Downregulation of Keap1 Confers Features of a Fasted Metabolic State

Knatko, Elena V.; Tatham, Michael H.; Zhang, Ying; Castro, Cecilia; Higgins, Maureen; Naidu, Sharadha Dayalan; Leonardi, Chiara; Vega, Laureano de la; Honda, Tadashi; Griffin, Julian L.; Hay, Ronald T.; Dinkova‐Kostova, Albena T.

doi:10.1016/j.isci.2020.101638

Cited by 24 publications

(23 citation statements)

References 85 publications

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“…Srxn1 , another NRF2 target gene, was also marginally upregulated in MK mice. One of the enzymes catalyzing β-oxidation of FAs, Acox2 , was found to be remarkably increased in MK mice compared with Cntl mice, which is consistent with the findings of a recent report describing that Acox2 is a target gene of NRF2 [ 34 ].…”

Section: Resultssupporting

confidence: 90%

Skeletal muscle-specific Keap1 disruption modulates fatty acid utilization and enhances exercise capacity in female mice

et al. 2021

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Skeletal muscle health is important for the prevention of various age-related diseases. The loss of skeletal muscle mass, which is known as sarcopenia, underlies physical disability, poor quality of life and chronic diseases in elderly people. The transcription factor NRF2 plays important roles in the regulation of the cellular defense against oxidative stress, as well as the metabolism and mitochondrial activity. To determine the contribution of skeletal muscle NRF2 to exercise capacity, we conducted skeletal muscle-specific inhibition of KEAP1, which is a negative regulator of NRF2, and examined the cell-autonomous and non-cell-autonomous effects of NRF2 pathway activation in skeletal muscles. We found that NRF2 activation in skeletal muscles increased slow oxidative muscle fiber type and improved exercise endurance capacity in female mice. We also observed that female mice with NRF2 pathway activation in their skeletal muscles exhibited enhanced exercise-induced mobilization and β-oxidation of fatty acids. These results indicate that NRF2 activation in skeletal muscles promotes communication with adipose tissues via humoral and/or neuronal signaling and facilitates the utilization of fatty acids as an energy source, resulting in increased mitochondrial activity and efficient energy production during exercise, which leads to improved exercise endurance.

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Section: Resultssupporting

confidence: 90%

Skeletal muscle-specific Keap1 disruption modulates fatty acid utilization and enhances exercise capacity in female mice

et al. 2021

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“…Because Gstp is involved in xenobiotic metabolism 28 as well as cell signaling, by sequestering c-Jun N-terminal kinase (JNK) 29 , we first asked whether deletion of Gstp affects the Nrf2-mediated transcription using the classical Nrf2-target NAD(P)H:quinone oxidoreductase 1 (Nqo1) as a marker, which is expressed in an Nrf2-dependent manner in the mouse colon 30 . The mRNA levels for Nqo1 in the colon tissues did not differ between Gstp +/+ and Gstp −/− animals (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Using LC-MS analysis of metabolites in colon tissue extracts, we recently found that the levels of glucose 6-phosphate and fructose 6-phosphate, metabolites involved in the initial steps of glycolysis, were higher in colons of Keap1-KD mice in comparison with their WT counterparts, whereas dihydroxyacetone phosphate and glyceraldehyde 3-phosphate, which are involved in the later steps of glycolysis, were lower 30 . Additionally, gas chromatography-MS (GC-MS) analysis showed that the levels of saturated and mono-unsaturated fatty acids were lower in Keap1-KD mice, whereas the levels of polyunsaturated fatty acids were higher.…”

Section: Discussionmentioning

confidence: 99%

Nrf2 activation does not affect adenoma development in a mouse model of colorectal cancer

et al. 2021

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Transcription factor nuclear factor erythroid 2 p45-related factor 2 (Nrf2) and its main negative regulator, Kelch-like ECH associated protein 1 (Keap1), are at the interface between redox and intermediary metabolism. Nrf2 activation is protective in models of human disease and has benefits in clinical trials. Consequently, the Keap1/Nrf2 protein complex is a drug target. However, in cancer Nrf2 plays a dual role, raising concerns that Nrf2 activators may promote growth of early neoplasms. To address this concern, we examined the role of Nrf2 in development of colorectal adenomas by employing genetic, pharmacological, and metabolomic approaches. We found that colorectal adenomas that form in Gstp−/−: ApcMin/+ mice are characterized by altered one-carbon metabolism and that genetic activation, but not disruption of Nrf2, enhances these metabolic alterations. However, this enhancement is modest compared to the magnitude of metabolic differences between tumor and peri-tumoral tissues, suggesting that the metabolic changes conferred by Nrf2 activation may have little contribution to the early stages of carcinogenesis. Indeed, neither genetic (by Keap1 knockdown) nor pharmacological Nrf2 activation, nor its disruption, affected colorectal adenoma formation in this model. We conclude that pharmacological Nrf2 activation is unlikely to impact the early stages of development of colorectal cancer.

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“…1f, Supplementary Table S1). Moreover, there exists independent published evidence that all of the 20 genes are direct Nrf2 targets [24][25][26][27][28] . We also confirmed that the tBHQ-induced expression of a selection of genes-Hmox1, Srxn1, and Slc7a11, was strongly abrogated in Nrf2-deficient cultures ( Fig.…”

Section: Tbhq Induces Nrf2-independent Induction Of Jun and Neurotoximentioning

confidence: 99%

Targeted de-repression of neuronal Nrf2 inhibits α-synuclein accumulation

et al. 2021

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Many neurodegenerative diseases are associated with neuronal misfolded protein accumulation, indicating a need for proteostasis-promoting strategies. Here we show that de-repressing the transcription factor Nrf2, epigenetically shut-off in early neuronal development, can prevent protein aggregate accumulation. Using a paradigm of α-synuclein accumulation and clearance, we find that the classical electrophilic Nrf2 activator tBHQ promotes endogenous Nrf2-dependent α-synuclein clearance in astrocytes, but not cortical neurons, which mount no Nrf2-dependent transcriptional response. Moreover, due to neuronal Nrf2 shut-off and consequent weak antioxidant defences, electrophilic tBHQ actually induces oxidative neurotoxicity, via Nrf2-independent Jun induction. However, we find that epigenetic de-repression of neuronal Nrf2 enables them to respond to Nrf2 activators to drive α-synuclein clearance. Moreover, activation of neuronal Nrf2 expression using gRNA-targeted dCas9-based transcriptional activation complexes is sufficient to trigger Nrf2-dependent α-synuclein clearance. Thus, targeting reversal of the developmental shut-off of Nrf2 in forebrain neurons may alter neurodegenerative disease trajectory by boosting proteostasis.

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Downregulation of Keap1 Confers Features of a Fasted Metabolic State

Cited by 24 publications

References 85 publications

Skeletal muscle-specific Keap1 disruption modulates fatty acid utilization and enhances exercise capacity in female mice

Skeletal muscle-specific Keap1 disruption modulates fatty acid utilization and enhances exercise capacity in female mice

Nrf2 activation does not affect adenoma development in a mouse model of colorectal cancer

Targeted de-repression of neuronal Nrf2 inhibits α-synuclein accumulation

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