of glucose rather than FA as a fuel source is not without cost, and that the metabolic and functional problems arising from this use may be dangerous for organ function and insulin signaling. We further hypothesize, in keeping with the proposition that each ACSL directs FA towards a specific fate, that the ACSL4 isoform functions to regulate the entry of arachidonate into pathways of phospholipid synthesis versus eicosanoid formation. Our studies will address critical gaps in our knowledge about the metabolic fates of FA as substrates for complex lipid formation, as metabolic fuels, as precursors for eicosanoid signaling, as regulators of insulin action, and as transcription factor ligands.

描述（由适用提供）：饮食摄入过量的脂肪或碳水合物会导致三酰基甘油（TAG）的合成和储存增加。必须首先通过长链酰基-COA合成酶（ACSL）将有助于TAG合成的长链脂肪酸（FA）转化为酰基-COA。由于酰基-COA位于储存和线粒体»氧化的分支，因此形成的酰基-COA的命运可能有助于或抵消营养障碍与增加的标签存储（如物体，脂肪肝，动脉粥样硬化和糖尿病）有关。我们假设1）ACSL1能够将FA引导到高度氧化时机中的氧化，因为该酶与肉碱酰基转移酶相互作用以移除其酰基-COA产物； 2）ACSL1的功能在肝脏中有所不同，因为至少50％的蛋白质在内质网上呈现，并与甘油脂肪酰基转移酶相互作用。 3）这些差异的机制在于膜的关联和ACSL1的磷酸化状态。此外，我们建议使用葡萄糖而不是FA作为燃料来源的组织使用并非没有成本，并且由于这种使用而引起的代谢和功能问题可能对器官功能和胰岛素信号传导危险。我们进一步假设每个ACSL都将FA引导到特定的命运的主张，即ACSL4同工型功能可以调节蛛网膜酸盐进入磷脂合成途径与eicosanoid形成的途径。我们的研究将解决有关FA代谢命运作为复杂脂质形成的底物，作为代谢燃料的底物的关键差距，作为eicosanoid信号传导的前体，作为胰岛素作用的调节剂和转录因子配体。