Impaired Acyl-CoA Synthetase-Muscle Lipid Oxidation in African American Women

非裔美国女性酰基辅酶 A 合成酶肌肉脂质氧化受损

基本信息

批准号：
7289706
负责人：
RONALD CORTRIGHT
金额：
$ 25.6万
依托单位：
EAST CAROLINA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-09-30 至 2010-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7289706
关键词：
1,2-diacylglycerol Accounting Acyl Coenzyme A Acyltransferase Address Adenoviruses Aerobic Exercise African American Age Antibodies Biochemical Biochemical Pathway Bioenergetics Biological Assay Biopsy Carnitine Carnitine O-Palmitoyltransferase Caucasians Caucasoid Race Cells Ceramides Chronic Citrate (si)-Synthase Clinical Coenzyme A Ligases Coupled Cultured Cells Data Defect Depressed mood Development Diabetes Mellitus Diet Diglycerides Disease Drug or chemical Tissue Distribution Endoplasmic Reticulum Environmental Risk Factor Enzymes Epidemic Esters Exercise Exhibits Family Family member Fatty Acids Functional disorder Gene Expression Genetic Transcription Goals Health Human Impairment In Vitro Incidence Incubated Influentials Inherited Insulin Insulin Resistance Intervention Intramuscular Investigation Laboratories Lead Length Link Lipids Mass Chromatography Measurement Measures Messenger RNA Metabolic Microsomes Mitochondria Muscle Muscle Cells Muscle Fibers Non obese Non-Insulin-Dependent Diabetes Mellitus Obesity Palmitates Palmitoyl Coenzyme A Pathway interactions Phenotype Physiological Play Pliability Polymerase Chain Reaction Prevalence Principal Investigator Procedures Production Protein Isoforms Proteins Race Radiolabeled Rate Recombinants Regulation Research Research Design Research Personnel Risk Rodent Role Sampling Screening procedure Severities Site Skeletal Muscle Small Interfering RNA Socioeconomic Status Spectrum Analysis Subcellular Fractions Suggestion Technology Testing Therapeutic Time Tissue Extracts Tissues Training Transfection United States Weight Gain Western Blotting Woman Women&apos s Health acylcarnitine base clinically relevant fatty acid oxidation in vivo lipid metabolism long chain fatty acid metabolomics novel therapeutics obesity treatment oxidation oxidized lipid peroxisome programs racial and ethnic radiotracer research study response restoration success trait

项目摘要

DESCRIPTION (provided by applicant): Obesity has become an epidemic health threat, the prevalence which is greater among African-American (AAW) than Caucasian (CW) women. Although environmental factors may be influential, it is apparent that inherent biochemical defects also underlie obesity in AAW. We have demonstrated that muscle fatty acid oxidation (FAO) is significantly lower in obese AAW vs. CW. This is important as reductions in muscle FAO leads to accumulation of bioactive lipids, which is strongly associated with insulin resistance and diabetes. Despite the significance of these findings, the cellular mechanisms to explain the racial/ethnic specific metabolic dysfunction remain undefined. However, using combinations of radiolabeled fatty acids, our research group has now identified a specific defect in skeletal muscle FAO present in obese AAW. In muscle homogenates, we have demonstrated that activation of palmitate to its acyl-CoA derivative by acyl-CoA synthetase (ACSL) is impaired to a greater extent in obese AAW vs. CW. We have also demonstrated that palmitate oxidation is impaired in cultured primary myocytes obtained from obese AAW vs. CW, suggesting that reduced ACSL activity is an inherited, race specific trait. Startlingly, this metabolic dysfunction may pre- exist in non-obese AAW, who also exhibit suppressed rates of palmitate oxidation. We hypothesize that the impairment in skeletal muscle FAO in AAW is due to a defect in acyl-CoA synthetase, the enzyme required for activating fatty acids prior to transport and oxidation in the mitochondria. This defect likely contributes to the greater incidence of obesity and diabetes in this racial group of women. However, in lean CW, endurance exercise training (EET) stimulates the muscle's capacity to oxidize long-chain fatty acids. Our secondary hypothesis is that AAW will respond to EET by increasing the capacity of skeletal muscle to oxidize lipids, due in part to a normalization of ACSL activity. To test our hypothesis, we propose the following specific aims: 1) to determine the cellular site and specific isoform(s) of ACSL responsible for reducing the fatty acid oxidative capacity of skeletal muscle from AAW 2) to extend our findings from specific aim 1 by determining the specific intramuscular lipid species that are altered by impaired ACSL activity and which contribute to muscle insulin resistance 3) using siRNA and adenovirus transfection technologies, we will demonstrate in human skeletal muscle cells that impaired ACSL activity is an inherited dysfunction in AAW which when corrected can restore fatty acid oxidation and insulin action and 4) to determine the potential for expanding ACSL activity and subsequently the oxidative capacity of skeletal muscle in AAW by aerobic exercise training. Our long term objective is to define the cellular mechanism(s) which pre-dispose AAW to obesity and diabetes. This research is clinically relevant as findings are likely to lead to the discovery of new therapeutic strategies for the treatment of obesity and diabetes in AAW.

描述（由申请人提供）：肥胖已成为流行病的威胁，在非裔美国人（AAW）中，肥胖症的流行率远高于高加索人（CW）妇女。尽管环境因素可能具有影响力，但很明显，固有的生化缺陷也是AAW肥胖的基础。我们已经证明，肥胖AAW与CW的肌肉脂肪酸氧化（FAO）显着降低。这很重要，因为肌肉粮农组织的减少会导致生物活性脂质的积累，这与胰岛素抵抗和糖尿病密切相关。尽管这些发现具有重要意义，但解释种族/种族特异性代谢功能障碍的细胞机制仍然不确定。但是，使用放射标记的脂肪酸的组合，我们的研究小组现在已经确定了肥胖AAW中存在的骨骼肌FAO中的特定缺陷。在肌肉匀浆中，我们已经证明，棕榈酸酯通过酰基-COA合成酶（ACSL）激活其酰基辅酶A衍生物，在肥胖AAW与CW中更大程度地受到了损害。我们还证明，从肥胖AAW与CW获得的培养的原发性肌细胞中受损棕榈酸盐的氧化，这表明ACSL活性降低是一种遗传性的，特定于种族的特征。令人震惊的是，这种代谢功能障碍可能存在于非肥胖AAW中，后者也表现出受抑制的棕榈酸酯氧化速率。我们假设AAW中骨骼肌粮农组织的损伤是由于酰基-COA合成酶的缺陷，这是激活脂肪酸在线粒体中运输和氧化之前激活脂肪酸所需的酶。这种缺陷可能有助于这一种族妇女群体中肥胖和糖尿病的发生率更大。但是，在精益CW中，耐力运动训练（EET）刺激了肌肉氧化长链脂肪酸的能力。我们的第二个假设是，AAW将通过增加骨骼肌氧化脂质的能力来对EET做出反应，这部分是由于ACSL活性的归一化。为了检验我们的假设，我们提出以下特定目的：1）确定ACSL的细胞位点和特定的同工型，负责降低AAW骨骼肌的脂肪酸氧化能力2）从特定目标1扩展我们的发现，从特定目标1中扩展我们的发现，通过确定使用损害的ACSL ACSL活性的特定内部抑制作用，从而延伸特定的ACSL肌肉，从而使ACSL的抑制作用变化，从而使ACSL的活性改变了。转染技术，我们将在人类骨骼肌细胞中证明ACSL活性受损是AAW中的遗传功能障碍，校正后可以恢复脂肪酸氧化和胰岛素的作用，以及4），以确定ACSL活性的潜力，随后通过自动化训练AAW骨骼肌的氧化能力。我们的长期目标是定义细胞机制，该机制将AAW预先介绍至肥胖和糖尿病。这项研究在临床上是相关的，因为发现可能导致发现新的治疗策略来治疗AAW的肥胖和糖尿病。