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

• 批准号: 7134293
• 负责人: RONALD CORTRIGHT
• 金额: $ 26.36万
• 依托单位: EAST CAROLINA UNIVERSITY
• 依托单位国家: 美国
• 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/7134293
• 关键词: African American; acyl coA; biopsy; blood chemistry; clinical research; diabetes mellitus; disease /disorder proneness /risk; enzyme activity; exercise; female; human subject; lipids; long chain fatty acid; mass spectrometry; metabolomics; muscle strength; obesity; oxidation; patient oriented research; protein isoforms; small interfering RNA; striated muscles; transfection

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性健康威胁，非裔美国人（AAW）的患病率高于白人（CW）妇女。虽然环境因素可能有影响，但很明显，固有的生化缺陷也是AAW肥胖的基础。我们已经证明，肌肉脂肪酸氧化（FAO）是显着较低的肥胖AAW与CW。这一点很重要，因为肌肉FAO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。尽管这些发现的意义，细胞机制，以解释种族/民族特异性代谢功能障碍仍然不明确。然而，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中存在的骨骼肌FAO的特定缺陷。在肌肉匀浆中，我们已经证明，在肥胖的AAW与CW相比，棕榈酸酯通过酰基辅酶A合成酶（ACSL）活化为酰基辅酶A衍生物在更大程度上受损。我们还证明，棕榈酸氧化受损，在培养的原代肌细胞获得肥胖AAW与CW，表明ACSL活性降低是一种遗传，种族特异性性状。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氧化的抑制速率。我们假设AAW中骨骼肌FAO的损伤是由于酰基辅酶A合成酶的缺陷，该酶是在线粒体中运输和氧化之前激活脂肪酸所需的酶。这种缺陷可能导致该种族女性中肥胖和糖尿病的发病率更高。然而，在瘦CW，耐力运动训练（EET）刺激肌肉的能力，氧化长链脂肪酸。我们的次要假设是，AAW将通过增加骨骼肌氧化脂质的能力来对EET作出反应，部分原因是ACSL活性正常化。为了检验我们的假设，我们提出了以下具体目标：1）确定负责降低AAW骨骼肌脂肪酸氧化能力的ACSL的细胞位点和特异性亚型2）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异性肌内脂质种类，扩展我们的特定目标1的发现3）使用siRNA和腺病毒转染技术，我们将在人骨骼肌细胞中证明受损的ACSL活性是AAW中的遗传性功能障碍，当其被纠正时可以恢复脂肪酸氧化和胰岛素作用，以及4）确定通过有氧运动训练扩大ACSL活性的潜力和随后的AAW中骨骼肌的氧化能力。我们的长期目标是确定使AAW易患肥胖症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新的治疗策略，用于治疗AAW中的肥胖和糖尿病。