Peroxisome proliferator-activated receptor α agonist induces mouse hepatomegaly through the spatial hepatocyte enlargement and proliferation  

作　　者：Jie Yang Xiao Yang Yi-fei Zhang Jia-ning Tian Shi-cheng Fan Yue Gao Hui-lin Li Cheng-hui Cai Min Huang Hui-chang Bi 

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

出　　处：《Acta Pharmacologica Sinica》2023年第10期2037-2047,共11页中国药理学报（英文版）

基　　金：supported by the National Key R&D Program of China(2022YFA1104900);the National Natural Science Foundation of China(82025034,82000593,81973392,82020108031);the Shenzhen Science and Technology Program(KQTD20190929174023858);the Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program(2017BT01Y093);the China Postdoctoral Science Foundation(2019TQ0398,2020M673028).

摘　　要：Peroxisome proliferator-activated receptor alpha(PPARα)activation-induced hepatomegaly is accompanied by hepatocyte hypertrophy around the central vein(CV)area and hepatocyte proliferation around the portal vein(PV)area.However,the molecular mechanisms underlying this spatial change of hepatocytes remains unclear.In this study,we examined the characteristics and possible reasons for the zonation distinction of hypertrophy and proliferation during PPARαactivation-induced mouse liver enlargement.Mice were injected with corn oil or a typical mouse PPARαagonist WY-14643(100 mg·kg^(−1)·d^(−1),i.p.)for 1,2,3,5 or 10 days.At each time point,the mice were sacrificed after the final dose,and liver tissues and serum were harvested for analysis.We showed that PPARαactivation induced zonal changes in hepatocyte hypertrophy and proliferation in the mice.In order to determine the zonal expression of proteins related to hepatocyte hypertrophy and proliferation in PPARα-induced liver enlargement,we performed digitonin liver perfusion to separately destroy the hepatocytes around the CV or PV areas,and found that PPARαactivation-induced increase magnitude of its downstream targets such as cytochrome P450(CYP)4 A and acyl-coenzyme A oxidase 1(ACOX1)levels around the CV area were higher compared with those around the PV area.Upregulation of proliferation-related proteins such as cell nuclear antigen(PCNA)and cyclin A1(CCNA1)after WY-14643-induced PPARαactivation mainly occurred around the PV area.This study reveals that the zonal expression of PPARαtargets and proliferation-related proteins is responsible for the spatial change of hepatocyte hypertrophy and proliferation after PPARαactivation.These findings provide a new insight into the understanding of PPARαactivation-induced liver enlargement and regeneration.

关 键 词：peroxisome proliferator-activated receptorα HEPATOMEGALY spatial distribution hepatocyte proliferation hepatocyte hypertrophy 

分 类 号：R965[医药卫生—药理学]