Activation of AhR by polycyclic aromatic hydrocarbons may contribute to alterations of glucose transport in liver cells

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00027162%3A_____%2F24%3AN0000184" target="_blank" >RIV/00027162:_____/24:N0000184 - isvavai.cz</a>

Výsledek na webu

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DOI - Digital Object Identifier

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Jazyk výsledku

angličtina

Název v původním jazyce

Activation of AhR by polycyclic aromatic hydrocarbons may contribute to alterations of glucose transport in liver cells

Popis výsledku v původním jazyce

The aryl hydrocarbon receptor (AhR) is one of the receptors regulating the metabolism of a number of potentially dangerous xenobiotics. It is a cytosolic receptor expressed throughout most of the human tissues, highly abundant in the liver. Upon activation by a ligand (endogenous or exogenous), it is translocated into the cell nucleus where it functions as a transcription factor for its target genes. The best known group of AhR target genes are those encoding cytochrome P450 family 1 enzymes (e.g. CYP1A1, CYP1B1). Polycyclic aromatic hydrocarbons (PAHs) are one of the most significant groups of AhR ligands that are highly abundant in many environmental compartments, including polluted air. They are produced by anthropogenic activities (exhaust fumes, heavy industry fumes) and they have a number of deleterious effects on animals and humans. In the past, PAHs or environmental matrices containing PAHs and other toxic AhR ligands have been associated e.g. with endocrine disruption, modulation of immune responses, development of cancer, or increased risk of metabolic diseases. In the present study, we focus on changes in energy metabolism (specifically glucose metabolism and transport) in human liver cells. We used HepaRG (differentiated hepatocyte-like cells) and other liver cell lines derived from human hepatocytes or human hepatoblastoma. By screening of expression of various glucose transporters (GLUTs) after exposure to TCDD and benzo(k)fluoranthene (BkF), which both belong among potent AhR ligands, we aimed to characterize potential alterations in glucose transport. Our results revealed a significant suppression of a number of GLUTs (that are known to be expressed in liver cells) induced by these toxic AhR ligands in HepaRG cells after 24h exposure. The suppression occurred at concentrations associated with significant upregulation of canonical AhR target, CYP1A1 mRNA. Using AhR-deficient liver cells, we confirmed functional role of AhR in the observed effect. When HepaRG cells were cultivated in glucose-free medium after exposure to the AhR ligands for 48 h, the release of glucose into the medium was significantly reduced; however, this effect was not observed for PAHs that do not activate AhR or are poor AhR ligands. Our results suggest that AhR activation by strong AhR ligands among PAHs may lead to suppression of numerous GLUTs in human liver-derived cells, as well as alterations of glucose production/release. These observations may assist to identify links between AhR and metabolic disorders in humans; nevertheless, further studies are necessary to identify the mechanisms leading to suppression of glucose transport and production by toxic AhR ligands.

Název v anglickém jazyce

Activation of AhR by polycyclic aromatic hydrocarbons may contribute to alterations of glucose transport in liver cells

Popis výsledku anglicky

The aryl hydrocarbon receptor (AhR) is one of the receptors regulating the metabolism of a number of potentially dangerous xenobiotics. It is a cytosolic receptor expressed throughout most of the human tissues, highly abundant in the liver. Upon activation by a ligand (endogenous or exogenous), it is translocated into the cell nucleus where it functions as a transcription factor for its target genes. The best known group of AhR target genes are those encoding cytochrome P450 family 1 enzymes (e.g. CYP1A1, CYP1B1). Polycyclic aromatic hydrocarbons (PAHs) are one of the most significant groups of AhR ligands that are highly abundant in many environmental compartments, including polluted air. They are produced by anthropogenic activities (exhaust fumes, heavy industry fumes) and they have a number of deleterious effects on animals and humans. In the past, PAHs or environmental matrices containing PAHs and other toxic AhR ligands have been associated e.g. with endocrine disruption, modulation of immune responses, development of cancer, or increased risk of metabolic diseases. In the present study, we focus on changes in energy metabolism (specifically glucose metabolism and transport) in human liver cells. We used HepaRG (differentiated hepatocyte-like cells) and other liver cell lines derived from human hepatocytes or human hepatoblastoma. By screening of expression of various glucose transporters (GLUTs) after exposure to TCDD and benzo(k)fluoranthene (BkF), which both belong among potent AhR ligands, we aimed to characterize potential alterations in glucose transport. Our results revealed a significant suppression of a number of GLUTs (that are known to be expressed in liver cells) induced by these toxic AhR ligands in HepaRG cells after 24h exposure. The suppression occurred at concentrations associated with significant upregulation of canonical AhR target, CYP1A1 mRNA. Using AhR-deficient liver cells, we confirmed functional role of AhR in the observed effect. When HepaRG cells were cultivated in glucose-free medium after exposure to the AhR ligands for 48 h, the release of glucose into the medium was significantly reduced; however, this effect was not observed for PAHs that do not activate AhR or are poor AhR ligands. Our results suggest that AhR activation by strong AhR ligands among PAHs may lead to suppression of numerous GLUTs in human liver-derived cells, as well as alterations of glucose production/release. These observations may assist to identify links between AhR and metabolic disorders in humans; nevertheless, further studies are necessary to identify the mechanisms leading to suppression of glucose transport and production by toxic AhR ligands.

Druh

O - Ostatní výsledky

CEP obor

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OECD FORD obor

30108 - Toxicology

Projekt

<a href="/cs/project/GA24-10086S" target="_blank" >GA24-10086S: Dopady působení polycyklických aromatických uhlovodíků na buněčné procesy spojené se stresovou signalizací a deregulací metabolismu</a><br>

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2024

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů