Cited by 231Genomics, phytochemicals, and oxidative stressEndoplasmic Reticulum Stress and DiseaseRedox biology and oxidative stress

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The Keap1-Nrf2 system and diabetes mellitus

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Uruno, Akira, Yagishita, Yoko, Yamamoto, Masayuki·2015·Archives of Biochemistry and Biophysics

DOI 10.1016/j.abb.2014.12.012

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Abstract

Nrf2 (NF-E2-related factor 2) plays a key role in the protection of vertebrates against environmental stress by contributing to the inducible expression of detoxification and antioxidant enzymes. Keap1 (Kelch-like ECH-associated protein 1) is a sensor for oxidative and electrophilic stresses. Keap1 also acts as an E3 ubiquitin ligase substrate-recognition subunit that specifically targets Nrf2. Keap1 causes Nrf2 to be degraded through the ubiquitin-proteasome pathway and thus ensures that Nrf2 is constitutively suppressed under unstressed conditions. Upon exposure to oxidative or electrophilic stress, Keap1 loses its ability to ubiquitinate Nrf2. Many lines of evidence have recently clarified that the Keap1-Nrf2 system also plays critical roles in the maintenance of cellular homeostasis. One of the most salient examples is the contribution of Keap1-Nrf2 to metabolic and energy-balance regulation. In particular, how the Keap1-Nrf2 system protects the body against diabetes mellitus and how perturbations in this system provoke the disease condition are now under intense investigation. This review will summarize the recent progress made in this area.

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“Previous studies indicated that Nrf2 regulates the antioxidant enzyme system in pancreatic β-cells [96], contributes to protection against inflammation, and regulates autophagy and the expression of proteosome catalytic subunits in β-cells [97,98].”
Background
Mechanisms behind Retinal Ganglion Cell Loss in Diabetes and Therapeutic Approach
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“Perturbations on the Keap1/Nrf2 system, like in diabetes mellitus, promote the disease condition [74].”
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Scutellarin Prevents Nonalcoholic Fatty Liver Disease (NAFLD) and Hyperlipidemia via PI3K/AKT-Dependent Activation of Nuclear Factor (Erythroid-Derived 2)-Like 2 (Nrf2) in Rats
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Activation of GSK3β/β-TrCP axis via PHLPP1 exacerbates Nrf2 degradation leading to impairment in cell survival pathway during diabetic nephropathy
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Natural Coumarin Derivatives Activating Nrf2 Signaling Pathway as Lead Compounds for the Design and Synthesis of Intestinal Anti-Inflammatory Drugs
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Association between the NF-E2 Related Factor 2 Gene Polymorphism and Oxidative Stress, Anti-Oxidative Status, and Newly-Diagnosed Type 2 Diabetes Mellitus in a Chinese Population
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Nrf2 protects against diabetic dysfunction of endothelial progenitor cells via regulating cell senescence
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“5c), while ROS production was increased (Fig.”
Influential
Cr (VI) induces abnormalities in glucose and lipid metabolism through ROS/Nrf2 signaling
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Oxidative stress-induced miR-27a targets the redox gene nuclear factor erythroid 2-related factor 2 in diabetic embryopathy
Zhao, Y., Dong, D., Reece, E. A., Wang, A. R., & Yang, P. (2017) · American Journal of Obstetrics and Gynecology · doi:10.1016/j.ajog.2017.10.040 · Cited by 50
Nrf2 represses the onset of type 1 diabetes in non-obese diabetic mice
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Atorvastatin Regulates MALAT1/miR-200c/NRF2 Activity to Protect Against Podocyte Pyroptosis Induced by High Glucose
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“expression is downregulated under high glucose (HG) condition.(12) Hu et al(13) found that the mice knocked out NRF2 are more sensitive to oxidative damage and respond”
Background
miRNA-155 silencing reduces sciatic nerve injury in diabetic peripheral neuropathy
Ji, C., Li, C., Liu, W., Yan, B., Hu, X., & Yang, F. (2019) · Journal of Molecular Endocrinology · doi:10.1530/jme-19-0067 · Cited by 48
“Nrf2 inducers have been shown to prevent the development of DPN (Uruno et al. 2015).”
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Association of Nuclear Factor‐Erythroid 2‐Related Factor 2, Thioredoxin Interacting Protein, and Heme Oxygenase‐1 Gene Polymorphisms with Diabetes and Obesity in Mexican Patients
Jiménez‐Osorio, A. S., González-Reyes, S., García‐Niño, W. R., Moreno-Macías, H., Rodríguez-Arellano, M. E., Vargas‐Alarcón, G., Zúñiga, J., Barquera, R., & Pedraza‐Chaverrí, J. (2016) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2016/7367641 · Cited by 47
“On the other hand, Kim [36] reported that there were no associations between the rs1800566 polymorphism and BMI, blood pressure, lipid profile, HbA1c, postprandial glucose, and homeostasis model assessment-insulin resistance (HOMA-IR).”
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Polysaccharides in Medicinal and Food Homologous Plants regulate intestinal flora to improve type 2 diabetes: Systematic review
Liu, W., Zhang, Y., Zheng, M., Ye, Y., Shi, M., Wang, X., Cao, L., & Wang, L. (2024) · Phytomedicine · doi:10.1016/j.phymed.2024.156027 · Cited by 52
The Keap1–Nrf2 protein–protein interaction: A suitable target for small molecules
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Therapeutic Potential of Salviae Miltiorrhizae Radix et Rhizoma against Human Diseases Based on Activation of Nrf2‐Mediated Antioxidant Defense System: Bioactive Constituents and Mechanism of Action
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“The activation of Nrf2-regulated antioxidant response relieved the pathogenesis and progression of diabetes [79, 80].”
Carnosol as a Nrf2 Activator Improves Endothelial Barrier Function Through Antioxidative Mechanisms
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“As a key pathway for oxidative stress, the Keap1/Nrf2/ARE system plays an important role in the study of diabetes [12].”
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The Therapeutic Potential of Kaemferol and Other Naturally Occurring Polyphenols Might Be Modulated by Nrf2-ARE Signaling Pathway: Current Status and Future Direction
Hussain, Y., Khan, H. Z., Alsharif, K. F., Khan, A. H., Aschner, M., & Saso, L. (2022) · Molecules · doi:10.3390/molecules27134145 · Cited by 41
“In diabetes mellitus, Nrf2, in addition to its protective response, exerts other significant functions that contribute to the management of diabetes mellitus [37].”
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The novel Nrf2 inducer TFM-735 ameliorates experimental autoimmune encephalomyelitis in mice
Higashi, C., Kawaji, A., Tsuda, N., Hayashi, M., Saito, R., Yagishita, Y., Suzuki, T., Uruno, A., Nakamura, M., Nakao, K., et al. (2017) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2017.02.044 · Cited by 44
“, 2014) and that Nrf2 contributes to the pathogenesis of metabolic disorders associated with oxidative stress (Suzuki and Yamamoto, 2015; Uruno and Motohashi, 2011; Uruno et al., 2015).”
Background
Polygonatum sibiricum polysaccharide alleviates inflammatory cytokines and promotes glucose uptake in high‑glucose‑ and high‑insulin‑induced 3T3‑L1 adipocytes by promoting Nrf2 expression
Cai, J., Zhu, Y., Zuo, Y., Tong, Q., Zhang, Z., Yang, L., Li, X., & Yi, G.-Q. (2019) · Molecular Medicine Reports · doi:10.3892/mmr.2019.10626 · Cited by 41
Absence of TXNIP in Humans Leads to Lactic Acidosis and Low Serum Methionine Linked to Deficient Respiration on Pyruvate
Katsu-Jiménez, Y., Vazquez‐Calvo, C., Maffezzini, C., Halldin, M., Peng, X., Freyer, C., Wredenberg, A., Giménez-Cassina, A., Wedell, A., & Arnér, E. S. J. (2019) · Diabetes · doi:10.2337/db18-0557 · Cited by 37
“Indeed, both TXNIP and Nrf2 are known to display tissue-specific effects in their strong influences on metabolic pathways and tissue integrity (3,15,25,30).”
Background
Novel Grb14-Mediated Cross Talk between Insulin and p62/Nrf2 Pathways Regulates Liver Lipogenesis and Selective Insulin Resistance
Popineau, L., Morzyglod, L., Carré, N., Caüzac, M., Bossard, P., Prip‐Buus, C., Lenoir, V., Ragazzon, B., Fauveau, V., Robert, L., et al. (2016) · Molecular and Cellular Biology · doi:10.1128/mcb.00170-16 · Cited by 37
Alterations in System xc− Expression in the Retina of Type 1 Diabetic Rats and the Role of Nrf2
Carpi-Santos, R., & Calaza, K. D. C. (2018) · Molecular Neurobiology · doi:10.1007/s12035-018-0961-8 · Cited by 38
Activation of Nrf2 Is Required for Normal and ChREBPα-Augmented Glucose-Stimulated β-Cell Proliferation
Kumar, A. T., Katz, L. S., Schulz, A. M., Kim, M.-S., Honig, L. B., Li, L. Q., Davenport, B., Homann, D., Garcı́a-Ocaña, A., Herman, M. A., et al. (2018) · Diabetes · doi:10.2337/db17-0943 · Cited by 37
DPHC From Alpinia officinarum Ameliorates Oxidative Stress and Insulin Resistance via Activation of Nrf2/ARE Pathway in db/db Mice and High Glucose-Treated HepG2 Cells
Zhang, X., Zhang, Y., Zhou, M., Xie, Y., Dong, X., Bai, F., & Zhang, J. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.792977 · Cited by 37
Genetic variants of nuclear factor erythroid‐derived 2‐like 2 associated with the complications in Han descents with type 2 diabetes mellitus of Northeast China
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“in the patients with T2DM may play a crucial role in the development of diabetic complications [23, 31].”
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Succinylation of a KEAP1 sensor lysine promotes NRF2 activation
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Fermented noni ( Morinda citrifolia L.) fruit juice improved oxidative stress and insulin resistance under the synergistic effect of Nrf2/ARE pathway and gut flora in db/db mice and HepG2 cells
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Effects of PP2A/Nrf2 on experimental diabetes mellitus-related cardiomyopathy by regulation of autophagy and apoptosis through ROS dependent pathway
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Perilipin 5 Reduces Oxidative Damage Associated With Lipotoxicity by Activating the PI3K/ERK-Mediated Nrf2-ARE Signaling Pathway in INS-1 Pancreatic β-Cells
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Authors: Uruno, A., Yagishita, Y., & Yamamoto, M.
Affiliations: Tohoku University (JP)
Corresponding author: Uruno, Akira
Yamamoto, Masayuki
ORCID: Uruno, Akira
Yamamoto, Masayuki
Venue: Archives of Biochemistry and Biophysics
Publisher: Elsevier BV
Published: 2015-01
Volume: 566
Pages: 76-84
ISSN: 0003-9861 (ISSN-L)
DOI: 10.1016/j.abb.2014.12.012
OpenAlex: W2091259533
Cited by: 231
References: 109
Citations by year: 2026: 15 · 2025: 7 · 2024: 19 · 2023: 20 · 2022: 26 · 2021: 23 · 2020: 28 · 2019: 24 · 2018: 20 · 2017: 13 · 2016: 16 · 2015: 20
FWCI: 1.54
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (am, 440 d)
Locations: Archives of Biochemistry and Biophysics (acceptedVersion)
PubMed (publishedVersion)
Funders: Ministry of Education, Science, Sports and Culture
Create Revolutionary Technological Seeds for Science and Technology Innovation program (CREST) of the Japanese Technology Agency
Japan Society for the Promotion of Science (24249015, 90396474, 26893008)
Takeda Foundation
Naito Foundation
Japanese Foundation for Applied Enzymology
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
Keywords: Keap1, Nrf2, diabetes mellitus, oxidative stress, electrophilic stress, ubiquitin-proteasome system, E3 ubiquitin ligase, antioxidant defense, metabolic homeostasis, energy balance
MeSH terms: Kelch-Like ECH-Associated Protein 1, Animals, Diabetes Mellitus, Type 2, Gene Expression Regulation, Humans, Signal Transduction, Oxidative Stress, Ubiquitin-Protein Ligases, Proteasome Endopeptidase Complex, Intracellular Signaling Peptides and Proteins, Insulin-Secreting Cells, NF-E2-Related Factor 2, Ubiquitination, Proteolysis

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The Keap1-Nrf2 system and diabetes mellitus

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