Glucose availability is a decisive factor for Nrf2-mediated gene expression

Abstract

Activation of the transcription factor Nrf2 (nuclear factor-erythroid 2-related factor 2) is one of the major cellular defense lines against oxidative and xenobiotic stress, but also influences genes involved in lipid and glucose metabolism. It is unresolved whether the cytoprotective and metabolic responses mediated by Nrf2 are connected or separable events in non-malignant cells. In this study we show that activation of Nrf2, either by the small molecule sulforaphane or knockout of the Nrf2 inhibitor Keap1, leads to increased cellular glucose uptake and increased glucose addiction in fibroblasts. Upon Nrf2 activation glucose is preferentially metabolized through the pentose phosphate pathway with increased production of NADPH. Interference with the supply of glucose or the pentose phosphate pathway and NADPH generation not only hampers Nrf2-mediated detoxification of reactive oxygen species on the enzyme level but also Nrf2-initiated expression of antioxidant defense proteins, such as glutathione reductase and heme-oxygenase1. We conclude that the Nrf2-dependent protection against oxidative stress relies on an intact pentose phosphate pathway and that there is crosstalk between metabolism and detoxification already at the level of gene expression in mammalian cells.

Dual regulation of transcription factor Nrf2 by Keap1 and by the combined actions of β-TrCP and GSK-3

“…in response to redox and electrophilic stressors as well as by stimulation by growth factors. The diverse biological effects of Nrf2 are exerted through its ability to mediate induction of genes that contain in their promoter regions an antioxidant response element {ARE [The ARE has also been designated the electrophile response element (EpRE)], 5 -A / G TGA C / G NNNGC A / G -3 } [20] upon exposure to a wide spectrum of oxidants and soft electrophiles (see Figure 1 for some examples) [21][22][23] or stimulation by epidermal growth factor [24,25], fibroblast growth factor [26], insulin [27,28], insulin-like growth factor [29], keratinocyte growth factor [30,31], nerve growth factor [32], platelet-derived growth factor [33] or supply of glucose [34]. To date, approximately 250 genes that contain ARE sequences have been reported in mice and humans [35][36][37][38][39].…”

A Glance at… Broccoli, glucoraphanin, and sulforaphane

“…Additionally, sulforaphane-induced activation of AREencoded genes, glutathione recycling, and NQO1 detoxification of quinones all require reduced nicotinamide adenine dinucleotide phosphate (NADPH); it has been reported that sulforaphane appears to direct intracellular glucose to the NADPH-producing pentose phosphate pathway while increasing cellular uptake of glucose [66]. These observations, in conjunction with the induction of antioxidant defense systems, may in part explain the reports that oral sulforaphane attenuates hyperglycemia-induced kidney damage [67] and diabetesassociated aortic wall hyperplasia and hypertrophy [68] in mice.…”

PHLPP: a putative cellular target during insulin resistance and type 2 diabetes

“…Reports indicate the involvement of Nrf2 in regulating enzymes of the non-oxidative arm of PP pathway i.e. TKT (transketolase) and TALDO (transaldolase) (Heiss et al 2013). Livers of Nrf2 null mice are reported to decrease expression of G6PD, PGD, IDH1 and ME1 enzymes involved in NADPH synthesis (Holmström et al 2013).…”