The Keap1-Nrf2 System Prevents Onset of Diabetes Mellitus

Uruno, Akira; Furusawa, Yuki; Yagishita, Yoko; Fukutomi, Toshiaki; Muramatsu, Hiroyuki; Negishi, Takaaki; Sugawara, Akira; Kensler, Thomas W.; Yamamoto, Masayuki

doi:10.1128/mcb.00225-13

Cited by 291 publications

(283 citation statements)

References 44 publications

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“…Further supporting this complex role of Nrf2, recent studies have shown that overexpression of Nrf2 through the use of graded knockdown of Keap1 actually provides protection against the onset of diabetes in genetic models of diabetes in mice (79). This suggests a beneficial role for Nrf2 in the protection against the development of diabetes with increased expression of Nrf2 resulting in decreased blood glucose and protection against obesity in a db/db mouse background.…”

Section: ) Was Not Altered In Nrf2mentioning

confidence: 86%

Increased Energy Expenditure, Ucp1 Expression, and Resistance to Diet-induced Obesity in Mice Lacking Nuclear Factor-Erythroid-2-related Transcription Factor-2 (Nrf2)

Schneider

Valdez

Nguyen

et al. 2016

Journal of Biological Chemistry

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The NRF2 (also known as NFE2L2) transcription factor is a critical regulator of genes involved in defense against oxidative stress. Previous studies suggest that Nrf2 plays a role in adipogenesis in vitro, and deletion of the Nrf2 gene protects against diet-induced obesity in mice. Here, we demonstrate that resistance to diet-induced obesity in Nrf2 ؊/؊ mice is associated with a 20 -30% increase in energy expenditure. Analysis of bioenergetics revealed that Nrf2 ؊/؊ white adipose tissues exhibit greater oxygen consumption. White adipose tissue showed a >2-fold increase in Ucp1 gene expression. Oxygen consumption is also increased nearly 2.5-fold in Nrf2-deficient fibroblasts. Oxidative stress induced by glucose oxidase resulted in increased Ucp1 expression. Conversely, antioxidant chemicals (such as N-acetylcysteine and Mn(III)tetrakis(4-benzoic acid) porphyrin chloride) and SB203580 (a known suppressor of Ucp1 expression) decreased Ucp1 and oxygen consumption in Nrf2-deficient fibroblasts. These findings suggest that increasing oxidative stress by limiting Nrf2 function in white adipocytes may be a novel means to modulate energy balance as a treatment of obesity and related clinical disorders.

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Section: ) Was Not Altered In Nrf2mentioning

confidence: 86%

Increased Energy Expenditure, Ucp1 Expression, and Resistance to Diet-induced Obesity in Mice Lacking Nuclear Factor-Erythroid-2-related Transcription Factor-2 (Nrf2)

Schneider

Valdez

Nguyen

et al. 2016

Journal of Biological Chemistry

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“…This is illustrated by the oxidative stress-response regulated by NRF2, which prevents the onset of diabetes 80 , systemic lupus erythematosus 81 , rheumatoid arthritis 82 and multiple sclerosis 83 in murine models for these diseases. Damage responses also exert protective effects against autoimmune diseases, as illustrated for the UPR in the context of type 1 diabetes, where impaired expression of the the UPR components activating transcription factor 6 (ATF6) and XBP1 in -cells of the pancreas are associated with disease progression in both mice and humans 84 .…”

Section: Tissue Damage Control In Non-communicable Diseasesmentioning

confidence: 99%

Tissue damage control in disease tolerance

Soares

Gozzelino

Weis

2014

Trends in Immunology

159

174

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The deposited article is a prost-print version.This publication hasn't any creative commons license associated.This deposit is composed by the main article, and it hasn't any supplementary materials associated.Immune-driven resistance mechanisms are the prevailing host defense strategy against infection. By contrast, disease tolerance mechanisms limit disease severity by preventing tissue damage or ameliorating tissue function without interfering with pathogen load. We propose here that tissue damage control underlies many of the protective effects of disease tolerance. We explore the mechanisms of cellular adaptation that underlie tissue damage control in response to infection as well as sterile inflammation, integrating both stress and damage responses. Finally, we discuss the potential impact of targeting these mechanisms in the treatment of disease.Fundação para a Ciência e Tecnologia grants: (PTDC/SAU-TOX/116627/2010, HMSP-ICT/0022/2010, SFRH/BPD/44256/2008); European Commission 7th Framework grant: (ERC-2011-AdG. 294709-DAMAGECONTROL); Deutsche Forschungsgemeinschaft grant: (DFG WE 4971/3-1).info:eu-repo/semantics/publishedVersio

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“…Loss of Keap1 in hematopoietic cells suppresses differentiation toward the erythroid lineage (82), so the anemia in NEKO mice is likely due to a lack of Keap1 in hematopoietic cells. Growth retardation in NEKO mice might be caused by Nrf2 activation in skeletal muscle and adipose tissue, because Keap1 deletion in skeletal muscle reduces body weight (83), and loss of Keap1 represses the differentiation of adipose cells (84).…”

Section: Novel Function Of Nrf2mentioning

confidence: 99%

Stress-sensing mechanisms and the physiological roles of the Keap1–Nrf2 system during cellular stress

Suzuki

Yamamoto

2017

Journal of Biological Chemistry

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346

272

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Edited by Ruma BanerjeeTranscription factor Nrf2 (NF-E2-related factor 2) is a master regulator of cellular responses against environmental stresses. Nrf2 induces the expression of detoxification and antioxidant enzymes and suppresses the induction of pro-inflammatory cytokine genes. Keap1 (Kelch-like ECH-associated protein 1) is an adaptor subunit of Cullin 3-based E3 ubiquitin ligase. Keap1 regulates the activity of Nrf2 and acts as a sensor for oxidative and electrophilic stresses. In this review, we discuss the molecular mechanisms by which the Keap1-Nrf2 system senses and regulates the cellular response to environmental stresses. In particular, we focus on the multiple stress-sensing mechanisms of Keap1 and novel regulatory functions of Nrf2.Our body is equipped with a defense system that up-regulates the expression levels of cytoprotective enzyme genes. Nrf2 is the central player in the inducible expression of cellular defense enzymes (1, 2). Nrf2 belongs to the CNC (cap-n-collar) subfamily of basic region-leucine zipper-type transcription factors (3). Nrf2 dimerizes with one of the small Maf proteins (sMaf). The Nrf2-sMaf heterodimer binds to the antioxidantresponse element (ARE) 2 or electrophile-response element located in the regulatory regions of many cytoprotective enzyme genes (1, 4 -6). In this way, Nrf2 activates a wide range of cellular defense processes, thereby eliminating harmful substances.Keap1 acts as an E3 ubiquitin ligase substrate-recognition subunit and specifically targets Nrf2 (7-10). In the absence of stress, Nrf2 is efficiently ubiquitinated by the Keap1-Cul3 E3 ligase and degraded rapidly through the proteasome pathway, such that cellular Nrf2 activity is constitutively suppressed. Upon exposure to oxidative or electrophilic stresses, Keap1 loses its ability to ubiquitinate Nrf2, allowing Nrf2 to accumulate in the nucleus and activate its target genes.Recent studies expanded our knowledge on the targets of the Keap1-Nrf2 system, and the molecular mechanisms underpinning how this system senses a variety of environmental stresses. Keap1 primarily regulates Nrf2 in the cytoplasm; however, a Keap1-independent mechanism utilizing ␤-TrCP (␤-transducin repeat-containing protein) in the nucleus also operates (11). Anti-inflammation by Nrf2Several hundred Nrf2 target genes have been identified through gene expression profiling analysis and chromatin immunoprecipitation (ChIP) analysis (12-17). The Nrf2 target genes identified in these studies include enzymes involved in detoxification, anti-oxidation, and metabolism, as summarized in Fig. 1 (18).In addition to protecting against oxidative and xenobiotic insults, Nrf2 has also been known to attenuate inflammation (19). Nrf2 deficiency exacerbates inflammation, such as sepsis, pleurisy, and emphysema, in a variety of murine models (20 -22). In human clinical studies, the Nrf2 inducer Tecfidera (dimethyl fumarate) has been approved for the treatment of multiple sclerosis (23, 24)-at least in part based on its antiinflammatory function. Thus, N...

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The Keap1-Nrf2 System Prevents Onset of Diabetes Mellitus

Cited by 291 publications

References 44 publications

Increased Energy Expenditure, Ucp1 Expression, and Resistance to Diet-induced Obesity in Mice Lacking Nuclear Factor-Erythroid-2-related Transcription Factor-2 (Nrf2)

Increased Energy Expenditure, Ucp1 Expression, and Resistance to Diet-induced Obesity in Mice Lacking Nuclear Factor-Erythroid-2-related Transcription Factor-2 (Nrf2)

Tissue damage control in disease tolerance

Stress-sensing mechanisms and the physiological roles of the Keap1–Nrf2 system during cellular stress

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