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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）：肥胖已成为一种流行的健康威胁，其患病率在非裔美国人（AAW）中高于白人（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）在肥胖的AAW中明显低于CW。这一点很重要，因为肌肉组织的减少会导致生物活性脂质的积累，而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/民族特异性代谢功能障碍的细胞机制仍不明确。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中骨骼肌FAO的特定缺陷。在肌肉均质中，我们已经证明，在肥胖的AAW和CW中，通过酰基辅酶a合成酶（ACSL）激活棕榈酸酯对其酰基辅酶a衍生物的活性受到更大程度的损害。我们还证明，在肥胖AAW与CW获得的培养原代肌细胞中，棕榈酸酯氧化受损，表明ACSL活性降低是一种遗传的、种族特异性的特征。令人惊讶的是，这种代谢功能障碍可能在非肥胖的AAW中预先存在，他们也表现出棕榈酸盐氧化率的抑制。我们假设AAW骨骼肌FAO的损伤是由于酰基辅酶a合成酶的缺陷，这种酶在线粒体运输和氧化之前激活脂肪酸。这一缺陷可能会导致该种族女性中肥胖和糖尿病的发病率更高。然而，在精益连续训练中，耐力训练（EET）刺激肌肉氧化长链脂肪酸的能力。我们的第二个假设是AAW会通过增加骨骼肌氧化脂质的能力来应对EET，部分原因是ACSL活性的正常化。为了验证我们的假设，我们提出以下具体目标：1)利用siRNA和腺病毒转染技术，确定ACSL的细胞位置和特定的异构体，负责从AAW中降低骨骼肌的脂肪酸氧化能力2)通过确定特定的肌内脂质种类来扩展我们的研究结果，这些脂质种类被受损的ACSL活性改变，并有助于肌肉胰岛素抵抗3)。我们将证明，在人类骨骼肌细胞中，ACSL活性受损是AAW的一种遗传性功能障碍，这种功能障碍在纠正后可以恢复脂肪酸氧化和胰岛素作用。4)通过有氧运动训练确定扩大ACSL活性和随后骨骼肌氧化能力的潜力。我们的长期目标是确定AAW易致肥胖和糖尿病的细胞机制。这项研究具有临床意义，因为研究结果可能导致发现治疗AAW患者肥胖和糖尿病的新治疗策略。