非酒精性脂肪性肝病发病机制及治疗进展_武绍梅

△※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