Acyl-CoA Synthetase: Structure, Function and Regulation

酰基辅酶 A 合成酶：结构、功能和调节

• 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
• 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

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（由申请方提供）：膳食摄入过量脂肪或碳水化合物导致三酰甘油（TAG）的合成和储存增加。有助于TAG合成的长链脂肪酸（FA）必须首先通过长链酰基辅酶A合成酶（ACSL）转化为酰基辅酶A。由于酰基辅酶A位于储存和线粒体氧化的分支点，形成的酰基辅酶A的命运可能有助于或抵消营养失调 与TAG储存增加有关，如肥胖、脂肪肝、动脉粥样硬化和糖尿病。我们假设：1）ACSL 1能够在高度氧化的组织中引导FA进行氧化，因为该酶与肉毒碱酰基转移酶相互作用以传递其酰基辅酶A产物; 2）ACSL 1的功能在肝脏中不同，因为至少50%的蛋白质存在于内质网上，在内质网中它与甘油酯酰基转移酶相互作用; 3）这些差异的机制在于ACSL 1的膜结合和磷酸化状态。此外，我们认为组织使用葡萄糖而不是FA作为燃料来源并非没有成本，并且这种使用所产生的代谢和功能问题可能对器官功能和胰岛素信号传导是危险的。我们进一步假设，与每个ACSL将FA导向特定命运的主张一致，ACSL 4亚型的功能是调节花生四烯酸进入磷脂合成途径与类花生酸形成途径。我们的研究将解决关键的差距，我们的知识FA作为底物的复杂脂质形成的代谢命运，作为代谢燃料，作为类花生酸信号的前体，作为胰岛素作用的调节剂，并作为转录因子配体。