AHR Regulates Metabolic Reprogramming to Promote SIRT1-Dependent Keratinocyte Differentiation

Abstract

Activation of the transcription factor, AHR, in normal human epidermal keratinocytes increased AHR binding in the gene regions of the glucose transporter, SLC2A1, and the glycolytic enzyme, ENO1. This increased chromatin binding corresponded with AHR-dependent decreases in levels of SLC2A1 and ENO1 mRNA, protein, and activities. Studies of the ENO1 promoter showed activation of the AHR decreases the transcription of ENO1. Glycolysis was lowered by activation of the AHR as measured by decreases in glucose uptake and the production of pyruvate and lactate. Levels of ATP were also decreased. Downregulation of glucose metabolism, either by activation of the AHR, inhibition of glycolysis, inhibition of glucose transport, or inhibition of enolase, increased SIRT1 protein levels in normal human epidermal keratinocytes and the immortalized keratinocyte cell line, N/TERT-1. This increase in SIRT1 was abrogated by the addition of exogenous pyruvate. Moreover, keratinocyte differentiation in response to downregulation of glycolysis, either by activation of the AHR, inhibition of glucose transport, or inhibition of enolase, was dependent on SIRT1. These results indicate that regulation of glycolysis controls keratinocyte differentiation, and that activation of the AHR, by lowering the expression of SLC2A1 and ENO1, can determine this fate.

The Aryl Hydrocarbon Receptor (AhR) in the Aging Process: Another Puzzling Role for This Highly Conserved Transcription Factor

“…Several polyphenols indeed were shown to activate Sirt1 (reviewed in Ajami et al, 2017). Considering the interaction between AhR and Sirt1 (Koizumi et al, 2014;Ming et al, 2015;Sutter et al, 2019), the notion that ROS activates AhR (Smirnova et al, 2016), and the multiple roles polyphenols may exert on mitochondria, these findings provide indirect evidence for a possible crosstalk between AhR, Sirt1 and mitochondria of relevance for the aging process.…”

“…To avoid the constant activation of the AhR, negative feedback loops regulate the AhR cascade pathway (Mulero-Navarro and Fernandez-Salguero, 2016;Xue et al, 2017). It is interesting to note that different AhR target genes (e.g., enzymes involved in glutathione synthesis and modulation) as well as genes regulating or regulated by AhR (e.g., Sirt1, p53, Hif1, p300, and HSP90) are involved in the aging process (Henry and Gasiewicz, 1993;Marlowe et al, 2004;Koizumi et al, 2014;Li et al, 2014;Ming et al, 2015;Panchanathan et al, 2015;Ajami et al, 2017;Janssens et al, 2019;Sutter et al, 2019).…”

Psoriatic Dermal-derived Mesenchymal Stem Cells Reduce Keratinocyte Junctions, and Increase Glycolysis

“…The present study also showed that psoriatic DMSCs increased expression levels of proteins involved in the progression of the tricarboxylic acid cycle and cellular glucose homeostasis. Glycolysis is a key metabolic pathway that provides energy for cellular activities and consumes equivalents to sustain cell division (27). Glycolysis also plays an essential role in cell proliferation by maintaining high levels of glycolytic intermediates to support cellular anabolic reactions (28).…”

“…Glycolysis also plays an essential role in cell proliferation by maintaining high levels of glycolytic intermediates to support cellular anabolic reactions (28). Conversely, the decreased glycolysis is related to cell differentiation (29,30), particularly keratinocyte differentiation (27). Hence, increased KC proliferation in psoriasis could be attributable to DMSC-induced elevations in glycolysis.…”

Effect of Chronic, Low-Dose TCDD Exposure on Glucose Homeostasis and Beta Cell Function in Wild Type and Cyp1a1/1a2 Systemic Knock-Out Adult Mice

“…In line with this, a decrease in pancreatic glucose uptake following in vivo micromolar exposure of TCDD has been previously reported (Novelli et al, 2005), albeit it in male mice. Although Novelli and colleagues (2005) did not find differences in Glut-2 expression of male mice, others have found decreases in glucose uptake following in vivo nanomolar TCDD exposure in male and female mice, rats and guinea pigs (Enan and Matsumura 1994) and in immortalized cells (Sutter et al, 2019;Tonak et al, 2007). In the future, analysis of genes associated with β-cell glucose sensitivity and uptake such as…”