Non-canonical NRF2 activation promotes a pro-diabetic shift in hepatic glucose metabolism
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Author
Liu, P.Dodson, M.
Li, H.
Schmidlin, C.J.
Shakya, A.
Wei, Y.
Garcia, J.G.N.
Chapman, E.
Kiela, P.R.
Zhang, Q.-Y.
White, E.
Ding, X.
Ooi, A.
Zhang, D.D.
Affiliation
Department of Pharmacology and Toxicology, College of Pharmacy, University of ArizonaUniversity of Arizona Cancer Center, University of Arizona
Issue Date
2021
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Elsevier GmbHCitation
Liu, P., Dodson, M., Li, H., Schmidlin, C. J., Shakya, A., Wei, Y., Garcia, J. G. N., Chapman, E., Kiela, P. R., Zhang, Q.-Y., White, E., Ding, X., Ooi, A., & Zhang, D. D. (2021). Non-canonical NRF2 activation promotes a pro-diabetic shift in hepatic glucose metabolism. Molecular Metabolism, 51.Journal
Molecular MetabolismRights
Copyright © 2021 The Author(s). This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Collection Information
This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.Abstract
Objective: NRF2, a transcription factor that regulates cellular redox and metabolic homeostasis, plays a dual role in human disease. While it is well known that canonical intermittent NRF2 activation protects against diabetes-induced tissue damage, little is known regarding the effects of prolonged non-canonical NRF2 activation in diabetes. The goal of this study was to determine the role and mechanisms of prolonged NRF2 activation in arsenic diabetogenicity. Methods: To test this, we utilized an integrated transcriptomic and metabolomic approach to assess diabetogenic changes in the livers of wild type, Nrf2−/−, p62−/−, or Nrf2−/−; p62−/− mice exposed to arsenic in the drinking water for 20 weeks. Results: In contrast to canonical oxidative/electrophilic activation, prolonged non-canonical NRF2 activation via p62-mediated sequestration of KEAP1 increases carbohydrate flux through the polyol pathway, resulting in a pro-diabetic shift in glucose homeostasis. This p62- and NRF2-dependent increase in liver fructose metabolism and gluconeogenesis occurs through the upregulation of four novel NRF2 target genes, ketohexokinase (Khk), sorbitol dehydrogenase (Sord), triokinase/FMN cyclase (Tkfc), and hepatocyte nuclear factor 4 (Hnf4A). Conclusion: We demonstrate that NRF2 and p62 are essential for arsenic-mediated insulin resistance and glucose intolerance, revealing a pro-diabetic role for prolonged NRF2 activation in arsenic diabetogenesis. © 2021 The Author(s)Note
Open access journalISSN
2212-8778PubMed ID
33933676Version
Final published versionae974a485f413a2113503eed53cd6c53
10.1016/j.molmet.2021.101243
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Except where otherwise noted, this item's license is described as Copyright © 2021 The Author(s). This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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