{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T14:20:18Z","timestamp":1790778018163,"version":"4.1.0"},"reference-count":48,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2023,4,21]],"date-time":"2023-04-21T00:00:00Z","timestamp":1682035200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"PNRPE Synepest"},{"name":"ANSES Xenomix"},{"name":"ANR Syneract"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>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\u2019s 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.<\/jats:p>","DOI":"10.3390\/cells12081201","type":"journal-article","created":{"date-parts":[[2023,4,21]],"date-time":"2023-04-21T01:33:43Z","timestamp":1682040823000},"page":"1201","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Steatosis and Metabolic Disorders Associated with Synergistic Activation of the CAR\/RXR Heterodimer by Pesticides"],"prefix":"10.3390","volume":"12","author":[{"given":"Yannick","family":"Dauwe","sequence":"first","affiliation":[{"name":"Toxalim (Research Centre in Food Toxicology), Universit\u00e9 de Toulouse, INRAE, ENVT, INP-Purpan, UPS, 31027 Toulouse, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucile","family":"Mary","sequence":"additional","affiliation":[{"name":"Toxalim (Research Centre in Food Toxicology), Universit\u00e9 de Toulouse, INRAE, ENVT, INP-Purpan, UPS, 31027 Toulouse, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabiana","family":"Oliviero","sequence":"additional","affiliation":[{"name":"Toxalim (Research Centre in Food Toxicology), Universit\u00e9 de Toulouse, INRAE, ENVT, INP-Purpan, UPS, 31027 Toulouse, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Grimaldi","sequence":"additional","affiliation":[{"name":"Institut de Recherche en Canc\u00e9rologie de Montpellier, Inserm U1194-Universit\u00e9 Montpellier-Institut r\u00e9gional du Cancer Montpellier, CEDEX 5, F-34298 Montpellier, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3524-3622","authenticated-orcid":false,"given":"Patrick","family":"Balaguer","sequence":"additional","affiliation":[{"name":"Institut de Recherche en Canc\u00e9rologie de Montpellier, Inserm U1194-Universit\u00e9 Montpellier-Institut r\u00e9gional du Cancer Montpellier, CEDEX 5, F-34298 Montpellier, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"V\u00e9ronique","family":"Gayrard","sequence":"additional","affiliation":[{"name":"Toxalim (Research Centre in Food Toxicology), Universit\u00e9 de Toulouse, INRAE, ENVT, INP-Purpan, UPS, 31027 Toulouse, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"La\u00efla","family":"Mselli-Lakhal","sequence":"additional","affiliation":[{"name":"Toxalim (Research Centre in Food Toxicology), Universit\u00e9 de Toulouse, INRAE, ENVT, INP-Purpan, UPS, 31027 Toulouse, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1002\/hep.28431","article-title":"Global Epidemiology of Nonalcoholic Fatty Liver Disease\u2014Meta-Analytic Assessment of Prevalence, Incidence, and Outcomes","volume":"64","author":"Younossi","year":"2016","journal-title":"Hepatology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1038\/ajg.2017.5","article-title":"Prevalence of Nonalcoholic Steatohepatitis-Associated Cirrhosis in the United States: An Analysis of National Health and Nutrition Examination Survey Data","volume":"112","author":"Kabbany","year":"2017","journal-title":"Off. 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