Nrf2_ARE信号通路参与肝脏疾病病理机制研究进展_曹玲娟

2015－7－221042http//．cnki．net/kcms/detail/34．1086．R．20150727．0901．009．htmlNrf2-ARE12121212121．4100112．410013doi10．3969/j．issn．1001－1978．2015．08．006A1001－1978201508－1057－05R-05R322.47R349.1R575R575.2R575.5R735.7NF-E22Nrf2AREⅡ。Nrf2-ARE、Nrf2。Nrf2-ARE。[e-mail][e-mail]1Nrf2-ARENF-E22nuclearfactorerythroid-2re-latedfactor2Nrf2Keap1。Fig1Nrf2NKelchECH1Kelch-likeECH-associatedprotein1Keap1Nrf2Ⅱ。reactiveoxygenspeciesROSNrf2Keap1Nrf2MafantioxidantresponseelementAREⅡhemeoxygenase-1HO-1、NADPHNADPHquinoneoxidoreductase1NQO1、glutamate-cysteineligaseGCL、-S-glutathione-S-transferaseGSTepoxidehydrolaseEH1。ROS、。、3、CNrf2Nrf2Keap1ARE2。Nrf2-ARE。Nrf2-ARE。、、CDDO-ImNrf2-ARE。α-α-naphthylisothiocyanateANIT4。CDDO-ImAconcanavalinAConANrf2。Nrf2Keap1-KO、Keap1-CKOKeap1-kd。700mg·kg－1acetaminophenAPAPKeap1-CKONrf2NQO1、GCL、GSTAPAPConA5。Fig1SchematicdiagramofNrf2-AREsignalingpathway32Nrf2-ARENrf2-ARE、drug-in-·7501·ChinesePharmacologicalBulletin2015Aug3181057～61ducedliverinjuryDILI、、non-alcoholicfattyliverdiseaseNAFLD/NASH、alcoholicliverdiseaseALD、。2．1Nrf2-AREDILICYP450、、Ca2+-ATPCa2+、DILI。APAPDILI、GSH。APAPCYPN-N-acetyl-14-benzoquinoneimineNAPQIglutathioneGSH。APAPGSHNAPQIROS。Nrf2AREAPAPUGT、GST、NQO1Nrf2APAP。APAPNrf2。APAPNrf260minEH、HO-1、GCL6。CDDO-ImNrf2-AREHO-1、NQO1GCLCAPAPNrf27。APAP3multidrugresist-ance-associatedprotein3Mrp3、Mrp4Nrf2Nrf2Mrp3Mrp4Nrf2APAP。Keap1Nrf2NADPH8。DILINrf21-GSH9。CCl4Nrf210。11、Nrf2。Nrf2Nrf2-AREDILI。2．2Nrf2-ARE/。bilesaltexportpumpBSEPMRPABCNrf2BSEPMRP。bileductligationBDL。BDLNrf2Mrp3、Mrp4CYP7A1、CYP8B1。BDLKeap1-kdROSKeap1-kdNrf2Mrp13。Nrf2BDLX14。ANIT。Nrf2ANIT75mg·kg－1BSEPMrp3Nrf2。Nrf2ANITNrf2ANITNrf24。Nrf2。NF-κBTGF-β/SmadNrf2HO-115。ANrf2Nrf2HO-1NQO116。2．3Nrf2-ARENAFLD/NASHNAFLD、、、NASH。NAFLDROSGSHsuperoxidedismutaseSOD。Kim1712Nrf2ALT、GLUP＜0.01。、Nrf2Nrf2。Nrf2NAFLDNrf2NAFLD。Nrf2-ARENAFLD/NASHShin18CDDO-ImNrf2Nrf2-ARE。Nrf2NF-κBNrf2NF-κB。Nrf2·8501·ChinesePharmacologicalBulletin2015Aug318HO-1NQO1。βtransforminggrowthfactor-βTGF-βNrf219。hepaticstellatecellHSCNrf2TGF-β-αα-smoothmuscleactinα-SMA、Ⅰ、119Nrf2NASH。、NAFLDYates20Nrf2Nrf2。2．4Nrf2-AREALDALDCYP2E1ROSHepG2E47Nrf2Nrf2、Nrf2-ARENrf2GCLCHO-1CYP2E1ROSN-。siRNANrf2ROS21。Nrf2-ARE。Nrf2Nrf2、KupfferGSH22。Keap1-kdKeap1-HKONrf223。Nrf2NADPHNrf2NADPH8。Nrf2-AREALD。Nrf2ALDALD。2．5Nrf2-AREHSCextra-cellularmatrixECM、。TGF-βECMHSCSmad-3GST、GCLC、SODNrf2NF-κBTGF-βGST、GCLC、SODNrf2-ARENrf2。Nrf2TGF-β/SmadHSCⅠ、α-SMA19。、HSCNrf2/AREⅡNrf2HSC。Wang24Nrf2HO-1。Nrf2Nrf2Xu10Nrf2CCl4IL-1α、TNF-αIFN-γ。CCl4Nrf2/Nrf2CCl410。2．6Nrf2-ARENrf2、。2--3-45－fNrf2Nrf2。Nrf2-ARENrf2Nrf225。Nrf2。Nrf2Nrf2、。tBHQHepa-1Nrf2-AREBcl-xLBaxcaspase3/7、siRNANrf2Bcl-xL26。Bao27Nrf2A2780Atg3、Atg6、Atg1。A2780Nrf2Atg3、Atg6、Atg12、p62mRNA3-beclin1siRNAA2780。Bao27Nrf2。Nrf2。3Nrf2-ARE·9501·ChinesePharmacologicalBulletin2015Aug318。Nrf2-ARENrf2-ARE。Nrf2-ARENrf2。1．Nrf2-AREJ．2011273300－3．1LiHDuanHJ．Nrf2/AREpathwayanddownstreamantioxidantgenesJ．ChinPharmacolBull2011273300－3．2KumarHKimISMoreSVetal．Naturalproduct-derivedpharmacologicalmodulatorsofNrf2/AREpathwayforchronicdis-easesJ．NatProdRep2014311109－39．3LeeDHGoldRLinkerRA．MechanismsofoxidativedamageinmultiplesclerosisandneurodegenerativediseasestherapeuticmodulationviafumaricacidestersJ．IntJMolSci201213911783－803．4TanakaYAleksunesLMCuiYJetal．ANIT-inducedintra-hepaticcholestasisaltershepatobiliarytransporterexpressionviaNrf2-dependentandindependentsignalingJ．ToxicolSci20091082247－57．5OsburnWOYatesMSDolanPDetal．Geneticorpharmaco-logicamplificationofNrf2signalinginhibitsacuteinflammatoryliv-erinjuryinmiceJ．ToxicolSci20081041218－27．6GoldringCEKitteringhamNRElsbyRetal．ActivationofhepaticNrf2invivobyacetaminopheninCD-1miceJ．Hepatol-ogy20043951267－76．7ReismanSABuckleyDBTanakaYetal．CDDO-ImprotectsfromacetaminophenhepatotoxicitythroughinductionofNrf2-de-pendentgenesJ．ToxicolApplPharmacol20092361109－14．8WuKCCuiJYKlaassenCD．BeneficialroleofNrf2inregu-latingNADPHgenerationandconsumptionJ．ToxicolSci20111232590－600．9LiuFIchiharaSValentineWMetal．IncreasedsusceptibilityofNrf2-nullmiceto1-bromopropane-inducedhepatotoxicityJ．ToxicolSci20101152596－606．10XuWHellerbrandCKhlerUAetal．TheNrf2transcriptionfactorprotectsfromtoxin-inducedliverinjuryandfibrosisJ．LabInvest200888101068－78．11．Nrf2J．2014304546－9．11PangCJiangPJiLL．BaicaleininducedNrf2activationanditsprotectionagainsthepatotoxicityJ．ChinPharmacolBull2014304546－9．12．MRP2BSEPJ．2015311147－8．12NiuLJinJChenPHuangM．EffectofbaicaleinonexpressionofMRP2andBSEPinHepG2cellsJ．ChinPharmacolBull2015311147－8．13OkadaKShodaJTaguchiKetal．Nrf2counteractscholestaticliverinjuryviastimulationofhepaticdefensesystemsJ．BiochemBiophysResCommun20093893431－6．14WeerachayaphornJMennoneASorokaCJetal．Nuclearfac-tor-E2-relatedfactor2isamajordeterminantofbileacidhomeo-stasisintheliverandintestineJ．AmJPhysiolGastrointestLiverPhysiol20123029G925－36．15PanPHLinSYWangYY．ProtectiveeffectsofrutinonliverinjuryinducedbybiliaryobstructioninratsJ．FreeRadicBiolMed201473106－16．16WangGXiuPLiF．VitaminAsupplementationalleviates