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

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

doi:10.1016/j.molmet.2021.101243

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

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

Research output: Contribution to journal › Article › peer-review

7 Scopus citations

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.

Original language	English (US)
Article number	101243
Journal	Molecular Metabolism
Volume	51
DOIs	https://doi.org/10.1016/j.molmet.2021.101243
State	Published - Sep 2021

Keywords

Diabetes
Liver carbohydrate metabolism
NRF2
Polyol pathway

ASJC Scopus subject areas

Molecular Biology
Cell Biology

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10.1016/j.molmet.2021.101243

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@article{78d74f556a684fc7a5cbe521752e14b6,

title = "Non-canonical NRF2 activation promotes a pro-diabetic shift in hepatic glucose metabolism",

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.",

keywords = "Diabetes, Liver carbohydrate metabolism, NRF2, Polyol pathway",

author = "Pengfei Liu and Matthew Dodson and Hui Li and Schmidlin, {Cody J.} and Aryatara Shakya and Yongyi Wei and Garcia, {Joe G.N.} and Eli Chapman and Kiela, {Pawel R.} and Zhang, {Qing Yu} and Eileen White and Xinxin Ding and Aikseng Ooi and Zhang, {Donna D.}",

note = "Funding Information: This study was supported by the following grants from the National Institutes of Health : R01CA226920 (A.O.), R21ES027920 (A.O.), ES004940 (P.R.K., X.D., Q.Z., A.O., and D.D.Z.), and ES031575 (D.D.Z.). Publisher Copyright: {\textcopyright} 2021 The Author(s)",

year = "2021",

month = sep,

doi = "10.1016/j.molmet.2021.101243",

language = "English (US)",

volume = "51",

journal = "Molecular Metabolism",

issn = "2212-8778",

publisher = "Elsevier GmbH",

}

TY - JOUR

T1 - Non-canonical NRF2 activation promotes a pro-diabetic shift in hepatic glucose metabolism

AU - Liu, Pengfei

AU - Dodson, Matthew

AU - Li, Hui

AU - Schmidlin, Cody J.

AU - Shakya, Aryatara

AU - Wei, Yongyi

AU - Garcia, Joe G.N.

AU - Chapman, Eli

AU - Kiela, Pawel R.

AU - Zhang, Qing Yu

AU - White, Eileen

AU - Ding, Xinxin

AU - Ooi, Aikseng

AU - Zhang, Donna D.

N1 - Funding Information: This study was supported by the following grants from the National Institutes of Health : R01CA226920 (A.O.), R21ES027920 (A.O.), ES004940 (P.R.K., X.D., Q.Z., A.O., and D.D.Z.), and ES031575 (D.D.Z.). Publisher Copyright: © 2021 The Author(s)

PY - 2021/9

Y1 - 2021/9

N2 - 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.

AB - 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.

KW - Diabetes

KW - Liver carbohydrate metabolism

KW - NRF2

KW - Polyol pathway

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U2 - 10.1016/j.molmet.2021.101243

DO - 10.1016/j.molmet.2021.101243

M3 - Article

C2 - 33933676

AN - SCOPUS:85106866169

SN - 2212-8778

VL - 51

JO - Molecular Metabolism

JF - Molecular Metabolism

M1 - 101243

ER -

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

Abstract

Keywords

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