PXR所致小鼠肝增大的肝细胞动态变化研究  

Dynamic change of hepatocyte during PXR-induced liver enlargement

作　　者：田佳宁 王锐敏 杨潇 杨洁 张翼飞 黄民 毕惠嫦 TIAN Jia-ning;WANG Rui-min;YANG Xiao;YANG Jie;ZHANG Yi-fei;HUANG Min;BI Hui-chang(Lab of Drug Metabolism and Pharmacokinetics,School of Pharmaceutical Sciences,Sun Yat-sen University,Guangzhou 510006,China)

机构地区：[1]中山大学药学院,药物代谢与药动学实验室,广东广州510006

出　　处：《药学学报》2021年第5期1360-1368,共9页Acta Pharmaceutica Sinica

基　　金：国家自然科学基金资助项目(81973392,82025034)。

摘　　要：孕烷X受体(pregnane X receptor, PXR)是核受体超家族成员,在内外源物质代谢、内分泌平衡和细胞增殖等过程中发挥重要调控作用。本课题组前期研究表明,给予PXR鼠源激动剂孕烯醇酮16α-腈(pregnenolone 16α-carbonitrile, PCN)可致小鼠肝增大,并发现此过程肝细胞的变化具有区域性分布的特征:中央静脉(central vein,CV)区肝细胞增大,而门静脉(portal vein, PV)区肝细胞增殖。本研究旨在评估PXR所致肝增大过程肝细胞动态变化的特点。雄性C57BL/6小鼠给予PCN后1、2、3、5天后采集血清及肝脏样本进行生化和病理检测,此动物实验经由中山大学动物伦理委员会批准。结果表明,随着给药时间的延长,小鼠CV区肝细胞体积逐渐增大, PV区肝细胞增殖增加;同时肝细胞增大相关因素如PXR下游细胞色素P450 (cytochrome P450, CYP450)代谢酶和转运体的表达以及肝脏甘油三酯(triglyceride, TG)含量均逐渐增加,而肝细胞增殖的增殖相关蛋白的上调以及细胞周期抑制蛋白的下调则在给药初期即有显著变化,提示在PXR所致小鼠肝增大过程中肝细胞增殖的发生早于肝细胞增大。本研究阐明了PXR所致肝增大过程中肝细胞增大与增殖的动态变化,为PXR促进肝增大的研究提供新数据和新观点。Pregnane X receptor(PXR),a member of nuclear receptor superfamily,plays an important role in xenobiotic and endogenous metabolism,endocrine balance,and cell proliferation,etc.Previous study has shown that pregnenolone 16α-carbonitrile(PCN),a mouse PXR agonist,could induce liver enlargement.And we found that the change in hepatocytes exhibits regional distribution characteristics:hepatocyte enlargement occurs around the central vein(CV)area,while hepatocyte proliferation occurs around the portal vein(PV)area.In this study,the dynamic changes of hepatocytes during PXR-induced liver enlargement were determined.Serum and liver samples from male C57 BL/6 mice were collected for biochemical and pathological analysis after PCN treatment for 1,2,3,5 days,respectively.The animal experiment was approved by the Animal Ethics Committee of Sun Yat-Sen University.The results showed that with the increase in the PCN treatment days,the feature of this regional change of hepatocyte around the CV and PV areas became more and more obvious.At the same time,the factors related to hepatocyte enlargement,such as the expression of PXR downstream genes and the hepatic content of triglyceride(TG),has gradually increased.The upregulation of proliferation-related proteins and downregulation of cyclin-dependent kinases inhibitor proteins were observed in the early stage of PCN treatment,suggesting that hepatocyte proliferation occurs earlier than hepatocyte enlargement during PXR-induced liver enlargement.This study reveals the dynamic change of hepatocytes during PXR-induced liver enlargement and provides a new insight in liver enlargement promoted via PXR activation.

关 键 词：孕烷X受体 肝增大 肝细胞增大 肝细胞增殖 

分 类 号：R966[医药卫生—药理学]