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：
7664461
负责人：
RONALD CORTRIGHT
金额：
$ 25.09万
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 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7664461
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 Cell Culture Techniques Cells Ceramides Chromatography Chronic Citrate (si)-Synthase Clinical Coenzyme A Ligases Coupled Cultured Cells Data Defect 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 Spectrum Analysis 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 Prevalence Procedures Production Protein Isoforms Proteins Race Radiolabeled Recombinants Regulation Research Research Design Risk Rodent Role Sampling Screening procedure Severities Site Skeletal Muscle Small Interfering RNA Socioeconomic Status 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 depressed fatty acid oxidation flexibility 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 therapeutic development trait treatment strategy

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）：肥胖已成为一种流行病健康威胁，非裔美国人 (AAW) 女性的患病率高于白人 (CW) 女性。尽管环境因素可能有影响，但很明显，固有的生化缺陷也是 AAW 肥胖的原因。我们已经证明，与 CW 相比，肥胖 AAW 的肌肉脂肪酸氧化 (FAO) 显着降低。这一点很重要，因为肌肉脂肪酸的减少会导致生物活性脂质的积累，而生物活性脂质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/民族特异性代谢功能障碍的细胞机制仍不清楚。然而，通过使用放射性标记脂肪酸的组合，我们的研究小组现在已经确定了肥胖 AAW 中骨骼肌FAO的特定缺陷。在肌肉匀浆中，我们已经证明，与 CW 相比，肥胖 AAW 中酰基辅酶 A 合成酶 (ACSL) 将棕榈酸激活为其酰基辅酶 A 衍生物的作用受到更大程度的损害。我们还证明，从肥胖 AAW 与 CW 获得的培养原代肌细胞中，棕榈酸氧化受损，这表明 ACSL 活性降低是一种遗传性种族特异性特征。令人惊讶的是，这种代谢功能障碍可能预先存在于非肥胖的 AAW 中，他们也表现出棕榈酸酯氧化率受到抑制。我们推测，AAW 中骨骼肌FAO 的损伤是由于酰基辅酶A 合成酶的缺陷造成的，酰基辅酶A 合成酶是在线粒体中转运和氧化之前激活脂肪酸所需的酶。这种缺陷可能导致该种族女性群体肥胖和糖尿病的发病率更高。然而，在精益 CW 中，耐力运动训练 (EET) 会刺激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，部分原因是 ACSL 活性的正常化。为了检验我们的假设，我们提出以下具体目标：1) 确定负责降低 AAW 骨骼肌脂肪酸氧化能力的 ACSL 的细胞位点和特定亚型 2) 扩展我们从具体目标 1 的发现通过确定因 ACSL 活性受损而改变并导致肌肉胰岛素抵抗的特定肌内脂质种类 3) 使用 siRNA 和腺病毒转染技术，我们将在人类骨骼肌细胞中证明 ACSL 活性受损AAW 中的遗传性功能障碍，纠正后可以恢复脂肪酸氧化和胰岛素作用，4) 确定通过有氧运动训练扩大 ACSL 活性以及随后 AAW 中骨骼肌氧化能力的潜力。我们的长期目标是确定 AAW 导致肥胖和糖尿病的细胞机制。这项研究具有临床相关性，因为研究结果可能会导致发现治疗 AAW 肥胖和糖尿病的新治疗策略。