Organ-specific effects on glycolysis by the dioxin-activated aryl hydrocarbon receptor

Abstract

Activation of the aryl hydrocarbon receptor (AHR) by the environmental toxin dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin, TCDD) causes diverse toxicities, including thymus atrophy and hepatosteatosis. The mechanisms by which AHR activation by TCDD leads to these toxicities are not fully understood. Here we studied the effects of TCDD on a major energy pathway, glycolysis, using the chick embryo close to hatching, a well-established model for studying dioxin toxicity. We showed that 24 hr of TCDD treatment causes changes in glycolysis in both thymus and liver. In thymus glands, TCDD decreased mRNAs for glycolytic genes and glucose transporters, glycolytic indices and levels of IL7 mRNA, phosphorylated AKT (pAKT) and HIF1A, stimulators of glycolysis and promoters of survival and proliferation of thymic lymphocytes. In contrast, in liver, TCDD increased mRNA levels for glycolytic genes and glucose transporters, glycolytic endpoints and pAKT levels. Similarly, increases by TCDD in mRNA levels for glycolytic genes and glucose transporters in human primary hepatocytes showed that effects in chick embryo liver pertain also to human cells. Treatment with the glycolytic inhibitor 2-deoxy-d-glucose exacerbated the effects on thymus atrophy by TCDD, supporting a role for decreased glycolysis in thymus atrophy by TCDD, but did not prevent hepatosteatosis. NAD+ precursors abolished TCDD effects on glycolytic endpoints in both thymus and liver. In summary, we report here that dioxin disrupts glycolysis mediated energy metabolism in both thymus and liver, and that it does so in opposite ways, decreasing it in the thymus and increasing it in the liver. Further, the findings support NAD+ boosting as a strategy against metabolic effects of environmental pollutants such as dioxins.

Hexokinase 2 is a transcriptional target and a positive modulator of AHR signalling

“…Nonetheless, the details of the proteins and pathways involved in the regulation of AHR signalling activity are still far from complete and it might depend on features proper to each cellular context such as possible genetic mutations, exposure to exogenous cues and stage of cell differentiation ( 7 ). In here, we provide evidences that HK2 is a transcriptional target of AHR, as suggested by previous large-scale gene expression studies ( 22 , 57–59 ), and studies indicating that AHR might be an important regulator of glycolytic genes expression and glycolysis end-points ( 3 , 7 , 51 , 60–62 ). In MCF-7 cells, we identified a cluster of AHR binding sites in the vicinity of exon 3 of HK2 gene; and binding of AHR at the promoter of HK2 in two other cell lines GM17212 and HepG2.…”

The impact of fine particulate matter (PM) on various beneficial functions of human endometrial stem cells through its key regulator SERPINB2

“…Several previous studies found that dioxin (TCDD) exposure can enhance glycolysis in an organ-specific manner as part of the toxic response. For instance, Moore et al observed that dioxin increased the mRNA levels of various glycolytic genes in the liver 66 . Wu et al also found that AMPK treatment significantly enhanced glycolysis as an adaptive response to oxidative stress in human skin fibroblasts 67 .…”

Aryl hydrocarbon receptor (AHR) functions in infectious and sterile inflammation and NAD+-dependent metabolic adaptation

“…Effects of TCDD were found to be organ specific leading to decreased glycolytic enzymes and glucose transporters in thymus and increased glycolytic enzymes and glucose transporters in liver. In TCDD-treated primary cultures of human hepatocytes glycolysis and GLUT1 were also increased (Diani-Moore et al 2020). These findings provide hints to molecular AHR targets of energy metabolism.…”