High Fat Diet and Deficient Antioxidant Status as Contributing Factors to Mitocho

高脂肪饮食和缺乏抗氧化状态是三户町的影响因素

基本信息

批准号：
8270031
负责人：
Lucinda Carnell
金额：
$ 7.76万
依托单位：
CENTRAL WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-06-15 至 2014-08-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8270031
关键词：
Address Adverse effects Animal Feed Animal Model Animals Antioxidants Binding Caenorhabditis elegans Calcium Cells Consumption Data Defect Development Diet Dietary Fats Disease Environmental Risk Factor Epidemic Exposure to Fatty acid glycerol esters Feeding behaviors Functional disorder Generations Genetic Glucose Intolerance Glutathione Health Hydrogen Peroxide Insulin Intracellular Accumulation of Lipids Lead Link Lipid Peroxidation Lipids Longevity Maps Measures Membrane Membrane Potentials Metabolic Diseases Metabolism Mitochondria Mitochondrial Membrane Protein Mitochondrial Proteins Modeling Movement Mus Muscle function Mutation NAD(P)+ transhydrogenase NADP Nematoda Neurophysiology - biologic function Non-Insulin-Dependent Diabetes Mellitus Onset of illness Organism Oxidative Stress Pancreas Pathway interactions Patients Physiological Physiological Processes Play Potassium Channel Process Production Proteins Quantitative Trait Loci Reactive Oxygen Species Risk Factors Role Sensory Stearic Acids Superoxides System Testing Tissues Unsaturated Fats Work age related egg gene function insulin secretion mitochondrial dysfunction mitochondrial membrane model development mutant neuromuscular function prevent public health relevance respiratory response saturated fat therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Type 2 diabetes is a serious metabolic disorder that has reached epidemic proportions worldwide. Decreased insulin secretion associated with the pancreatic 2 cells is a risk factor for the development of the disease. One model for the development of this risk factor is increased mitochondrial dysfunction and reactive oxygen species (ROS) generation. Support of this model comes from identification of a genetic link between defective nicotinamide nucleotide transhydrogenase (NNT) gene function and decreased insulin secretion (Freeman 2006b). NNT is a mitochondrial membrane protein that generates NADPH, which is required for the reduction of glutathione, an important antioxidant in ROS scavenger pathways. Another factor linking type 2 diabetes to mitochondrial dysfunction is intracellular lipid accumulation. Consumption of high- fat diets is an environmental factor that is associated with disease onset and with mitochondrial damage through the generation of ROS. Exactly how high-fat diets or intracellular lipid accumulation lead to mitochondrial dysfunction or how mitochondrial proteins contribute to this process is unclear. Thus, the effects of saturated and unsaturated fat diets and the role of the mitochondrial protein, NNT, on mitochondrial function will be investigated using the nematode, C. elegans. C. elegans is an established model for examining mitochondrial function and its physiological consequences. Previous studies have demonstrated that nnt-1 mutants have increased sensitivity to oxidative stress and recent preliminary data suggests that animals fed a high saturated fat diet have increased ROS production and movement deficits. Whole animal studies measuring mitochondrial function can be performed in conjunction with physiological function over the life span of the animal thus allowing a direct comparison between mitochondrial function and overall health of the organism. The hypothesis that NNT mutations and high-fat diet in combination will exacerbate mitochondrial and physiological dysfunction via increased ROS production and lipid peroxidation will be tested. The prediction that treating animals with mitochondrial-targeted antioxidants will diminish adverse effects will also be tested. These studies will clarify the origin of ROS and indicate whether or not further studies on mitochondrial-targeted therapeutic treatments of patients with type 2 diabetes are warranted. PUBLIC HEALTH RELEVANCE: Type 2 diabetes is a serious disease that has reached epidemic proportions worldwide. Recent evidence suggests that mitochondria may play a critical role in the development of the disease, however, mitochondrial dysfunction has not been clearly linked to physiological consequences. The proposed work will address the potential effects of dietary fat and genetic pre-disposition on mitochondrial and physiological dysfunction. Results will clarify the role of mitochondria and indicate whether or not further studies on mitochondrial-targeted therapeutic treatments of patients with type 2 diabetes are warranted.

描述（由申请人提供）：2 型糖尿病是一种严重的代谢性疾病，已在全世界范围内流行。与胰腺 2 细胞相关的胰岛素分泌减少是该疾病发生的危险因素。这种危险因素发展的一个模型是线粒体功能障碍和活性氧（ROS）生成增加。该模型的支持来自对烟酰胺核苷酸转氢酶（NNT）基因功能缺陷与胰岛素分泌减少之间遗传联系的识别（Freeman 2006b）。 NNT 是一种线粒体膜蛋白，可产生 NADPH，这是还原谷胱甘肽（ROS 清除剂途径中重要的抗氧化剂）所需的。将 2 型糖尿病与线粒体功能障碍联系起来的另一个因素是细胞内脂质积累。高脂肪饮食的消耗是一种环境因素，与疾病的发生以及ROS的产生造成的线粒体损伤有关。高脂肪饮食或细胞内脂质积累究竟如何导致线粒体功能障碍或线粒体蛋白如何促进这一过程尚不清楚。因此，我们将使用线虫秀丽隐杆线虫来研究饱和和不饱和脂肪饮食的影响以及线粒体蛋白 NNT 对线粒体功能的作用。线虫是检查线粒体功能及其生理后果的既定模型。先前的研究表明，nnt-1突变体对氧化应激的敏感性增加，最近的初步数据表明，喂食高饱和脂肪饮食的动物增加了ROS的产生和运动缺陷。测量线粒体功能的整体动物研究可以与动物整个生命周期的生理功能结合起来进行，从而可以直接比较线粒体功能和生物体的整体健康状况。 NNT 突变和高脂肪饮食相结合将通过增加 ROS 产生和脂质过氧化而加剧线粒体和生理功能障碍的假设将得到检验。用线粒体靶向抗氧化剂治疗动物将减少副作用的预测也将得到测试。这些研究将阐明 ROS 的起源，并表明是否有必要对 2 型糖尿病患者的线粒体靶向治疗进行进一步研究。公众健康相关性：2 型糖尿病是一种严重疾病，已在全球范围内流行。最近的证据表明线粒体可能在疾病的发展中发挥关键作用，然而，线粒体功能障碍与生理后果尚未明确相关。拟议的工作将解决膳食脂肪和遗传倾向对线粒体和生理功能障碍的潜在影响。结果将阐明线粒体的作用，并表明是否有必要对 2 型糖尿病患者的线粒体靶向治疗进行进一步研究。