Long-term treatment with the mPXR agonist PCN promotes hepatomegaly and lipid accumulation without hepatocyte proliferation in mice  

作　　者：Yi-fei Zhang Yue Gao Jie Yang Yi-ming Jiang Min Huang Shi-cheng Fan Hui-chang Bi 

机构地区：[1]Guangdong Provincial Key Laboratory of New Drug Design and Evaluation,School of Pharmaceutical Sciences,Sun Yat-Sen University,Guangzhou,510006,China [2]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

出　　处：《Acta Pharmacologica Sinica》2023年第1期169-177,共9页中国药理学报（英文版）

基　　金：The work was supported by the National Natural Science Foundation of China [Grant number:82025034,81973392];the National Key Research and Development Program (Grant number:2017YFE0109900);the Shenzhen Science and Technology Program (KQTD20190929174023858);the 111 project (Grant number:B16047);the Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program [Grant number:2017BT01Y093].

摘　　要：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.

关 键 词：pregnane X receptor(PXR) AGONIST PCN HEPATOMEGALY LIPIDOMICS triglyceride accumulation 

分 类 号：R57[医药卫生—消化系统]