Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, China.
NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China.
Acta Pharmacol Sin. 2023 Jan;44(1):169-177. doi: 10.1038/s41401-022-00925-3. Epub 2022 Jun 30.
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) 在肝脏中高度表达，在异源生物和内源性代谢物的代谢中发挥关键作用。我们之前报道过，其特异性的小鼠激动剂孕烯醇酮 16α-腈 (PCN) 激活 PXR 可显著诱导肝脏增大和脂质积累。然而，长期 PCN 处理对 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 对小鼠肝脏和肝内脂质稳态的影响。雄性 C57BL/6 小鼠每周腹腔注射 PCN（100mg/kg，一次）42 周。收集血清和肝脏样本进行生化和组织学分析。通过 Western blot 检测 PXR 激活情况。采用超高效液相色谱-电喷雾电离高分辨质谱（UHPLC-ESI-HRMS）-基于脂质组学分析方法探讨不同脂质类别变化。结果表明，长期给予 PCN 可显著促进肝肿大，而不引起肝细胞增殖和增大。长期给予 PCN 并未上调小鼠 PXR 靶蛋白，CYP3A11、CYP2B10、UGT1A1、MRP2 或 MRP4 也没有明显上调。脂质组学分析显示，PCN 处理的小鼠肝脏有明显的脂质蓄积，其中变化最明显的是甘油三酯 (TGs)。此外，长期给予 PCN 不会增加致癌风险。这些发现表明，长期给予 PCN 可诱导肝肿大和脂质蓄积，但不引起肝细胞增殖或增大。
