Research Unit of Biomedicine, Pharmacology and Toxicology, University of Oulu, Oulu, Finland.
Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland.
Sci Rep. 2019 Nov 13;9(1):16728. doi: 10.1038/s41598-019-53101-9.
Pregnane X receptor (PXR) regulates glucose and lipid metabolism, but little is known of the nutritional regulation of PXR function. We investigated the genome wide effects of the nutritional status on the PXR mediated gene regulation in the liver. Mice were treated with a PXR ligand pregnenolone 16α-carbonitrile (PCN) for 4 days and subsequently either fasted for 5 hours or after 4-hour fast treated with intragastric glucose 1 hour before sample collection. Gene expression microarray study indicated that PCN both induced and repressed much higher number of genes in the glucose fed mice and the induction of multiple well-established PXR target genes was potentiated by glucose. A subset of genes, including bile acid synthesis gene Cyp8b1, responded in an opposite direction during fasting and after glucose feeding. PXR knockout abolished these effects. In agreement with the Cyp8b1 regulation, PCN also modified the bile acid composition in the glucose fed mice. Contribution of glucose, insulin and glucagon on the observed nutritional effects was investigated in primary hepatocytes. However, only mild impact on PXR function was observed. These results show that nutritional status modifies the PXR regulated transcriptome both qualitatively and quantitatively and reveal a complex crosstalk between PXR and energy homeostasis.
pregnane X 受体 (PXR) 调节葡萄糖和脂质代谢，但人们对营养状态对 PXR 功能的调节知之甚少。我们研究了营养状态对肝脏中 PXR 介导的基因调控的全基因组影响。用 PXR 配体孕烯醇酮 16α-腈 (PCN) 处理小鼠 4 天，然后在取样前 1 小时禁食 5 小时或在禁食 4 小时后经胃内给予葡萄糖。基因表达微阵列研究表明，PCN 在给予葡萄糖的小鼠中诱导和抑制了更多数量的基因，并且葡萄糖增强了多种已确立的 PXR 靶基因的诱导。一组基因，包括胆汁酸合成基因 Cyp8b1，在禁食和葡萄糖喂养后表现出相反的反应。PXR 敲除消除了这些影响。与 Cyp8b1 的调节一致，PCN 也改变了葡萄糖喂养小鼠中的胆汁酸组成。在原代肝细胞中研究了葡萄糖、胰岛素和胰高血糖素对观察到的营养效应的贡献。然而，仅观察到对 PXR 功能的轻微影响。这些结果表明，营养状态既定性又定量地改变了 PXR 调节的转录组，并揭示了 PXR 与能量稳态之间的复杂相互作用。
