Nrf2 and AhR in metabolic reprogramming after contaminant exposure

Abstract

International audienceBeside their crucial role in xenobiotic biotransformation, AhR and Nrf2 are involved in the regulation of energetic metabolism. Nrf2, as a cytoprotective transcription factor, supply energy for detoxification and antioxidant response. AhR is ligand-activated transcriptional factor implicated in several physiological function. Following pollutant exposure, it acts as a chemosensor to eliminate harmful chemicals. Altogether, AhR and Nrf2 cooperate to contribute to protective responses upon contaminant exposure, including metabolic remodelling. This fine-tuned energetic coupling with detoxification can lead to prominent dysfunction under a chronic exposure to pollutants, and promote a long-term reprogramming that affects multiple cellular activities. In the article, we review the involvement of Nrf2 and AhR in the metabolic adaptations that occur during the short-term cell defence upon toxicant exposure, and in the metabolic reprogramming caused by their sustained activation. We also provide several clues to highlight the potential role of the Nrf2/AhR-induced metabolic changes in environmental carcinogenesis. © 201

Comparison of Hepatic NRF2 and Aryl Hydrocarbon Receptor Binding in 2,3,7,8-Tetrachlorodibenzo-p-dioxin–Treated Mice Demonstrates NRF2-Independent PKM2 Induction

“…Several members of what was classically known as the "AhR gene battery" have been shown to require NRF2 activation, resulting in the establishment of the AhR-NRF2 gene battery (Yeager et al, 2009). These genes may Bortoli et al, 2018). To further investigate their complementary roles, TCDD-elicited changes in AhR and NRF2 genomic DNA binding were integrated with time-dependent differential gene expression RNA-seq data to further investigate the composition and regulation of the AhR-NRF2 gene battery.…”

“…This suggests the AhR serves a complementary defensive role by inducing PKM2 to provide glycolytic intermediates for serine/glycine biosynthesis, whereas NRF2 upregulates other factors required for glutathione biosynthesis, such as the influx of cystine via the xCT (also known as Slc7a11) gene (e.g., dose-dependent induction of Slc7a11, ∼900-fold in male mice; GSE87519). Therefore, AhR and NRF2 cooperate to increase PPP gene expression and NADPH production to support cell survival from TCDD-induced oxidative stress (Wu et al, 2011;Mitsuishi et al, 2012a,b;Hayes and Dinkova-Kostova, 2014;Nault et al, 2016b;Bortoli et al, 2018).…”

Disturbances in H+ dynamics during environmental carcinogenesis

“…However, the impact of B[a]P on cell metabolism might also involve regulation of gene expression, as observed upon co-exposing lung epithelial transformed cells to both B[a]P and arsenic[84]. Of note, AhR activation, as triggered upon B[a]P exposure, appears to regulate the expression of several enzymes involved in energy metabolism; this cytosolic receptor is also known to interact with the F0F1ATPase (see[85] for review). In this context, how H + dynamics and AhR could act together to induce metabolic reprogramming upon B[a]P exposure remains an open question, as previously emphasized[4].…”

Investigation of possible hazards and benefits of use of 'Ashkulebya' (Maerua subcordata (Gilg) DeWolf) as famine and/or potential functional food

“…Originally thought to be involved in not only drug metabolism but also carcinogenic and toxicological responses against environmental contaminants like 2,3,7,8-tetrachlorodibenzo-pdioxin (TCDD), recent studies demonstrate that the AhR plays multiple intrinsic roles in host defense and homeostasis as well, including immunity, stem cell maintenance, and cell differentiation, upon binding with an increasing number of newly defined dietary, cellular, and microbe-derived ligands [113][114]. Unliganded AhR is located in the cytoplasm forming a complex with several chaperones among which are two heat shock protein 90 (HSP90) molecules, at least one immunophilin-like protein hepatitis B virus X-associated protein 2 (XAP2), and a co-chaperone p23.…”

“…The AhR-ARNT heterodimer binds to AhR responsive elements (AHREs, also known as dioxin responsive elements (DRE) or xenobiotic responsive elements (XRE)) in the promoter of target genes that encode several phase I and phase II metabolizing enzymes ( Fig. 6) but also of several other genes [114][115][116][117].…”