Khoo Lab

Nicholas Khoo, PhD

1. Define the formation and signaling actions of electrophilic nitro-fatty acids. Electrophilic nitroalkene-containing fatty acids (NO₂-FA) are products of nitric oxide (NO)/nitrogen dioxide reactions with unsaturated fatty acids that are generated at increased rates during metabolic stress and inflammation.  These endogenously produced mediators display a broad range of adaptive signaling actions. While the nitroalkene moiety confers reversible electrophilic reactivity with nucleophiles such as cysteine and histidine, promoting the post-translational modification of reactive protein thiols, the exact signaling mechanisms underlying the physiological actions of NO₂-FA and their conditions of formation and metabolism remain unclear.
2. Determining the interplay between mechanisms of adipose dysfunction and electrophilic nitro-fatty acid signaling to modulate obesity and insulin resistance. Obesity, a low-grade systemic inflammatory disease, is central to the pathogenesis of insulin resistance and type 2 diabetes. White adipose tissue, a major physiological compartment affected by obesity, has emerged as a signaling nexus that strongly impacts energy balance and glucose homeostasis. While our studies suggest that adipose tissue is a unique environment for NO₂-FA signaling, the molecular mechanism(s) by which obesity impacts NO₂-FA actions and those accounting for the therapeutic actions of NO₂-FA remain unclear. Some of the publications listed below demonstrate the significant impact adipose tissue has on glucose homeostasis, the esterification process of NO₂-FAs in adipocytes and that NO₂-FAs improve glucose tolerance. 
3. Define fundamental signaling mechanisms of tissue generation and reactions of reactive oxygen species (ROS). Oxidative stress, which occurs when ROS levels are higher than the antioxidant enzyme activities within a cell, is linked with a plethora of pathologies. However, ROS also have been described as signaling molecules that regulate physiological homeostasis. Assessment of reactive species in tissues and cells is routinely accomplished by measuring the accumulation of more stable secondary byproducts of redox reactions and/or the reduction in concentration of small molecule antioxidants (such as glutathione). Over the last few years we have published techniques to accurately detect reactive species in vivo (DMPO method), determine the source of oxidants from enzymes and the regulation of antioxidant enzymatic activities. These publications are seminal in defining conditions of oxidative stress in tissues and cells.