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

描述(申请人提供)：肥胖及其相关并发症，如脂肪肝和糖尿病，对美国和世界各地的人口健康构成越来越大的威胁。更好地了解导致肥胖的饮食因素和细胞机制，对于制定预防和治疗这些代谢性疾病的策略至关重要。氧化应激，如高脂饮食引起的氧化应激，被认为是肥胖发展的一个原因。氧化应激会对细胞成分造成损害，包括DNA，如果不加以修复，可能会导致突变和肿瘤发生。DNA氧化损伤的修复是通过碱基切除修复途径进行的，该途径是由8-氧鸟嘌呤DNA糖基酶(OGG1)等DNA糖基酶启动的。OGG1识别并切除最常见的氧化性DNA损伤8-oxo-G。有趣的是，最近有报道称，缺乏OGG1的小鼠容易患肥胖症和脂肪肝，这表明这种DNA修复酶在代谢性疾病的发展中发挥了意想不到但至关重要的作用。该项目的总体目标是描述氧化DNA损伤与肥胖和代谢综合征之间的联系机制，并确定有助于发展或预防DNA损伤的饮食因素。初步数据表明，OGG1缺陷小鼠的肝脏脂肪堆积增加，同时肝脏脂肪氧化的标志减少。这些小鼠还表现出糖耐量受损和骨骼肌线粒体形态标记物的变化。因此，该项目的前两个目标将解决DNA损伤在改变肝脏脂质氧化和骨骼肌线粒体动力学方面的机制作用。这些目标将通过新的细胞和转基因肥胖模型来实现，这些模型是由DNA修复缺陷引起的，并建立了测量DNA损伤、脂肪氧化、线粒体形态和呼吸以及胰岛素信号的方法。这些目标的完成将进一步加深我们对脂肪肝病发生和发展过程中氧化应激诱导的损伤以及最终导致糖尿病发展的胰岛素敏感性受损的理解。随着从这些研究中获得的知识，第三个目标将扩大调查范围，以描述不同程度减饱和的饮食脂肪酸在诱导代谢活跃的组织，包括肝脏、心脏、肌肉和脂肪组织中的DNA损伤中的作用。此外，第三个目标将利用新开发的过度表达线粒体OGG1的转基因小鼠模型来确定饮食脂肪暴露和线粒体DNA修复在改变线粒体功能和细胞活力方面的作用。这一关键目标将解决我们对饮食和饮食之间相互作用的理解上的重大差距。 DNA损伤和代谢性疾病。完成这一最终目标所获得的知识也将指导未来的研究，重点是开发新的靶向疗法，通过调节DNA损伤识别和修复的途径来对抗代谢功能障碍。

DESCRIPTION (provided by applicant): 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 high- fat 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.