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National Institute of Environmental Health Sciences

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Your Environment. Your Health.

Publication Detail

Title: Non-canonical NRF2 activation promotes a pro-diabetic shift in hepatic glucose metabolism.

Authors: Liu, Pengfei; Dodson, Matthew; Li, Hui; Schmidlin, Cody J; Shakya, Aryatara; Wei, Yongyi; Garcia, Joe G N; Chapman, Eli; Kiela, Pawel R; Zhang, Qing-Yu; White, Eileen; Ding, Xinxin; Ooi, Aikseng; Zhang, Donna D

Published In Mol Metab, (2021 09)

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.

PubMed ID: 33933676 Exiting the NIEHS site

MeSH Terms: Animals; Arsenic/toxicity; Diabetes Mellitus, Experimental/chemically induced; Diabetes Mellitus, Experimental/genetics*; Gene Expression Profiling; Gluconeogenesis/genetics*; Humans; Insulin Resistance/genetics*; Kelch-Like ECH-Associated Protein 1/genetics; Kelch-Like ECH-Associated Protein 1/metabolism; Liver/drug effects; Liver/metabolism; Metabolomics; Mice; NF-E2-Related Factor 2/genetics; NF-E2-Related Factor 2/metabolism*; Sequestosome-1 Protein/genetics; Sequestosome-1 Protein/metabolism*

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