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Steatosis and Metabolic Disorders Associated with Synergistic Activation of the CAR/RXR Heterodimer by Pesticides

The nuclear receptor, constitutive androstane receptor (CAR), which forms a heterodimer with the retinoid X receptor (RXR), was initially reported as a transcription factor that regulates hepatic genes involved in detoxication and energy metabolism. Different studies have shown that CAR activation r...

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Autores principales: Dauwe, Yannick, Mary, Lucile, Oliviero, Fabiana, Grimaldi, Marina, Balaguer, Patrick, Gayrard, Véronique, Mselli-Lakhal, Laïla
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10137125/
https://www.ncbi.nlm.nih.gov/pubmed/37190111
http://dx.doi.org/10.3390/cells12081201
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author Dauwe, Yannick
Mary, Lucile
Oliviero, Fabiana
Grimaldi, Marina
Balaguer, Patrick
Gayrard, Véronique
Mselli-Lakhal, Laïla
author_facet Dauwe, Yannick
Mary, Lucile
Oliviero, Fabiana
Grimaldi, Marina
Balaguer, Patrick
Gayrard, Véronique
Mselli-Lakhal, Laïla
author_sort Dauwe, Yannick
collection PubMed
description The nuclear receptor, constitutive androstane receptor (CAR), which forms a heterodimer with the retinoid X receptor (RXR), was initially reported as a transcription factor that regulates hepatic genes involved in detoxication and energy metabolism. Different studies have shown that CAR activation results in metabolic disorders, including non-alcoholic fatty liver disease, by activating lipogenesis in the liver. Our objective was to determine whether synergistic activations of the CAR/RXR heterodimer could occur in vivo as described in vitro by other authors, and to assess the metabolic consequences. For this purpose, six pesticides, ligands of CAR, were selected, and Tri-butyl-tin (TBT) was used as an RXR agonist. In mice, CAR’s synergic activation was induced by dieldrin associated with TBT, and combined effects were induced by propiconazole, bifenox, boscalid, and bupirimate. Moreover, a steatosis, characterized by increased triglycerides, was observed when TBT was combined with dieldrin, propiconazole, bifenox, boscalid, and bupirimate. Metabolic disruption appeared in the form of increased cholesterol and lowered free fatty acid plasma levels. An in-depth analysis revealed increased expression of genes involved in lipid synthesis and lipid import. These results contribute to the growing understanding of how environmental contaminants can influence nuclear receptor activity and associated health risks.
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spelling pubmed-101371252023-04-28 Steatosis and Metabolic Disorders Associated with Synergistic Activation of the CAR/RXR Heterodimer by Pesticides Dauwe, Yannick Mary, Lucile Oliviero, Fabiana Grimaldi, Marina Balaguer, Patrick Gayrard, Véronique Mselli-Lakhal, Laïla Cells Article The nuclear receptor, constitutive androstane receptor (CAR), which forms a heterodimer with the retinoid X receptor (RXR), was initially reported as a transcription factor that regulates hepatic genes involved in detoxication and energy metabolism. Different studies have shown that CAR activation results in metabolic disorders, including non-alcoholic fatty liver disease, by activating lipogenesis in the liver. Our objective was to determine whether synergistic activations of the CAR/RXR heterodimer could occur in vivo as described in vitro by other authors, and to assess the metabolic consequences. For this purpose, six pesticides, ligands of CAR, were selected, and Tri-butyl-tin (TBT) was used as an RXR agonist. In mice, CAR’s synergic activation was induced by dieldrin associated with TBT, and combined effects were induced by propiconazole, bifenox, boscalid, and bupirimate. Moreover, a steatosis, characterized by increased triglycerides, was observed when TBT was combined with dieldrin, propiconazole, bifenox, boscalid, and bupirimate. Metabolic disruption appeared in the form of increased cholesterol and lowered free fatty acid plasma levels. An in-depth analysis revealed increased expression of genes involved in lipid synthesis and lipid import. These results contribute to the growing understanding of how environmental contaminants can influence nuclear receptor activity and associated health risks. MDPI 2023-04-21 /pmc/articles/PMC10137125/ /pubmed/37190111 http://dx.doi.org/10.3390/cells12081201 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Dauwe, Yannick
Mary, Lucile
Oliviero, Fabiana
Grimaldi, Marina
Balaguer, Patrick
Gayrard, Véronique
Mselli-Lakhal, Laïla
Steatosis and Metabolic Disorders Associated with Synergistic Activation of the CAR/RXR Heterodimer by Pesticides
title Steatosis and Metabolic Disorders Associated with Synergistic Activation of the CAR/RXR Heterodimer by Pesticides
title_full Steatosis and Metabolic Disorders Associated with Synergistic Activation of the CAR/RXR Heterodimer by Pesticides
title_fullStr Steatosis and Metabolic Disorders Associated with Synergistic Activation of the CAR/RXR Heterodimer by Pesticides
title_full_unstemmed Steatosis and Metabolic Disorders Associated with Synergistic Activation of the CAR/RXR Heterodimer by Pesticides
title_short Steatosis and Metabolic Disorders Associated with Synergistic Activation of the CAR/RXR Heterodimer by Pesticides
title_sort steatosis and metabolic disorders associated with synergistic activation of the car/rxr heterodimer by pesticides
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10137125/
https://www.ncbi.nlm.nih.gov/pubmed/37190111
http://dx.doi.org/10.3390/cells12081201
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