Role of oxidative DNA damage in the onset and progression of metabolic syndrome

肥胖及其相关并发症，如脂肪肝和糖尿病，对人口构成越来越大的威胁 美国和世界各地的健康状况。对饮食因素和细胞学有更深入的了解 导致肥胖的机制对于制定预防和治疗措施至关重要。 与这些代谢性疾病作斗争的策略。氧化应激，例如因摄入高脂肪而引起的氧化应激 饮食，被认为是肥胖发展的一个原因。氧化应激对人体造成损害 细胞成分，包括DNA，如果不修复，可能会导致突变和肿瘤发生。 DNA氧化损伤由DNA启动的碱基切除修复途径修复 糖基酶，如8-氧鸟嘌呤DNA糖基酶(OGG1)。OGG1识别和删除的内容最多 常见的氧化性DNA损伤，8-oxo-G。有趣的是，缺乏OGG1的小鼠最近 据报道易患肥胖症和脂肪肝，这表明这种DNA具有意想不到的关键作用 修复酶在代谢性疾病发展中的作用。这个项目的总体目标是勾勒出 氧化DNA损伤与肥胖和代谢综合征的联系机制及确定饮食因素 有助于发展或防止DNA损伤。初步数据表明，OGG1 缺陷小鼠的肝脏脂肪堆积增加，同时脂肪氧化的标志物减少。 肝脏。这些小鼠还表现出糖耐量受损和线粒体标志物的变化 骨骼肌的形态。因此，该项目的前两个目标将解决 DNA损伤改变肝脏脂质氧化和骨骼肌线粒体动力学。这些目标将 借助由DNA缺陷引起的肥胖的新细胞和转基因模型来完成 修复缺陷并建立测量DNA损伤、脂肪氧化、线粒体形态的方法 呼吸和胰岛素信号。这些目标的实现将加深我们对氧化的理解 应激诱导的损伤在脂肪肝疾病的发生和发展中的作用，以及胰岛素受损 敏感性，这最终可能导致糖尿病的发展。凭借从这些项目中获得的知识 研究，第三个目标将扩大调查，以描述不同程度的饮食脂肪酸的作用 在新陈代谢活跃的组织，包括肝脏，心脏，肌肉， 和脂肪组织。此外，第三个目标将利用新开发的转基因小鼠模型 过表达线粒体OGG1以确定膳食脂肪暴露和线粒体DNA的作用 通过改变线粒体功能和细胞活力进行修复。这一关键目标将解决我们在 了解饮食、DNA损伤和代谢性疾病之间的相互作用。所获得的知识 从这一最终目标的完成也将指导今后的研究重点放在开发有针对性的小说上 通过调节DNA损伤识别和修复途径来对抗代谢功能障碍的治疗。

Obesity and related complications such as fatty liver disease and diabetes pose a growing threat to population health in the United States and around the world. A greater understanding of the dietary factors and cellular mechanisms that lead to the development of obesity is essential to devising preventive and therapeutic strategies to combat these metabolic diseases. Oxidative stress, such as that induced by consumption of highfat diets, is thought to be a causal factor in the development of obesity. Oxidative stress induces damage to cellular components, including DNA, which, if left unrepaired, can lead to mutations and tumorigenesis. Oxidative DNA lesions are repaired by the base-excision repair pathway, which is initiated by DNA glycosylases such as 8-oxoguanine DNA glycosylase (OGG1). OGG1 recognizes and excises the most commonly formed oxidative DNA lesion, 8-oxo-G. Interestingly, mice deficient in OGG1 have been recently reported to be susceptible to obesity and fatty liver, indicating an unexpected but critical role for this DNA repair enzyme in the development of metabolic disease. The overall goal of this project is to delineate the mechanisms that link oxidative DNA damage to obesity and metabolic syndrome and to identify dietary factors contributing to the development or prevention of DNA damage. Preliminary data have indicated that OGG1 deficient mice have increased hepatic lipid accumulation, along with markers of decreased fat oxidation in the liver. These mice also display impaired glucose tolerance and alterations in markers of mitochondrial morphology in skeletal muscle. The first two aims of this project will therefore address the mechanistic role of DNA damage in altering hepatic lipid oxidation and skeletal muscle mitochondrial dynamics. These aims will be completed with the aid of novel cellular and transgenic models of obesity resulting from a defect in DNA repair deficiency and established methods to measure DNA damage, fat oxidation, mitochondrial morphology and respiration, and insulin signaling. The completion of these aims will further our understanding of oxidative stress-induced damage in the initiation and progression of fatty liver disease, as well as impaired insulin sensitivity, which can ultimately lead to the development of diabetes. With the knowledge gained from these studies, the third aim will broaden the investigation to delineate the role of dietary fatty acids of varying degrees of desaturation in the induction of DNA damage in metabolically active tissues, including liver, heart, muscle, and adipose tissue. Additionally, the third aim will utilize a newly developed transgenic mouse model overexpressing mitochondrial OGG1 to determine the role of dietary fat exposure and mitochondrial DNA repair in altering mitochondrial function and cell viability. This critical aim will address significant gaps in our understanding of the interplay between diet, DNA damage, and metabolic disease. The knowledge gained from the completion of this final aim will also guide future research focused on developing novel targeted therapeutics to combat metabolic dysfunction by modulating pathways of DNA damage recognition and repair.