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

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2021 · $388,750

## Abstract

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.

## Key facts

- **NIH application ID:** 10131794
- **Project number:** 5R01DK109964-05
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Kristofer S Fritz
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $388,750
- **Award type:** 5
- **Project period:** 2017-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10131794

## Citation

> US National Institutes of Health, RePORTER application 10131794, Regulation of insulin signaling and sensitivity by the xenobiotic metabolizing enzyme NQO1 (5R01DK109964-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10131794. Licensed CC0.

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