Metabolic syndrome comprises a group of cardiovascular risk factors including obesity, high blood pressure, glucose intolerance and dyslipidemia whose underlying pathology is related to insulin resistance. We have shown that the xenobiotic-metabolizing enzyme NQO1 is critical to insulin sensitivity and protection from diet-induced morbidities. Increasing NQO1 expression using NQO1 transgenic mice protects against the negative biochemical and physiological effects of a high fat diet and confers increased insulin sensitivity. Pharmacological inhibition of NQO1 using selective mechanism-based inhibitors led to a severe impairment in insulin sensitivity in mice. NQO1 knockout animals are insulin-insensitive resulting in a diabetes-like phenotype and a null NQO1 polymorphism is associated with metabolic syndrome phenotypes in humans. Our data shows that NQO1 is required for activation of AKT by enabling its insulin-inducible interaction with the protein complex TORC 2 allowing AKT serine phosphorylation and full glucose utilization. Insulin administration led to a rapid and marked increase in NQO1 tyrosine phosphorylation by the insulin receptor and mutational analysis suggests that phosphorylation leads to major changes in NQO1 functionality. Conformation-dependent antibodies and electrophoresis also indicated marked changes in NQO1 conformation as a result of either altered pyridine nucleotide redox ratios or addition of insulin. Based on the cellular functions of NQO1, we will test 3 biologically plausible mechanisms underlying the observed role of NQO1 in insulin signaling and protection against metabolic syndrome phenotypes. 1) NQO1 modulates insulin-dependent signaling by protein scaffolding. We will test the hypothesis that the observed effects of NQO1 on insulin sensitivity are modulated by a change in NQO1 conformation induced either by alterations in pyridine nucleotide levels or by phosphorylation of NQO1 by the insulin receptor, facilitating optimal association of AKT and Rictor and downstream insulin signaling; 2) NQO1 generates NAD+ for optimal SIRT activity. Deacetylation via SIRTs is critical in insulin signaling and NQO1 can rapidly generate high levels of NAD+ for optimal sirtuin activity; 3) Stabilization of critical metabolic regulators. The key metabolic regulator PGC1? is protected against proteasomal degradation by NQO1. Both PGC1? and AMPK influence mitochondrial oxidative phosphorylation and biogenesis and protect against metabolic syndrome. We will therefore define whether NQO1 influences metabolic syndrome by modulation of PGC1? and AMPK levels. Our working hypothesis is that NQO1 plays a critical role in insulin sensitivity and protection against metabolic syndrome phenotypes but the critical question that remains to be answered is the mechanism(s) underlying the beneficial effects of NQO1.

Public Health Relevance

We have discovered a new role for the xenobiotic-metabolizing enzyme NQO1 at the level of insulin signaling and modulation of insulin resistance. Increasing NQO1 expression using NQO1 transgenic mice protects against the negative biochemical and physiological effects of a high fat diet and confers increased insulin sensitivity.This application will define the mechanisms underlying the role of NQO1 in modulation of insulin signaling and sensitivity using an optimal investigative team with complementary skills.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Xenobiotic and Nutrient Disposition and Action Study Section (XNDA)
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Silva, Corinne M
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University of Colorado Denver
Schools of Pharmacy
United States
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Siegel, David; Dehn, Donna D; Bokatzian, Samantha S et al. (2018) Redox modulation of NQO1. PLoS One 13:e0190717
Ross, David; Siegel, David (2017) Functions of NQO1 in Cellular Protection and CoQ10 Metabolism and its Potential Role as a Redox Sensitive Molecular Switch. Front Physiol 8:595