Chapter17-liver-biochemistry

Chapter17BiochemistryinLiver,Preface,Liveristhelargestparenchymatousorganinhumanbody;Liveristhelargestgland,occupying2.5%ofbodyweight;Liverhasspecificmorphosisandchemicalcompositionfeatures;Liverhasdiversebiochemicalfunction.,Morphosisandchemicalcompositionfeatureofliver,Dualbloodsupply:hepaticarteryandportalvein;Dualoutputsystem:hepaticveinandbileduct;Alargenumberofhepaticsinusoid;Hepaticcellsarerichincellularorganelleandenzymes.,dualbloodsupply,portalvein（养分）,hepaticartery（O2）,kidney,urine,intestine,stool,hepaticvein,bileductsystem,systemiccirculation,dualoutputsystem,Morphosisandchemicalcompositionfeatureofliver,branchofhepaticportalveinbileductsinusoidscentralveinlivercells,portalareabranchofhepaticartery,Becomposedof510105hepaticlobule,including2.51011hepaticcells,Functionofliver,MetabolismBiotransformationBilesecretionExcretion,Section1LiverFunctioninMaterialMetabolism,Functionofliver,IncarbohydratemetabolismInlipidsmetabolismInproteinmetabolismInvitaminmetabolismInhormonemetabolism,I.Incarbohydratesmetabolism,StabilizingbloodglucoselevelsGlycolysisLiverglycogenesisandglycogenolysisGluconeogenesisPentosephosphatepathwayAerobicoxidationtosupplyenergy,-Importantfunctionindigestion、absorption、synthesis、decompositionandtransportationoflipids.,II.InthelipidsMetabolism,DigestionandabsorptionBileacidsynthesisandsecretionLipiddecomposition-oxidationoffattyacidsLDLdegradationCHdegradationintobileacids,LipidsynthesisSynthesisofTG,PL,CHSynthesisofketonebodiesTransportationoflipidsSynthesisVLDL,HDL,apoCII,LCATapoCII：activateLPLLCAT:EsterifyingcholestoralintoCE,VLDL,blood,Functionincholestoralmetabolism,LiveristhemajororganinthesynthesisofCHCholestoraldegradationintobileacidCholestoralexcretionEsterifyingcholestoralintoCE,III.IntheProteinMetabolism,Synthesisandsecreteplasmaproteins.Albumin12g/day.SynthesisureaandglutamineFetussynthesisAFP.livercancerAFP(+)liverisdamagedbloodNH3falseneurotransmitter,IV.IntheVitaminMetabolism,AbsorptionoffatsolublevitaminStorevitaminsA,E,KandB12.TransportationofvitaminsA,DTransformationofVitaminsVitaminsCoenzymes,VitPPNAD+andNADP+pantothenicacidCoAcaroteneVitAVitB1TPP,V.Inthehormonemetabolism,LiverhaveimportantactionsintheTransformationDegradationLostactiveofhormone.,Section2.Biotransformationinliver,I.DefinitionofBiotransformation:Somenon-nutrientsubstancescanbeconvertedtomorepolarmetabolitesbyvariouschemicalreactionssuchasoxidation,reduction,hydrolyzation,andconjugation,whicharethenexcretedfromthebody.Theseprocessesmainlyoccurinliver.,exogenouscompounds:drugs,foodadditives,toxicity,andenvironmentalpollutantsetc.endogenouscompounds:hormone,neurotransmitter,amines,ammonia，putrefactionalproductsetc.,Non-nutrientsubstances:,Significance:Theoverallpurposeofthetwophasesofmetabolismistodecreaseoreliminatebiologicalactivityandtoxicity.Increasetheirsolubility(polarity).Facilitatetheirexcretionfromthebody.(excretedintheurineandbile)Increasetheirbiologicactivityandtoxicity.,II.MajortypesofbiotransformationPhaseIreaction:oxidation,reduction,andhydrolysisThesereactionsarecatalysedbyaseriesofenzymes.Theproductsareconvertedfromnon-polargroupstomorepolargroups.PhaseIIreaction:conjugationreaction,(I)oxidationreactionmonooxygenasescytp450(inmicrosome)RH+O2+NADPH+H+ROH+NADP+H2O,ThesubstrateRHishydroxylatedbyhydroxylases(mixed-functionoxidases).,monoamineoxidase,MAO(inMit)RCH2NH2+O2+H2ORCHO+NH3+H2O2(amine)(aldehyde)RCHO+NADH+H2ORCOOH+NADH+H+(aldehyde)aldehydedehydrogenase,alcoholdehydrogenase(ADH)aldehydedehydrogenase(ALDH),inMit,ALDH,MEOS(P450)microsomeethanoloxidizingsystem,(II)reductionreactionnitroreductase;azoreductase(NADPH)（硝基还原酶）（偶氮还原酶）,HH,NADPH,NADPH,(III)hydrolyzedreactionhydrolases(incytosolandmicrosome),SubstratesareLipids,amides,glycosides.,Phase2reaction:conjugationInphase2,thehydroxylatedorothercompoundsproducedinphase1areconvenedbyspecificenzymestovariouspolarmetabolitesbyconjugation.Mostoftheseenzymesareinthecytosol.GenerallyoccuratahigherratethanphageIreaction.,(IV)conjugationreaction(-OH,COOH,NH3)Glucuronicaciddonor:UDPGAglucuronyltransferase,葡萄糖醛酸基转移酶(UDPGT),UDPGA,UDP,肝微粒体,苯甲酸,苯酚,苯葡萄糖醛酸苷(醚型),苯甲酰葡萄糖醛酸苷(酯型),sulfatedonor:3-phosphoadenosyl-5-phosphosulphate(PAPS)Sulfatetransferase,(Inactive),.,acylationDonor:acetyl-CoAacetylase,(Inactive),sulfanilamide,Solubility+NaHCO3,GlutathioneGSH-s-transferase,glycine(-COOH)acylCoAligaseandacyltransferase,BileacidconjucatedBileacid,Methylation(incytosolandmicrosome)Donor:S-adenosylmethionine.(SAM)methyltransferaseSubstants:Aminesanddrugs,(Inactive),Characteristicofbiotransformation,ContinuityofreactionPhageIphageIIVarietyofreactiontypesDualismofdetoxicificationandtoxicification,III.factorsofaffectbiotransformationLiverfunction,age,sex,andnutritionalstatus,healthconditionsandotherfactorscertaindrugs,variousdiseases.,SummaryThetermdetoxificationisnotalwaysappropriatebecause,asmentionedabove,thereactionsmayincreasetheirbiologicactivityandtoxicity.,Section3bileandbileacidmetabolism,I.Bile:,Bile,hepaticbile,gallbladderbile,Components,bileacidsproteinslecithincholesterolbilepigmentslipasephospholipaseseveralionswater,Theliverproduce300to700mlbiledaily.pHofbileisaround8.1.Bilesaltsaremadeupofsodiumandpotassiumsaltsofbileacids.Thebileacidsaretheendproductsofcholesterol.helptheabsorptionanddigestionoffatsandfat-solublevitamins.,II.metabolismofbileacid,1,7,3,12,24,OH,Cholicacid(3,7,12),accodingtotheStructure:FreebileacidbileacidConjugatedbileacidaccodingtotheSouce:Primarybileacid:synthesisinliverbileacidSecondarybileacid:synthesisinintestine,1.classificationofbileacid,Cholicacid(3,7,12)Chenodeoxycholicacid(3,7,)Deoxycholicacid(3,12)lithocholicacid(3),GlycocholicacidTaurocholicacidGlycochenodeoxycholicacidTaurochenodeoxycholicacidGlycodeoxycholicacid(3,12)Taurodeoxycholicacid(3,12),Freebileacid,Conjugatdbileacid(majortype),accodingtotheStructure:,Glycocholicacid,Taurocholicacid,Conjugatdbileacid,accodingtotheSouce:,Primarybileacid,Secondarybileacid,Cholicacid(3,7,12)Chenodeoxycholicacid(3,7,)GlycocholicacidTaurocholicacidGlycochenodeoxycholicacidTaurochenodeoxycholicacid,Deoxycholicacid(3,12)lithocholicacid(3)GlycodeoxycholicacidTaurodeoxycholicacid,Primarybileacid,Cholicacid,Secondarybileacid,Deoxycholicacid,2.metabolismofbileacidFormationofprimarybileacids(inliver),Synthesisofthe2kindofprimarybileacids,cholicacidandchenodeoxycholicacid.Rate-limitingenzyme:7a-hydroxylaseCholesterolisconvertedtothebileacids.Majorformoflivereliminatecholesterol,27,7,GlycocholicacidTaurocholicacid,Cholicacid,H2O,CoA-SH,HS-CoA,初级结合型胆汁酸的生成,初级结合型胆汁酸的生成,(2)Formationofsecondarybilate,ConjugatedbilatefreebilatesecondarybilateGly,taurine7-OH(cholicacid)(deoxycholicacid)(chenodeoxycholicacid)(lithocholicacid),(bacteriaactionintheintestine),(石胆酸),Definition:Bileacidsaresecretedfromtheliverthroughbileductstothegallbladder,thenintotheintestine,wheretheyaidtheemulsificationofdietarylipids.Thebileacidsarethenreabsorbed(activeandpassive)inthelowersmallintestine,andreturnedtotheliverforreusethroughtheportalvein.,Enterohepaticcirculationofbileacid.,Enterohepaticcirculationofbileacid.(612time/day,1232g),PassiveabsorptionActiveabsorption,回肠,胆烷酸,cholesteral,Secondarybileacids,Secondarybileacids,Secondarybileacids,Primarybileacids,Primarybileacids,GlycineTaurine,GlycineTaurine,PrimaryandSecondarybileacids,PORTALVEIN,Bileacidsaresecretedfromtheliverintobileductsandthengetintotheintestine,wheretheyaidintheemulsificationofdietarylipids.Morethan95%ofthebileacidssecretedintotheintestinearereabsorbed(passiveandactive)inthelowersmallintestine,andreturnedtotheliverbywayoftheportalveincirculation.Inliverthereabsorbedfreebileacidsareconvertedintotheconjugatedbileacidsandsecretedintotheintestineforreuse.,Enterohepaticcirculation,asemulsifyingagentsofthedigestionandabsorptionofdietarylipids.Facilitateabsorptionoffat-solublevitaminsintheintestine.bileacidsandphospholipidssolubilizecholesterolinthebile,preventingtheprecipitationofcholesterolinthegallbladder.,Bilate+lecithin/cholesteral10:1If10:1bilestones,3.functionofbileacid,Liver,Cholesterol,Bilesalts,DietaryFat,Emulsifiesdietaryfat,Fatgetsabsorbed,95%,Enterohepaticcirculation,5%(inthestools),BloodCholesterol,Storedinthegallbladder,Overviewofbilesaltmetabolism,Section4Bilepigmentmetabolismandjundice,bilepigmentarecatabolismproductsofcontaining-ionporphyrincompoundsexcretedbybile.,hemoglobinMyoglobinCytochromeCatalaseperoxidase,Bilirubin(toxic)(Colorofbile)biliverdinbilinogenBilin,globin,heme,aminoacids,I.Formationandtransportofbilirubin,Hb,Erythrocyteshavealifeofabout120days.Agederythrocytesaredestroyeduponpassagethroughthespleenorliver.,bilirubin,Sources:HemeDegradation(hemecatabolism),6g/day,Macrophagereticuloendothelialsystem,ThebreakdownpathwayofHb,(insoluble),Macrophagespleen,M=methyl,P=proprionic,V=vinyl,Formation,6-氢键,fat-solubletoxic,Bilirubininblood,liver,albumin,Bilirubin(unconjugated),blood,(Unconjugatedbilirubin),increasingthesolubilityofbilirubinandfacilitatingitstransportationinblood.increasingthesizeofbilirubinandlimitingitspenetrabilitytomembrane,II.BilirubinInliver1.TakeupBilirubin-A(receptorforbindingbilirubin)2.Conjugation3.Excretion,Bilirubin+Y.ZPr,A,Bilirubin-YPr.ZPr,Bilirubin+UDP-GAbilirubin-GA+UDP,bileductintestine,UDP-GAtransferase,(ligandin),bilirubindiglucuronicacid,Bilirubin-albumincomplex,BilirubinGlucuronyl2UDP-GAtransferraseBilirubindiglucuronide(conjugated,water-soluble),intestine,Blood,Liver,Bileduct,Plasma0.20.9mg/dl,2UDP,bilirubindiglucuronicacid,GA,bilirubin,bilinogen,bilin,bilin(colorofstool),O2,kidney,liver,(colorofurine)urobilin,bacteria,.,三.Bilirubininintestine,+4H,10-20%,O2,80-90%,bilin,IV.Serumbilirubinandjaundice,Diazoreagent“directreaction”(conjugated)Bilirubin+diazocolor“Indirectreaction”(unconjugated)Bilirubin+alcohol+diazocolor,Vandenberghtest:,Thedifferencesbetweenfreebilirubinandconjugatedbilirubin,Jaundice(hyperbilirubinemia),Bilirubinistoxicwasteproduct.Normally,theconcentrationofbilirubininplasmaisverylow.Bilirubinmetabolismdisordersleadtohyperbilirubinemia(bilirubincontentelevationsintheserum).Accumulationofbilirubininthe