非酒精性脂肪性肝病发病机制及治疗进展_武绍梅

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△※650032R575.5A1006-2084201424-4455-03doi10.3969/j.issn.1006-2084.2014.24.016NAFLD。IR。IRNAFLDNASH、。NAFLD。NAFLD。ProgressonthePathogenesisandTreatmentofNon-alcoholicFattyLiverDiseasWUShao-meiMALan-qing.DepartmentofGastroenterologyFirstAffiliatedHospita1ofKunmingMedicalUniversityKun-ming650032ChinaAbstractNon-alcoholicfattyliverdiseaseNAFLDwhichisapartofthemetabolicsyndromeintheliverisaprevalentchronicliverdiseaseworldwide.InsulinresistanceIRcausesliverlipidmetabolismdis-turbanceleadingtohepaticsteatosis.TheinteractionbetweenadipokinesandcytokinescanleadtoinsulinresistanceIRandcauseinflammatorychangesoffattyliveratthesametimeinwhichcouldmakeNAFLDpatientsprogresstonon-alcoholicsteatohepatitisNASHliverfibrosisorhepatocellularcarcinoma.InsulinresistanceplaysanimportantroleinthepathogenesisofNAFLD.Insulinsensitizersmetforminandthiazo-lidinedionecanimproveinsulinresistanceandregulateadipokinesandcytokinesinpatientsofNAFLD.HereistomakeareviewofthepathogenesisofNAFLDandresistantmechanismofinsulinsensitizersandtheirefficacyintreatingNAFLD.KeywordsInsulinresistanceNon-alcoholicsteatohepatitisMetforminThiazolidinedionenon-alcoholicfattyliverdiseaseNAFLD、non-alcoholicsteatohepatitisNASH1。NAFLDNAFLD80%~90%30%~50%90%2。NAFLD。NAFLD。1NAFLDNAFLD“”insulinresistanceIR、P50NASH。1.1IR。。IR。IR、、。IRCεNAFLD3。sterol-regulatoryelementbindingproteinSREBP1SREBP-2SREBP-1a、-1c、-2。SREBP-1cIRSREBP-1cSREBP-1cNAFLD4。SREBP-2CREBγA5。1.2NAFLDP50、NAFLDNASH。IRNASH、NAFLD6。X1RNAXBP1XBP1、A1、A1A27。NAFLDNAFLD/8。1.3NAFLD、、IRNAFLD。·5544·2014122024MedicalRecapitulateDec.2014Vol.20No.241994167β9-10。A11。、、、、IR、、、。12。1βγ1α1γ1α/、IR13。αtumornecrosisfactoralphaTNF-α、interleukinIL-6、IL-1、IL-8、IL-18、1NAFLD。NAFLDIR14。Sabio15NAFLD3IL-63IR。NAFLDTNF-α、IL-6IL-4、IL-10。TNF-αIRTNF-αTNF-α416-17。IR18。3。、1、3-、、B/Akt19。β1TNF-αRNANAFLD20。NAFLDJung2168、、、/、/。Kumar22NAFLD、TNF-α、IL-1、IL-6、C、。、NAFLD。2NAFLD2.1NAFLD2β1123。IR、、IR。Kita24NASH40.1%、αSREBP-1cβ。NAFLDZiyaOmera25NAFLDIR。2.2NAFLDγperoxisomeproliferator-activatedreceptor-γPPAR-γ1、、、2SREBP-1A1。PPAR-γTNF-αIL-6β。PPAR-γNASH26。PPAR-γ1IR、27-28。NAFLD29。Zhou30NAFLD。2CoA3β3β2。NAFLD、、31。PPAR-γPPAR-γNAFLD32-33。PPAR-γ·6544·2014122024MedicalRecapitulateDec.2014Vol.20No.24RNA34。、。、NAFLD。IRNAFLDNAFLDNAFLD。2.3NASHRakoski35MetaNASHNASH。NASH。25%1IR36。3NAFLDNAFLD。IRNAFLDNAFLD。NAFLDNAFLD。NAFLD、。。1Jian-gaoF.GuidelinesformanagementofnonalcoholicfattyliverdiseaseanupdatedandrevisededitionJ.ZhonghuaGanZangBingZaZhi2010183163-166.2BellentaniSScaglioniFMarinoMetal.Epidemiologyofnon-alcoholicfattyliverdiseaseJ.DigDis2010281155-161.3JornayvazFRBirkenfeldALJurczakMJetal.Hepaticinsulinresistanceinmicewithhepaticoverexpressionofdiacylglycerolacyltransferase2J.ProcNatlAcadSciUSA2011108145748-5752.4MohamedHAhmedBChristopherD.Modulationofsterolregulato-ryelementbindingproteinsSREBPsaspotentialtreatmentsfornon-alcoholicfattyliverdiseaseNAFLDJ.DrugDiscovToday20071217/18740-747.5WooCWSiowYLPierceGNetal.HyperhomocysteinemiainduceshepaticcholesterolbiosynthesisandlipidaccumulationviaactivationoftranscriptionfactorsJ.AmJPhysiolEndocrinolMetab20052885E1002-1010.6JiCKaplowitzN.ERstressCanthelivercopeJ.JHepatol2006452321-333.7LeeAHScapaEFCohenDEetal.Glimcher1regulationofhepaticlipogenesisbythetranscriptionfactorXBP1J.Science200832058821492-1496.8NarasimhanSGokulakrishnanKSampathkumarRetal.Oxidativestressisindependentlyassociatedwithnon-alcoholicfattyliverdis-easeNAFLDinsubjectswithandwithouttype2diabetesJ.ClinBiochem20104310/11815-821.9ZhangYProencaRMaffeiMetal.PositionalcloningofthemouseobesegeneanditshumanhomologueJ.Nature19943726505425-432.10WangJLeclercqIBrymoraJMetal.Kupffercellsmediateleptin-inducedliverfibrosisJ.Gastroenterology20091372713-723.11BiddingerSBMiyazakiMBoucherJetal.Leptinsuppressesstearoyl-CoAdesaturase1bymechanismsindependentofinsulinandsterolregulatoryelementbindingprotein-1cJ.Diabetes20065572032-2041.12YamauchiTKamonJMinokoshiY.Adiponectinstimulatesglu-coseutilizationandfatty-acidoxidationbyactivatingAMP-activa-tedproteinkinaseJ.NatMed20028111288-1295.13IwabuMYamauchiTOkada-IwabuM.AdiponectinandAdipoR1regulatePGC-1alphaandmitochondriabyCa2+andAMPK/SIRT1J.Nature201072934641313-1319.14PolyzosSAKountourasJZavosCetal.Theroleofadiponectininthepathogenesisandtreatmentofnon-alcoholicfattyliverdiseaseJ.DiabetesObesMetab2010125365-383.15SabioGDasMMoraAetal.Astresssignalingpathwayinadi-posetissueregulateshepaticinsulinresistanceJ.Science200832259071539-1543.16HotamisligilGSSpiegelmanBM.Tumornecrosisfactor-akeycom-ponentoftheobesity-diabeteslinkJ.Diabetes199443111271-1278.17MollerDE.PotentialroleofTNF-αinthepathogenesisofinsulinresistanceandtype2diabetesJ.TrendsEndocrinolMetab2000116212-217.18RajalaMWObiciSSchererPEetal.Adipose-derivedresistinandgut-derivedresistin-likemolecule-betaselectivelyimpairinsu-linactiononglucoseproductionJ.JClinInvest20031112225-230.19SteppanCMWangJWhitemanELetal.ActivationofSOCS-3byResistinJ.MolCellBiol20052541569-1575.20.NAFLDJ.2012334367-372.21JungCHRheeEJChoiJHetal.Therelationshipofadiponectin/leptinratiowithhomeostasismodelass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