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：
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
项目类别：
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

项目摘要

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（由申请人提供）：来自脂肪或碳水化合物的过量饮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。酰基辅酶A掺入三酰甘油储存和脂蛋白分泌以及它们进入氧化途径的减少导致营养相关疾病，例如肥胖、脂肪肝和动脉粥样硬化。此外，由于 FA 和酰基辅酶 A 据称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 FA 代谢途径。我们的假设是，每种亚型在将 FA 引导至特定途径方面发挥着独立的作用，这一假设得到了过表达和敲低研究的支持。我们现在建议研究一种主要酰基辅酶A合成酶亚型的缺乏如何影响组织和全身代谢。通过靶向基因破坏，我们培育出了肝脏和全身 ACSL1 基因敲除的小鼠。我们将研究这些 ACSL1 缺失小鼠，以确定 ACSL1 缺乏对 a) 对脂质代谢和能量平衡的代谢影响，以及 b) 对 FA 和酰基辅酶 A 介导的基因表达的代谢影响。第三个目标是研究其他 ACSL 同工型的过表达和敲低对肝细胞和脂肪细胞中 FA 摄取和代谢的影响。拟议的研究将为酰基辅酶A代谢、不同膳食FA（包括必需FA）的影响以及过量热量引起的疾病提供新的见解。它们将使我们能够了解饮食成分如何影响肝脏、脂肪组织和心脏中 FA 代谢的特定途径，从而控制代谢途径。 ACSL 亚型不仅是控制肥胖的潜在靶标，而且它们与结肠癌和遗传性智力低下的关系表明，拟议的研究在人类疾病的治疗中具有实际意义。这项研究与肥胖、脂肪肝、糖尿病、脂毒性、基因表达的营养调节、癌症和智力障碍有关。