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: 7780420
• 负责人: Rosalind Anne Coleman
• 金额: $ 28.8万
• 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 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7780420
• 关键词: ASCL1 gene; Acyl Coenzyme A; Adenoviruses; Adipocytes; Adipose tissue; Affect; Atherosclerosis; Attention; Calories; Carbohydrates; Cardiac Myocytes; Cardiomyopathies; Cell Cycle; Cell Proliferation; Cell physiology; Cells; Coenzyme A Ligases; Colon Carcinoma; Complex; Cultured Cells; Data; Development; Diabetes Mellitus; Diet; Dietary Fatty Acid; Disease; Embryo; Energy Intake; Essential Fatty Acids; Exhibits; Family; Fatty Acids; Fatty Liver; Fatty acid glycerol esters; Fibroblasts; Gene Expression; Gene Expression Regulation; Gene Targeting; Genes; Genetic; Genetic Transcription; Heart; Hepatic; Hepatocyte; Insulin; Insulin Resistance; Knock-out; Knockout Mice; Ligands; Lipids; Lipoproteins; Liver; Mediating; Mental Retardation; Metabolic; Metabolic Pathway; Metabolism; Mus; Muscle; Neurons; Nuclear; Nutrient; Nutrition Disorders; Obesity; Pathogenesis; Pathway interactions; Peripheral; Phenotype; Phospholipids; Physiology; Play; Polyunsaturated Fatty Acids; Production; Protein Isoforms; Regulation; Research; Research Personnel; Role; Skeletal Muscle; Structure; Tissues; Triglycerides; Very low density lipoprotein; base; cancer gene expression; dietary excess; energy balance; fatty acid metabolism; fatty acid oxidation; gain of function; glucose uptake; hepatoma cell; human disease; in vivo; insight; lipid metabolism; loss of function; mouse model; nonalcoholic steatohepatitis; nutrition; overexpression; oxidation; programs; skeletal; small hairpin RNA; transcription factor; uptake

DESCRIPTION (provided by applicant): Excess dietary caloric intake from either fat or carbohydrate results in increased cell entry or synthesis of fatty acids (FA) and their activated products, acyl-CoAs. The incorporation of acyl-CoAs into triacylglycerol stores and lipoprotein secretion and their diminished entry into oxidation pathways contribute to nutrition- related disorders such as obesity, fatty liver, and atherosclerosis. Further, because both FA and acyl-CoAs are purported ligands for several nuclear transcription factors, dietary excess may alter fatty acid- and acyl- CoA-mediated regulation of a wide variety of cellular processes, including cell proliferation and neuronal function. In order to understand the effects of FA imbalance oh metabolism, we have been studying the long-chain acyl-CoA synthetases (ACSL) which promote FA uptake into cells and initiate virtually every pathway of FA metabolism. Our hypothesis that each isoform plays an independent role in channeling FA to specific pathways is supported by over-expression and knockdown studies. We now propose to investigate how the lack of one of the major acyl-CoA synthetase isoforms affects tissue and whole body metabolism. Using targeted gene disruption we have produced mice with liver and total body knockouts of ACSL1. We will study these ACSL1 null mice to determine the metabolic effects of ACSL1 lack a) on lipid metabolism and energy balance, and b) on FA- and acyl-CoA-mediated gene expression. A third objective will be to study the effects of overexpression and knockdown of other ACSL isoforms on FA uptake and metabolism in hepatocytes and adipocytes. The proposed studies will provide new insights into acyl-CoA metabolism, the effects of different dietary FA including essential FA, and disorders resulting from excess calories. They will enable us to understand how diet composition influences specific pathways of FA metabolism in liver, adipose tissue and heart to control metabolic pathways. Not only are the ACSL isoforms potential targets for the control of obesity, but their involvement in colon cancer and in genetic mental retardation shows that the proposed studies have practical relevance in the treatment of human disease. This research is relevant to obesity, fatty liver, diabetes, lipotoxicity, nutrient regulation of gene expression, cancer, and mental retardation.

描述（由申请方提供）：从脂肪或碳水化合物中摄入过量的膳食热量会导致脂肪酸（FA）及其活化产物酰基辅酶A的细胞进入或合成增加。酰基-CoA掺入三酰甘油储存和脂蛋白分泌中以及它们进入氧化途径的减少有助于营养相关病症，如肥胖、脂肪肝和动脉粥样硬化。此外，因为FA和酰基辅酶A都是几种核转录因子的配体，饮食过量可能会改变脂肪酸和酰基辅酶A介导的多种细胞过程的调节，包括细胞增殖和神经元功能。为了了解FA失衡对代谢的影响，我们一直在研究长链酰基辅酶A合成酶（ACSL），它促进FA摄取到细胞中，并启动几乎所有的FA代谢途径。我们的假设，每个异构体发挥了独立的作用，引导FA的特定途径是支持过表达和敲低研究。我们现在建议调查如何缺乏一个主要的酰基辅酶A合成酶异构体影响组织和全身代谢。使用靶向基因破坏，我们已经产生了ACSL 1的肝脏和全身敲除小鼠。我们将研究这些ACSL 1缺失小鼠，以确定ACSL 1缺失a）对脂质代谢和能量平衡以及B）对FA和酰基CoA介导的基因表达的代谢影响。第三个目标是研究过表达和敲低其他ACSL亚型对肝细胞和脂肪细胞中FA摄取和代谢的影响。拟议的研究将提供新的见解酰基辅酶A代谢，不同的饮食FA的影响，包括必需的FA，以及由过量的热量引起的疾病。它们将使我们能够了解饮食组成如何影响肝脏、脂肪组织和心脏中FA代谢的特定途径，以控制代谢途径。ACSL亚型不仅是控制肥胖的潜在靶点，而且它们与结肠癌和遗传性智力低下的关系表明，拟议的研究在治疗人类疾病方面具有实际意义。这项研究与肥胖、脂肪肝、糖尿病、脂毒性、基因表达的营养调控、癌症和智力低下有关。