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PCB 126 and Other Dioxin-Like PCBs Specifically Suppress Hepatic PEPCK Expression via the Aryl Hydrocarbon Receptor
Dioxins and dioxin-like compounds encompass a group of structurally related heterocyclic compounds that bind to and activate the aryl hydrocarbon receptor (AhR). The prototypical dioxin is 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a highly toxic industrial byproduct that incites numerous adverse p...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3353882/ https://www.ncbi.nlm.nih.gov/pubmed/22615911 http://dx.doi.org/10.1371/journal.pone.0037103 |
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author | Zhang, Wenshuo Sargis, Robert M. Volden, Paul A. Carmean, Christopher M. Sun, Xiao J. Brady, Matthew J. |
author_facet | Zhang, Wenshuo Sargis, Robert M. Volden, Paul A. Carmean, Christopher M. Sun, Xiao J. Brady, Matthew J. |
author_sort | Zhang, Wenshuo |
collection | PubMed |
description | Dioxins and dioxin-like compounds encompass a group of structurally related heterocyclic compounds that bind to and activate the aryl hydrocarbon receptor (AhR). The prototypical dioxin is 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a highly toxic industrial byproduct that incites numerous adverse physiological effects. Global commercial production of the structurally similar polychlorinated biphenyls (PCBs), however, commenced early in the 20(th) century and continued for decades; dioxin-like PCBs therefore contribute significantly to total dioxin-associated toxicity. In this study, PCB 126, the most potent dioxin-like PCB, was evaluated with respect to its direct effects on hepatic glucose metabolism using primary mouse hepatocytes. Overnight treatment with PCB 126 reduced hepatic glycogen stores in a dose-dependent manner. Additionally, PCB 126 suppressed forskolin-stimulated gluconeogenesis from lactate. These effects were independent of acute toxicity, as PCB 126 did not increase lactate dehydrogenase release nor affect lipid metabolism or total intracellular ATP. Interestingly, provision of cells with glycerol instead of lactate as the carbon source completely restored hepatic glucose production, indicating specific impairment in the distal arm of gluconeogenesis. In concordance with this finding, PCB 126 blunted the forskolin-stimulated increase in phosphoenolpyruvate carboxykinase (PEPCK) mRNA levels without affecting glucose-6-phosphatase expression. Myricetin, a putative competitive AhR antagonist, reversed the suppression of PEPCK induction by PCB 126. Furthermore, other dioxin-like PCBs demonstrated similar effects on PEPCK expression in parallel with their ability to activate AhR. It therefore appears that AhR activation mediates the suppression of PEPCK expression by dioxin-like PCBs, suggesting a role for these pollutants as disruptors of energy metabolism. |
format | Online Article Text |
id | pubmed-3353882 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-33538822012-05-21 PCB 126 and Other Dioxin-Like PCBs Specifically Suppress Hepatic PEPCK Expression via the Aryl Hydrocarbon Receptor Zhang, Wenshuo Sargis, Robert M. Volden, Paul A. Carmean, Christopher M. Sun, Xiao J. Brady, Matthew J. PLoS One Research Article Dioxins and dioxin-like compounds encompass a group of structurally related heterocyclic compounds that bind to and activate the aryl hydrocarbon receptor (AhR). The prototypical dioxin is 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a highly toxic industrial byproduct that incites numerous adverse physiological effects. Global commercial production of the structurally similar polychlorinated biphenyls (PCBs), however, commenced early in the 20(th) century and continued for decades; dioxin-like PCBs therefore contribute significantly to total dioxin-associated toxicity. In this study, PCB 126, the most potent dioxin-like PCB, was evaluated with respect to its direct effects on hepatic glucose metabolism using primary mouse hepatocytes. Overnight treatment with PCB 126 reduced hepatic glycogen stores in a dose-dependent manner. Additionally, PCB 126 suppressed forskolin-stimulated gluconeogenesis from lactate. These effects were independent of acute toxicity, as PCB 126 did not increase lactate dehydrogenase release nor affect lipid metabolism or total intracellular ATP. Interestingly, provision of cells with glycerol instead of lactate as the carbon source completely restored hepatic glucose production, indicating specific impairment in the distal arm of gluconeogenesis. In concordance with this finding, PCB 126 blunted the forskolin-stimulated increase in phosphoenolpyruvate carboxykinase (PEPCK) mRNA levels without affecting glucose-6-phosphatase expression. Myricetin, a putative competitive AhR antagonist, reversed the suppression of PEPCK induction by PCB 126. Furthermore, other dioxin-like PCBs demonstrated similar effects on PEPCK expression in parallel with their ability to activate AhR. It therefore appears that AhR activation mediates the suppression of PEPCK expression by dioxin-like PCBs, suggesting a role for these pollutants as disruptors of energy metabolism. Public Library of Science 2012-05-16 /pmc/articles/PMC3353882/ /pubmed/22615911 http://dx.doi.org/10.1371/journal.pone.0037103 Text en Zhang et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Zhang, Wenshuo Sargis, Robert M. Volden, Paul A. Carmean, Christopher M. Sun, Xiao J. Brady, Matthew J. PCB 126 and Other Dioxin-Like PCBs Specifically Suppress Hepatic PEPCK Expression via the Aryl Hydrocarbon Receptor |
title | PCB 126 and Other Dioxin-Like PCBs Specifically Suppress Hepatic PEPCK Expression via the Aryl Hydrocarbon Receptor |
title_full | PCB 126 and Other Dioxin-Like PCBs Specifically Suppress Hepatic PEPCK Expression via the Aryl Hydrocarbon Receptor |
title_fullStr | PCB 126 and Other Dioxin-Like PCBs Specifically Suppress Hepatic PEPCK Expression via the Aryl Hydrocarbon Receptor |
title_full_unstemmed | PCB 126 and Other Dioxin-Like PCBs Specifically Suppress Hepatic PEPCK Expression via the Aryl Hydrocarbon Receptor |
title_short | PCB 126 and Other Dioxin-Like PCBs Specifically Suppress Hepatic PEPCK Expression via the Aryl Hydrocarbon Receptor |
title_sort | pcb 126 and other dioxin-like pcbs specifically suppress hepatic pepck expression via the aryl hydrocarbon receptor |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3353882/ https://www.ncbi.nlm.nih.gov/pubmed/22615911 http://dx.doi.org/10.1371/journal.pone.0037103 |
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