Abstract
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.
Highlights
Pregnane X receptor (PXR, systematic name NR1I2) is a member of the nuclear receptor superfamily and is highly expressed in the liver and intestine of mammals [1]
There is an increasing amount of clinical evidence showing that pregnane X receptor (PXR) agonists cause hyperglycemia in humans [7] and pre-clinical work suggesting that PXR regulates hepatic glucose metabolism, there is still no solid understanding
Among these 30 genes, five are well-described target genes of peroxisome proliferator-activated receptor α (PPARα), a key hepatic transcriptional regulator involved in lipid homeostasis
Summary
Pregnane X receptor (PXR, systematic name NR1I2) is a member of the nuclear receptor superfamily and is highly expressed in the liver and intestine of mammals [1]. The “lipid metabolism” pathway was highly significantly enriched upon PXR activation and, among the 30 genes with the highest fold-change, the patatin-like phospholipase domain containing 3 (Pnpla3), the thyroid hormone-responsive spot (Thrsp or Spot14), and the growth/differentiation factor (Gdf15) belonged to this pathway. The regulation of genes involved in de novo lipogenesis was confirmed by qPCR and showed a significant increase of the SREBP-1 lipogenic pathway in Pxr-/- mice compared to WT mice (Figure S3). Among these 30 genes, five (namely Fgf, Cyp4a10, Cyp4a31, Acot, and Plin4) are well-described target genes of PPARα, a key hepatic transcriptional regulator involved in lipid homeostasis
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