Regulation of insulin signaling and sensitivity by the xenobiotic metabolizing enzyme NQO1

异生物质代谢酶 NQO1 对胰岛素信号传导和敏感性的调节

基本信息

批准号：
9905510
负责人：
Kristofer S. Fritz
金额：
$ 38.88万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9905510
关键词：
Acetylation Adipocytes Adipose tissue Animals Antibodies Binding Biochemical Biogenesis Biological Caloric Restriction Cardiovascular system Cell physiology Complex Data Deacetylation Diabetes Mellitus Diabetic Nephropathy Diet Docking Dose Dyslipidemias Electrophoresis Enzymes Epidemic Generations Genes Genetic Polymorphism Glucose Glucose Intolerance High Fat Diet Human Hypertension IRS1 gene Impairment Insulin Insulin Receptor Insulin Resistance Mediating Metabolic Metabolic syndrome Mitochondria Molecular Conformation Morbidity - disease rate Mus Muscle Cells Mutation Mutation Analysis NADH NQO1 gene Non-Insulin-Dependent Diabetes Mellitus Obesity Oxidation-Reduction Oxidative Phosphorylation Pathology Pharmacology Phenotype Phosphorylation Phosphotransferases Physical activity Physiological Play Proteins Proto-Oncogene Proteins c-akt Role SIRT1 gene Scaffolding Protein Serine Signal Transduction Signaling Molecule Signaling Protein Sirtuins Skeletal Muscle Structure Testing Transgenic Mice Transgenic Organisms Tyrosine Phosphorylation Work Xenobiotics base cardiovascular risk factor global health glucose uptake in vivo inhibitor/antagonist insulin regulation insulin sensitivity insulin signaling knock-down knockout animal mortality mutant novel overexpression protective effect protein complex pyridine nucleotide response scaffold skills

项目摘要

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 PGC1α is protected against proteasomal degradation by NQO1. Both PGC1α 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 PGC1α 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.

代谢综合征组成，一组心血管危险因素含有敬意，高血压，葡萄糖基础病理学的不稳态和血脂异常与胰岛素抗性有关。异源生物生物代谢酶NQO1对于胰岛素和饮食引起的病因的印刷至关重要。使用NQO1转基因小鼠增加NQO1表达可预防负生物化学和高脂饮食和同意胰岛素敏感性提高的生理粒细胞效应。使用基于选择性机制的吸入器导致小鼠的严重损伤胰岛素敏感性敲除动物对胰岛素不敏感，导致与人类代谢综合征表型有关。 AKT通过启用其与蛋白质复合物Torc 2的胰岛素诱导相互作用，允许Akt丝氨酸磷酸化和全葡萄糖利用率。胰岛素受体和突变分析酪氨酸磷酸化表明磷酸化导致主要 NQO1功能的变化。 NQO1构象的变化是由于吡啶核苷核苷酸比率改变或添加胰岛素而导致的。基于NQO1的细胞函数，我们将测试3个生物学上合理的机制 NQO1在胰岛素信号传导和对代谢综合征表型的保护中的作用胰岛素依赖性信号通过蛋白质支架来测试NQO1的假设关于胰岛素敏感性的NQO1构象的变化是模块化的通过胰岛素受体对NQO1的核苷酸水平或通过磷酸化，促进Akt的最佳关联 rictor和下游胰岛素信号传导；通过SIRTS对于胰岛素信号传导至关重要，NQO1可以迅速产生高水平的NAD+，以获得最佳的Sirtuin 活性； 3）临界代谢调节剂的稳定 NQO1的蛋白酶体降解。因此，生物发生和预防代谢综合征。通过调节PGC1α和AMPK水平的综合征。我们的工作假设是，NQO1在胰岛素敏感性和防止代谢方面起关键作用综合征表型，但仍有待回答的关键问题是该机制 NQO1的有益作用。