Research

Project 1: Regulation of lipid desaturation and its impact on tissue and whole body health

Dietary and cellular saturated fatty acids can be rapidly converted to monounsaturated fatty acids (MUFAs) by the ER-membrane resident enzyme, stearoyl-CoA desaturase-1 (SCD1).  These MUFAs are preferred substrates for synthesis of storage lipids such as triglycerides and have also been shown to regulate cellular processes such as de novo lipogenesis and insulin signaling.  SCD1 is a highly regulated enzyme, despite the fact that its products are highly abundant in our diets.  Work from many labs has established that SCD1 plays a critical role in regulating cellular metabolism.  Animals lacking SCD1 are lean and protected from metabolic disease.  Similarly, in human cohorts, plasma indices of increased SCD1 activity are associated with features of metabolic syndrome.  These prior findings have rendered SCD1 a very attractive target for manipulation of cellular metabolism. Current investigations in our lab are focused on delineating the tissue-specific roles for this highly regulated enzyme and the impact of aberrant lipid desaturation on tissue and whole body health.

SCD1
Figure title: The regulation of SCD1 and its role in regulating cellular metabolism                   Figure credit: Adapted from Sampath and Ntambi.  Future Lipidology 2008 3:163-73.

Project 2: Oxidative DNA damage and repair – implications to metabolic homeostasis

Oxidative stress such as that induced by consumption of high-fat diets is thought to be a causal factor in the development of obesity.  One of the intracellular targets of oxidative radicals is DNA bases within genomic and mitochondrial (mt) DNA pools. In order to counteract the deleterious effects of this oxidative damage to DNA, cells exclusively use the base excision repair (BER) pathway.  BER is initiated by DNA glycosylases, with the enzyme 8-oxoguanine DNA glycosylase (OGG1) being the primary enzyme responsible for the removal of the most prevalent ROS-induced DNA adduct, 7,8-dihydro-8-oxoguanine (8-oxoG).

OGG1 structure.png

Deficiencies in OGG1 have been associated with several diseases including cancers and neurodegenerative diseases, and type 2 diabetes. Our lab has shown an association between defects in DNA repair and metabolic disease by demonstrating that a lack of either of two different DNA repair glycosylases (Neil1-/- and Ogg1-/-) increases susceptibility to obesity and metabolic syndrome.  Conversely, overexpression of OGG1 confers protection against obesity and insulin resistance.  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 balance.