Abstract
Fumonisin B1 (FB1), a congener of fumonisins produced by Fusarium species, is the most abundant and most toxicologically active fumonisin. FB1 causes severe mycotoxicosis in animals, including nephrotoxicity, hepatotoxicity, and disruption of the intestinal barrier. However, mechanisms associated with FB1 toxicity are still unclear. Preliminary studies have highlighted the role of liver X receptors (LXRs) during FB1 exposure. LXRs belong to the nuclear receptor family and control the expression of genes involved in cholesterol and lipid homeostasis. In this context, the toxicity of FB1 was compared in female wild-type (LXR+/+) and LXRα,β double knockout (LXR−/−) mice in the absence or presence of FB1 (10 mg/kg body weight/day) for 28 days. Exposure to FB1 supplemented in the mice’s drinking water resulted in more pronounced hepatotoxicity in LXR−/− mice compared to LXR+/+ mice, as indicated by hepatic transaminase levels (ALT, AST) and hepatic inflammatory and fibrotic lesions. Next, the effect of FB1 exposure on the liver transcriptome was investigated. FB1 exposure led to a specific transcriptional response in LXR−/− mice that included altered cholesterol and bile acid homeostasis. ELISA showed that these effects were associated with an elevated FB1 concentration in the plasma of LXR−/− mice, suggesting that LXRs participate in intestinal absorption and/or clearance of the toxin. In summary, this study demonstrates an important role of LXRs in protecting the liver against FB1-induced toxicity, suggesting an alternative mechanism not related to the inhibition of sphingolipid synthesis for mycotoxin toxicity.
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Acknowledgements
MR was supported by a Fellowship from the Ministère de l’Education Nationale, de la Recherche et de la Technologie. This study was supported by the ANR Fumolip (ANR-16-CE21-0003) and ANR LipoReg (ANR-15-Carn0016), France. We thank Dr. David J. Mangelsdorf (Howard Hughes Medical Institute, Dallas, TX) for providing us with the LXR-deficient mice and for constructive discussions. We thank all members of the EZOP staff. We thank Aurore Laurent Monbrun for his excellent work on plasma biochemistry. We also thank the staff from the Genotoul: Anexplo, GeT-TriX, and Metatoul-Lipidomic facilities.
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Régnier, M., Polizzi, A., Lukowicz, C. et al. The protective role of liver X receptor (LXR) during fumonisin B1-induced hepatotoxicity. Arch Toxicol 93, 505–517 (2019). https://doi.org/10.1007/s00204-018-2345-2
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DOI: https://doi.org/10.1007/s00204-018-2345-2