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

• 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
• 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

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疾病，在全球范围内已达到流行病。与胰腺2细胞相关的胰岛素分泌减少是疾病发展的危险因素。这种危险因素发展的一种模型是增加线粒体功能障碍和活性氧（ROS）的产生。该模型的支持来自鉴定有缺陷的烟酰胺核苷酸转氢酶（NNT）基因功能与胰岛素分泌降低之间的遗传联系（Freeman 2006b）。 NNT是一种产生NADPH的线粒体膜蛋白，这是谷胱甘肽还原所必需的，谷胱甘肽是ROS清除途径中重要的抗氧化剂。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。高脂饮食的消耗是与疾病发作和通过ROS产生的线粒体损害相关的环境因素。确切的高脂饮食或细胞内脂质积累导致线粒体功能障碍或线粒体蛋白如何对这一过程的贡献尚不清楚。因此，将使用线虫秀丽隐杆线虫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。秀丽隐杆线虫是一种研究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，并且最近的初步数据表明，喂养高饱和脂肪饮食的动物增加了ROS的产生和运动不足。整个动物研究测量线粒体功能可以与动物生命周期中的生理功能一起进行，从而可以直接比较线粒体功能与生物体的整体健康。合并中NNT突变和高脂饮食的假说将通过增加ROS产生和脂质过氧化的方法加剧线粒体和生理功能障碍。用线粒体靶向抗氧化剂治疗动物的预测也将减少不良反应。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治疗进行进一步的研究。 公共卫生相关性：2型糖尿病是一种严重的疾病，在全球范围内已达到流行病。最近的证据表明，线粒体可能在疾病的发展中起关键作用，但是，线粒体功能障碍尚未与生理后果明确相关。拟议的工作将解决饮食脂肪和遗传前置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治疗进行进一步的研究。