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Open AccessArticle

Gene Expression Profiling Reveals that PXR Activation Inhibits Hepatic PPARα Activity and Decreases FGF21 Secretion in Male C57Bl6/J Mice

Institut National de la Recherche Agronomique (INRA), UMR1331 Toxalim, F31-027 Toulouse CEDEX 3, France
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Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2019, 20(15), 3767; https://doi.org/10.3390/ijms20153767
Received: 21 June 2019 / Revised: 29 July 2019 / Accepted: 31 July 2019 / Published: 1 August 2019
(This article belongs to the Special Issue PPARs in Metabolic Regulation: Implications for Health and Disease)
The pregnane X receptor (PXR) is the main nuclear receptor regulating the expression of xenobiotic-metabolizing enzymes and is highly expressed in the liver and intestine. Recent studies have highlighted its additional role in lipid homeostasis, however, the mechanisms of these regulations are not fully elucidated. We investigated the transcriptomic signature of PXR activation in the liver of adult wild-type vs. Pxr-/- C57Bl6/J male mice treated with the rodent specific ligand pregnenolone 16α-carbonitrile (PCN). PXR activation increased liver triglyceride accumulation and significantly regulated the expression of 1215 genes, mostly xenobiotic-metabolizing enzymes. Among the down-regulated genes, we identified a strong peroxisome proliferator-activated receptor α (PPARα) signature. Comparison of this signature with a list of fasting-induced PPARα target genes confirmed that PXR activation decreased the expression of more than 25 PPARα target genes, among which was the hepatokine fibroblast growth factor 21 (Fgf21). PXR activation abolished plasmatic levels of FGF21. We provide a comprehensive signature of PXR activation in the liver and identify new PXR target genes that might be involved in the steatogenic effect of PXR. Moreover, we show that PXR activation down-regulates hepatic PPARα activity and FGF21 circulation, which could participate in the pleiotropic role of PXR in energy homeostasis. View Full-Text
Keywords: nuclear receptors; hepatokines; transcriptomics nuclear receptors; hepatokines; transcriptomics
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Barretto, S.A.; Lasserre, F.; Fougerat, A.; Smith, L.; Fougeray, T.; Lukowicz, C.; Polizzi, A.; Smati, S.; Régnier, M.; Naylies, C.; Bétoulières, C.; Lippi, Y.; Guillou, H.; Loiseau, N.; Gamet-Payrastre, L.; Mselli-Lakhal, L.; Ellero-Simatos, S. Gene Expression Profiling Reveals that PXR Activation Inhibits Hepatic PPARα Activity and Decreases FGF21 Secretion in Male C57Bl6/J Mice. Int. J. Mol. Sci. 2019, 20, 3767.

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