Oxidative DNA damage impairs metabolic homeostasis
Obesity and related complications such as fatty liver disease, 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. We have reported that mice deficient in OGG1 are susceptible to obesity and fatty liver, indicating an unexpected by critical role for this DNA repair pathway in the development of metabolic disease. Additionally, preliminary data indicate that OGG1 may also play a role in the development of inflammatory bowel disease, especially ulcerative colitis. The overarching goals of the Sampath lab are to delineate the mechanisms that link oxidative DNA damage to obesity, metabolic syndrome, and inflammatory conditions and to identify dietary factors contributing to the development or prevention of DNA damage.
Base excision repair of oxidative DNA damage influences metabolic health
One of the greatest threats to public health is the increasing prevalence of adult and pediatric obesity. A proposed causative factor in metabolic pathologies is oxidative stress, resulting from endogenous and exogenous generation of reactive oxygen species (ROS) in response to environmental and dietary factors and pro-inflammatory states. One of the major intracellular targets of oxidative radicals are DNA bases within genomic and mitochondrial (mt) DNAs. In order to counteract the deleterious effects of this damage in both organelles, cells exclusively use the base excision repair (BER) pathway in which excision of the damaged bases is catalyzed by DNA glycosylases, with OGG1 being the only enzyme responsible for the removal of the most prevalent ROS-induced DNA adduct, 7,8-dihydro-8-oxoguanine (8-oxoG). Deficiencies in OGG1 have been associated with several diseases including cancers and neurodegenerative diseases, and type 2 diabetes. Our lab has shown an association of metabolic disease and deficiencies in DNA repair by demonstrating that two different mouse models lacking DNA repair glycosylases (Neil1-/-and Ogg1-/-) are prone to the development of obesity and metabolic syndrome, with mice displaying increased hepatic lipid accumulation and impairments in glucose tolerance. Current lines of investigation are aimed at delineating the differential roles of genomic and mitochondrial DNA damage to the development of metabolic disease and determining the tissue-specific effects of unrepaired DNA damage to whole body energy homestasis.
Relationships between changes in the diversity of the gut microbiome and metabolic and inflammatory diseases
The relationships between the diversity of the gut microbiome and the onset and maintenance of obesity and chronic inflammation are beginning to be well established. In both human and rodent models, analyses of changes in the balance of these microbial communities have revealed specific trends that are predictive of host energy balance and metabolism. Although dietary changes in the host can significantly change the balance of microbial speciation, the consequence of the altered microbiome can, in turn, modulate the capacity to harvest energy from the diet and release lipopolysaccharides that illicit inflammatory responses. In addition to changes in the diversity of the microbiome conferring obesity, genetic alterations in the host can also manifest in changes in the diversity of the microbiome. Thus, it appears that there are plausible cause and effect relationships which support obesity drivers originating from either host genetic alterations or changes in the homeostasis of the microbiome. Maintenance of genomic stability through efficient DNA repair is particularly important in tissues with a high rate of turnover, such as the intestine. Preliminary studies in the lab indicate that persistent DNA damage results in marked alterations in the gut microbiome and inflammation in the intestine and colon, which may be causally linked to pathologies such as metabolic syndrome and ulcerative colitis stemming from unrepaired DNA damage.
- Sampath H. Phenotypes of base excision repair deficient models. Environmental and Molecular Mutagenesis . 2014.
- Sampath H and Ntambi JM. The role of stearoyl-CoA desaturase-1 in skin integrity and whole body energy balance. J Biol Chem. 2014 289:2482-8.
- Sampath H, Vartanian V, Rollins R, Sakumi K, Nakabeppu Y, Lloyd RS. 8-Oxoguanine DNA Glycosylase (OGG1) Deficiency Increases Susceptibility to Obesity and Metabolic Dysfunction. PLoS ONE. 2012 7:E51697.
- Sampath H, McCullough AK, Lloyd RS. Regulation of DNA glycosylases and their role in limiting disease. Free Radic. Res. 2012 46:460-78.
- Sampath H, Batra AK, Vartanian V, Carmical JR, Prusak D, King IB, Lowell B, Earley LF, Wood TG, Marks DL, McCullough AK, Lloyd RS. Variable penetrance of metabolic phenotypes and development of high fat diet-induced adiposity in neil1- deficient mice. Am J Physiol Endocrinol Metab. 2011 300:E724-34.
- Sampath H and Ntambi JM. The role of stearoyl-CoA desaturase in obesity, insulin resistance, and inflammation. Ann NY Acad Sci. 2011 1243: 47-53.
- Sampath H, Flowers MT, Liu X, et al. Skin-specific deletion of Stearoyl-CoA Desaturase-1 alters skin lipid composition and protects mice from high-fat diet-induced obesity. J Biol Chem. 2009 284:19961-73.
- Miyazaki M, Flowers MT, Sampath H et al. Hepatic Stearoyl-CoA Desaturase-1 Deficiency Protects Mice from Carbohydrate-Induced Adiposity and Hepatic Steatosis. Cell Metab. 2007 6:484-96.
- Sampath H, Miyazaki M, Dobrzyn A, Ntambi JM. Stearoyl-CoA desaturase-1 mediates the pro-lipogenic effects of dietary saturated fat. J Biol Chem. 2007 282: 2483-93.
BER Animation adapted from WW Norton & Company 2010.