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Article

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

by
Yannick Dauwe
1,
Lucile Mary
1,
Fabiana Oliviero
1,
Marina Grimaldi
2,
Patrick Balaguer
2,
Véronique Gayrard
1 and
Laïla Mselli-Lakhal
1,*
1
Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRAE, ENVT, INP-Purpan, UPS, 31027 Toulouse, France
2
Institut de Recherche en Cancérologie de Montpellier, Inserm U1194-Université Montpellier-Institut régional du Cancer Montpellier, CEDEX 5, F-34298 Montpellier, France
*
Author to whom correspondence should be addressed.
Cells 2023, 12(8), 1201; https://doi.org/10.3390/cells12081201
Submission received: 17 February 2023 / Revised: 18 April 2023 / Accepted: 19 April 2023 / Published: 21 April 2023
(This article belongs to the Collection Functions of Nuclear Receptors)
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Abstract

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.
Keywords: CAR; RXR; nuclear; receptor; pesticides; steatosis; NAFLD; tributyltin; metabolism; synergism CAR; RXR; nuclear; receptor; pesticides; steatosis; NAFLD; tributyltin; metabolism; synergism

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MDPI and ACS Style

Dauwe, Y.; Mary, L.; Oliviero, F.; Grimaldi, M.; Balaguer, P.; Gayrard, V.; Mselli-Lakhal, L. Steatosis and Metabolic Disorders Associated with Synergistic Activation of the CAR/RXR Heterodimer by Pesticides. Cells 2023, 12, 1201. https://doi.org/10.3390/cells12081201

AMA Style

Dauwe Y, Mary L, Oliviero F, Grimaldi M, Balaguer P, Gayrard V, Mselli-Lakhal L. Steatosis and Metabolic Disorders Associated with Synergistic Activation of the CAR/RXR Heterodimer by Pesticides. Cells. 2023; 12(8):1201. https://doi.org/10.3390/cells12081201

Chicago/Turabian Style

Dauwe, Yannick, Lucile Mary, Fabiana Oliviero, Marina Grimaldi, Patrick Balaguer, Véronique Gayrard, and Laïla Mselli-Lakhal. 2023. "Steatosis and Metabolic Disorders Associated with Synergistic Activation of the CAR/RXR Heterodimer by Pesticides" Cells 12, no. 8: 1201. https://doi.org/10.3390/cells12081201

APA Style

Dauwe, Y., Mary, L., Oliviero, F., Grimaldi, M., Balaguer, P., Gayrard, V., & Mselli-Lakhal, L. (2023). Steatosis and Metabolic Disorders Associated with Synergistic Activation of the CAR/RXR Heterodimer by Pesticides. Cells, 12(8), 1201. https://doi.org/10.3390/cells12081201

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