Pregnane X receptor (PXR) is highly expressed in the liver and plays a pivotal role in xenobiotic and endobiotic metabolism. We previously reported that PXR activation by its specific mouse agonist pregnenolone 16α-carbonitrile (PCN) significantly induces liver enlargement and lipid accumulation. However, the effect of long-term PCN treatment on PXR and mouse liver is still unknown. This study aimed to explore the influence of long-term administration of PCN on mouse liver and hepatic lipid homeostasis. Male C57BL/6 mice were injected intraperitoneally with PCN (100 mg/kg once a week) for 42 weeks. Serum and liver samples were collected for biochemical and histological analysis. PXR activation was investigated by Western blot. Ultra-high-performance liquid chromatography coupled with electrospray ionization high-resolution mass spectrometry (UHPLC-ESI-HRMS)-based lipidomics analysis was performed to explore the change in different lipid categories. The results showed that long-term treatment with PCN significantly promoted hepatomegaly without hepatocyte proliferation and enlargement. Long-term treatment with PCN did not upregulate PXR target proteins in mice, and there was no significant upregulation of CYP3A11, CYP2B10, UGT1A1, MRP2, or MRP4. Lipidomics analysis showed obvious hepatic lipid accumulation in the PCN-treated mice, and the most significant change was found in triglycerides (TGs). Additionally, long-term treatment with PCN had no risk for carcinogenesis. These findings demonstrated that long-term PCN treatment induces hepatomegaly and lipid accumulation without hepatocyte proliferation or enlargement.

孕烷 X 受体 (PXR) 在肝脏中高表达，在外源性和内源性代谢中发挥关键作用。我们之前报道过，PXR 的特异性小鼠激动剂孕烯醇酮 16α-甲腈 (PCN) 激活可显着诱导肝脏肿大和脂质积累。然而，长期PCN治疗对PXR和小鼠肝脏的影响仍不清楚。本研究旨在探讨长期给予PCN对小鼠肝脏及肝脂质稳态的影响。雄性 C57BL/6 小鼠腹腔注射 PCN（100 mg/kg，每周一次），持续 42 周。收集血清和肝脏样本用于生化和组织学分析。通过蛋白质印迹研究 PXR 激活。采用超高效液相色谱结合电喷雾电离高分辨率质谱（UHPLC-ESI-HRMS）进行脂质组学分析，以探索不同脂质类别的变化。结果显示，长期使用PCN治疗可显着促进肝肿大，但肝细胞不增殖、增大。PCN长期治疗并没有上调小鼠体内的PXR靶蛋白，CYP3A11、CYP2B10、UGT1A1、MRP2或MRP4也没有显着上调。脂质组学分析显示，PCN 治疗的小鼠存在明显的肝脏脂质积累，最显着的变化是甘油三酯 (TG)。此外，长期使用 PCN 治疗没有致癌风险。这些发现表明，长期 PCN 治疗会导致肝肿大和脂质积累，但肝细胞不会增殖或增大。