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

• Main Authors: Sharon Ann Barretto, Frédéric Lasserre, Anne Fougerat, Lorraine Smith, Tiffany Fougeray, Céline Lukowicz, Arnaud Polizzi, Sarra Smati, Marion Régnier, Claire Naylies, Colette Bétoulières, Yannick Lippi, Hervé Guillou, Nicolas Loiseau, Laurence Gamet-Payrastre, Laila Mselli-Lakhal, Sandrine Ellero-Simatos
• Format: Article
• Language: English
• Published: MDPI AG 2019-08-01
• Series: International Journal of Molecular Sciences
• Subjects: nuclear receptors; hepatokines; transcriptomics
• Online Access: https://www.mdpi.com/1422-0067/20/15/3767
• ISSN: 1422-0067

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. <i>Pxr</i>^-/- C57Bl6/J male mice treated with the rodent specific ligand pregnenolone 16&#945;-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 &#945; (PPAR&#945;) signature. Comparison of this signature with a list of fasting-induced PPAR&#945; target genes confirmed that PXR activation decreased the expression of more than 25 PPAR&#945; target genes, among which was the hepatokine fibroblast growth factor 21 (<i>Fgf21</i>). 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 PPAR&#945; activity and FGF21 circulation, which could participate in the pleiotropic role of PXR in energy homeostasis.