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

Grant Number: 5R00DK100640-05
PI Name: Sampath
Project Title: Role of oxidative DNA damage in the onset and progression of metabolic syndrome

Abstract: 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-guanine. We have discovered that mice deficient in OGG1 are 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 the parent 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. Specifically, the parent award will elucidate the differential contributions of mitochondrial vs. genomic DNA damage to metabolic health.
The specific aims of the current application are additive and synergistic with those of the parent award. Specifically, one of the aims of the parent award is to identify dietary factors that regulate OGG1. In this regard, the original emphasis was on regulation of DNA damage and repair by dietary fats. Our ongoing investigations have led to the identification of an oral flavonoid compound, 7,8-dihydroxyflavone (DHF), as a modulator of the cellular DNA damage response. Therefore, the current application expands upon the parent award by investigating the mechanisms of action of DHF on OGG1 and its consequent impact on metabolic health in the whole animal. These studies will fill key gaps in our understanding of the mechanisms by which a commercially available flavonoid exerts its effects on energy balance. They will also identify novel modes of regulation of DNA repair processes by dietary flavonoids. The addition of these aims to the parent award therefore represents a significant step towards translation of the basic science findings of the parent project towards nutritional and clinical management of human metabolic disease.

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