Scientists at OHSU, the University of Texas Medical Branch and the University of Alabama found that generating mice that lack the gene encoding the DNA repair enzyme NEIL1 causes them to develop severe obesity and reach nearly twice the weight of their normal counterparts. The mice, according to the study appearing in the Proceedings of the National Academy of Sciences, also had enlarged, fatty yellow livers, insulin levels four times higher than normal, elevated levels of fat cell byproducts, and many internal organs almost entirely encased in thick pads of fatty tissue.
The results are the first to link DNA repair with the metabolic syndrome, and they suggest an important role for the NEIL1 gene product in the prevention of the diseases associated with the disorder, including obesity, hypertension, high cholesterol, insulin resistance and kidney disease.
"So if there are catalytically compromised forms of NEIL1 within the U.S. population, these people will be predicted to be at increased risk for developing the metabolic syndrome," a disease believed to affect more than 40 million Americans, said R. Stephen Lloyd, Ph.D., senior scientist at OHSU's Center for Research on Occupational and Environmental Toxicology (CROET) and co-author of the study.
Lloyd and his colleagues originally discovered the NEIL1-deficient mouse's propensity for developing the metabolic disorder about two years ago. Their interest in NEIL1 was initiated by their efforts to clone and crystallize homologs to the Escherichia coli endonuclease VIII gene. E. coli endonuclease VIII is part of a pathway of enzymes involved in repairing DNA damaged by free radicals that trigger oxidative stress on cell molecules. As a consequence of these studies, the Lloyd laboratory found human homologs to
Contact: Jonathan Modie
Oregon Health & Science University