Abstract：
Activation of pregnane X receptor (PXR) by xenobiotics has been associated with metabolic diseases. This study aimed to reveal the impact of PXR activation on hepatic metabolome and explore novel mechanisms underlying PXR-mediated lipid metabolism disorder in the liver. Wild-type and PXR-deficient male C57BL/6 mice were used as in vivo models, and hepatic steatosis was induced by pregnenolone-16α-carbonitrile, a typical rodent PXR agonist. Metabolomic analysis of liver tissues showed that PXR activation led to significant changes in metabolites involved in multiple metabolic pathways previously reported, including lipid metabolism, energy homeostasis, and amino acid metabolism. Moreover, the level of hepatic all-trans retinoic acid (ATRA), the main active metabolite of vitamin A, was significantly increased by PXR activation, and genes involved in ATRA metabolism exhibited differential expression following PXR activation or deficiency. Consistent with previous research, the expression of downstream target genes of peroxisome proliferator-activated receptor α (PPARα) was decreased. Analysis of fatty acids by Gas Chromatography-Mass Spectrometer further revealed changes in polyunsaturated fatty acid metabolism upon PXR activation, suggesting inhibition of PPARα activity. Taken together, our findings reveal a novel metabolomic signature of hepatic steatosis induced by PXR activation in mice.
摘要：
外源性物质对孕烷X受体（PXR）的激活与代谢疾病有关。本研究旨在揭示PXR激活对肝脏代谢组的影响，并探索PXR介导的肝脏脂质代谢紊乱的新机制。野生型和PXR缺陷的雄性C57BL/6小鼠用作体内模型，肝脂肪变性由孕烯醇酮-16α-甲腈诱导，一种典型的啮齿动物PXR激动剂。肝脏组织的代谢组学分析显示，PXR激活导致先前报道的多种代谢途径所涉及的代谢产物发生显著变化，包括脂质代谢，能量稳态，和氨基酸代谢。此外，肝全反式维甲酸（ATRA）的水平，维生素A的主要活性代谢产物,通过PXR激活显着增加，与ATRA代谢有关的基因在PXR激活或缺乏后表现出差异表达。与以前的研究一致，过氧化物酶体增殖物激活受体α（PPARα）下游靶基因的表达降低。通过气相色谱-质谱仪分析脂肪酸进一步揭示了PXR活化后多不饱和脂肪酸代谢的变化，提示PPARα活性的抑制。一起来看,我们的发现揭示了PXR激活诱导的小鼠肝脏脂肪变性的新代谢组学特征。
