AhR-activating polycyclic aromatic hydrocarbons and disruption of glucose metabolism in hepatocyte-like cells

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00027162%3A_____%2F24%3AN0000183" target="_blank" >RIV/00027162:_____/24:N0000183 - isvavai.cz</a>

Result on the web

—

DOI - Digital Object Identifier

—

Result language

angličtina

Original language name

AhR-activating polycyclic aromatic hydrocarbons and disruption of glucose metabolism in hepatocyte-like cells

Original language description

Polycyclic aromatic hydrocarbons (PAHs) are widely distributed environmental pollutants that are present both in the diet and in the environment. For a long time, they have been primarily studied as genotoxic and carcinogenic toxicants; however, many PAHs are also potent AhR ligands that can interfere with signaling pathways controlling immune and endocrine signaling. Using a set of PAHs representing both weak and strong AhR ligands among PAHs, we studied their effects on metabolism, in particular metabolism of glucose and lipids in the cellular models derived from hepatocytes: differentiated hepatocyte-like HepaRG cells, immortalized MIHA hepatocytes and HepG2 hepatoblastoma cells. We found that similar to 2,3,7,8-tetrachlorodibenzo-p-dioxin, exposure to benzo[k]fluoranthene (BkF), which belongs among the PAHs that strongly activate AhR, significantly decreased glucose release into the glucose-free medium after 48h exposure in differentiated HepaRG cells. At the same time, BkF reduced mRNA levels of SLC2A2/GLUT2 (a major glucose transporter in liver cells) and SLC2A9/GLUT9 (which acts as a transporter of uric acid, glucose and fructose). Simultaneously, mRNA levels of phosphoenolpyruvate carboxykinase 1 (PCK1), rate-limiting enzyme in both gluconeogenesis and glyceroneogenesis, were strongly reduced upon BkF exposure. Downregulation of their expression occurred in a dose-dependent manner already at nanomolar concentrations, it started early upon BkF exposure, and it persisted in HepaRG cells. A similar effect was observed also in other liver cell models used and the functional role of AhR in these effects was validated using AhR knockout cell model. Collectively, these results suggest that exposure of liver cells to BkF and other potent AhR ligands among PAHs may, in a similar manner as exposure to persistent AhR ligands, impair their ability to de novo produce and transport glucose. This finding also prompts us to study more deeply of the relationship between PAHs (and their metabolites), AhR activation and impaired intracellular glucose metabolism and transport.

Czech name

—

Czech description

—

Type

O - Miscellaneous

CEP classification

—

OECD FORD branch

30108 - Toxicology

Project

<a href="/en/project/GA24-10086S" target="_blank" >GA24-10086S: The impact of polycyclic aromatic hydrocarbons on cellular processes linked with stress signaling and deregulation of metabolism</a><br>

Continuities

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

Publication year

2024

Confidentiality

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