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LipidMetabolismLipidMetabolismLipidTransportinBloodLipidsarenot
watersolubleBloodismainlywater…PacklipidsinproteinChylomicronsMadeintheenterocytes(smallintestine)Lipoproteins
(lipidsandproteins)VLDL,LDL,HDLmadeinliverGroff&Gropper,1999LipidTransportinBloodLipidsReleaseofLipidsFromLipoproteinsLipoproteinlipase(LPL)Enzymeanchoredonthecellmembranes
inbloodvesselsReleasesglycerolandfreefattyacidsfromchylomicronsandlipoproteinsGlycerolandfreefattyacidsabsorbedbycellsMuscle(oxidizedasasourceofenergy)ReleaseofLipidsFromLipoproReleaseofLipidsChylomicronschylomicronremnantsCholesterol-richTakenupbyliverandfattyacidsaremetabolizedReleaseofLipidsChylomicronsRepackagingintheLiverLipidisrepackagedinthelivertoVLDLorverylowdensitylipoproteinLipoproteinsareclassifiedbydensityLipoproteinstransportlipidtotherestofthebodyVLDLTGLDLTGHDLRepackagingintheLiverLipidLipoproteinsClassifiedbydensityProtein:lipidratioMoreprotein,increaseddensityMorelipid,decreaseddensityFourclassesoflipoproteinsChylomicronsVLDLLDLHDLFormedinliverLipoproteinsClassifiedbydensLipoproteinsDifferaccordingtothelipid:proteinratioDensityChylomicronsVery-low–densitylipoproteins(VLDL)HighlipidcontentLow-densitylipoproteins(LDL)MaincholesteroltransportHigh-densitylipoproteins(HDL)LowlipidcontentLowHighLipoproteinsDifferaccordingtComplexSourceDensity(g/ml)%Protein%TGa%PLb%CEc%Cd%FFAeChylomicronIntestine<0.951-285-888310VLDLLiver0.95-1.0067-1050-5518-2012-158-101IDLVLDL1.006-1.01910-1225-3025-2732-358-101LDLVLDL1.019-1.06320-2210-1520-2837-488-101*HDL2Intestine,liver(chylomicronsandVLDLs)
1.063-1.12533-355-1532-4320-305-100*HDL3Intestine,liver(chylomicronsandVLDLs)
1.125-1.2155-573-1326-4615-302-66Albumin-FFAAdiposetissue>1.281990000100aTriacylglycerols,bPhospholipids,cCholesterylesters,dFreecholesterol,eFreefattyacids
*HDL2andHDL3derivedfromnascentHDLasaresultoftheacquisitionofcholesterylesters
ComplexSourceDensity(g/ml)%PrLowDensityLipoproteinsVLDLLDLCholesterol-richConvertedtobilesaltsCarriescholesteroltotissuesUsedformembranesynthesisLDL~‘badcholesterol’AssociatedwithplaqueformationinbloodvesselsHightriglycerideandcholesterolcontentLowDensityLipoproteinsVLDLHighDensityLipoproteinsRemovescholesterolfrom:CellsLipoproteinsDelivercholesteroltoliverforexcretionConvertedtobilesaltsandexcretedinfecesHDL~‘goodcholesterol’Ischolesterol‘bad’foryou?Cellmembranes,bilesalts,synthesisofsteroidhormonesRatioofLDL:HDLvs.totalcholesterolHighDensityLipoproteinsRemovLipidTransportFreefattyacidstransportedascomplexwithalbumininbloodLipidsrapidlyremovedfrombloodLiverFatdepotsOthertissueLipidTransportFreefattyacidAdiposeTissueAdipocytesarethemajorstoragesitefortriglyceridesAdiposetissue(storedforlateruse,orimmediatelyoxidizedasasourceofenergy)Containsuptoapproximately85%lipidContainsapproximately90%DMWhatistheDMcontentofmuscle?Only20-25%DM!!!AdiposeTissueAdipocytesaretSize=amountoffatstoredObesity=increaseinbothsizeandnumberMS,Lupus&otherdiseases=normaltissuedies,replacedbyfibroblasts,becomeadipocytesSize=amountoffatstoredAdiposeTissueGroff&Gropper,1999Fedstate...AdiposeTissueGroff&Gropper,AdiposeTissueFastedstateBloodglucoseleveldecreases
insulinlevelsdecreaseand
glucagonlevelsincreaseLipolyticactivityincreasesHormone-sensitivelipaseReleaseoffattyacidsFreefattyacidsreleasedintobloodFreefattyacid–albumincomplexLivertakesupfreefattyacidsOxidationorformationofketonebodiesAdiposeTissueFastedstateLeptinProteinhormoneproducedbyadipocytesLargercells=moreleptinproducedEffectsonmanytissuesHypothalamusRegulateseatingbehaviorNegative-feedbackmechanismLeptinProteinhormoneproducedLeptin-deficientmutants(left)failtolimittheireatingandbecomes3timestheweightofnormalmouse(right)Leptin-deficientmutants(leftLipolysis–Monogastric&RuminantMobilizationofbodytriglyceridesforuseasenergyTriglycerideGlycerol3FFA+LipoproteinLipaseGlycolysisGluconeogenesisΒ-oxidation*Freefattyacidsbindtoalbumintoformnon-esterifiedfattyacidsthataresolubleinblood*Lipolysis–Monogastric&RumiTriglycerideCatabolismHydrolysisoftriglyceridesyieldsOneglycerolThreeFFAGlycerolisusedforenergyorgluconeogenesisGlycerolentersglycolyticpathwaysFFAareoxidizedtoCO2andH2O
-OxidationTakesplaceinmitochondriaFA’scannotbeusedforgluconeogenesisTriglycerideCatabolismHydrolyBetaOxidationBetaOxidationβ-oxidation–SaturatedFattyAcidsFattyacidsarearichenergysourceOxidationoccursonlyinmitochondriaofspecifictissuesSkeletal&cardiacmuscleLiverAdiposetissueβ-oxidation–SaturatedFattyβ-oxidation–SaturatedFattyAcidsCleavestwocarbonsatatimefromthecarboxylendProducesNADH,FADH2andacetyl-CoAAcetyl-CoAentersTCAcycleNADHandFADH2enterelectrontransportchainYieldATPOCH3–C–CoA=β-oxidation–SaturatedFatty1stStepinBeta-OxidationActivation:Use2
ATPequivalentstoattachCoAOxidation:FADtakesH,CreatesnewdoublebondbetweenC2&3Hydration:addwateracrossdoublebondOxidation:NADtakesH’s,newO=formedAddition&Cleavage:AddnewCoA,cleaveoffacetyl-CoA.Lose2C1stStepinBeta-OxidationActi-OxidationPalmitate(16:0)Carbon–carboncleavage1FADH2+1NADH5ATP(viaelectrontransportchain) 7cleavagepointsx5ATP=35ATP Oxidationofacetyl–CoA8acetyl-CoAunitsenteringTCAcyclex12ATP=96ATP TotalATP35+96=131–2ATP=129ATP2ATPusedforfattyacidactivationandentryintomitochondria1st2nd3rd4th5th6thlast-OxidationPalmitate(16:0)1stSummaryofβ-oxidationSummaryofβ-oxidationEnergyyieldTheATPyieldforeveryoxidationcycleis14ATP,brokendownasfollows:1FADH2x1.5ATP=1.5ATP1NADHx2.5ATP=2.5ATP1acetylCoAx10ATP=10ATPForinstance,theATPyieldofpalmitateis:7FADH2x1.5ATP=10.5ATP7NADHx2.5ATP=17.5ATP8acetylCoAx10ATP=80ATPATPequivalentusedduringactivation=-2Total:106ATPEnergyyieldSpecialConsiderationsWhydoesn’tmuscleutilizefattyacids
duringexercise?RequiresoxygenavailableforoxidationUseanaerobicfermentationofglucosetolactatepreferentiallyWhydon’tredbloodcellsutilizefattyacidsfortheirenergymetabolism?NomitochondriainRBC’sSpecialConsiderationsWhydoesUnsaturatedFattyAcidsUnsaturatedfattyacidsmustbesaturatedbeforebeta-oxidationIsomeraseconvertscistotransandmovesdoublebondtothe2positionInpolyunsaturated:needreductaseAddH’stoseconddoublebondUnsaturatedFattyAcidsUnsaturOddChainFattyAcidsMinorspecies,oddchainsmadebymicrobes,degradationofAA’sB-oxidationoccurstoend:Leftwith3carbon+CoA(propionylCoA)VitaminB12cobalaminco-enzymeCatalyzesconversionofpropionylCoA(3C)tosuccinyl-CoA(4C)TCAcycleintermediateOddChainFattyAcidsMinorspeKetoneBodies(Ketogenesis)Acetone,acetoacetate,β-hydroxybutyrateProducedinliverfromincompleteoxidationoffattyacidsUsedbyextra-hepatic(non-liver)tissueinpreferencetofattyacidsasenergyTurnedintoacetyl-CoAExcessspillsoverintourineorexhaledasacetoneKetoneBodies(Ketogenesis)AceFattyAcidSynthesisInfedstate-lotsofglucoseGlycogenstoresfillupATPandcitrate
inhibitglycolysispathwaysGlucosedivertedthroughthe
pentose-phosphatepathwayNADPHformedandusedinfattyacidsynthesisPyruvateisformedFattyAcidSynthesisInfedstaFattyAcidSynthesis-MonogastricsWhataretheadvantagesof
storingexcessfeedorenergyasfat?Highenergydensitytissue,lowwatercontentMajorproducersoffattyacidsLiverAdiposetissueMammaryglandCananimalssynthesizeallfattyacids?NO–essentialfattyacidsMUSTcomefromdiet18:2,18:3Catscannotsynthesize20:4FattyAcidSynthesis-MonogasLipogenesis-MonogastricsMechanismoffattyacidsynthesisissimilarbetweendifferentspecies,butthecontributionoftissuetypesvarieswithspeciesMouse&rat-50%liverChicken-mostlyliverPig-mostlyadiposeLipogenesis-MonogastricsMechFattyAcidBiosynthesis-MonogastricOccursinendoplasmicreticulumOccurswhen:Energyneedsaremet(ATP>ADP)GlycogenstoresfullExcessnutrientspresentFattyAcidBiosynthesis-MonoFattyAcidBiosynthesis-MonogastricBeginswithacetyl-CoAfrom:Carbohydratemetabolism(glucose)SpecificaminoacidsDegradedlipidsFattyacidchainsarecreated2CunitsaddedfromcarboxyltomethylendEsterbondsUpto16C(palmitate)fattyacidscanbesynthesizedNADPHrequiredas“energysource”FattyAcidBiosynthesis-MonoMitochondriaCytosolAcetylCoATCACycleCitrateCitrateOxaloacetate(2C)AcetylCoAAcetylCoACarboxylase
(biotin)HCO3ATP(3C)MalonylCoACO2NADPH4CButyrylCoA2CAcetylCoA3CMalonylCoA6CCapraylCoACO2NADPHFattyAcidSynthaseMitochondriaCytosolAcetylCoATFattyAcidBiosynthesis-MonogastricCyclecontinuesbycontinuedadditionofmalonylCoAandlossofCO2Palmitate(16C)isfinalproductafter7cyclesDesaturationandelongationoccurelsewhere:ERFattyAcidBiosynthesis-MonoFattyAcidModificationsPalmitateanbeelongatedAdditionoftwo-carbonunitsatCOOH-endoffattyacidDesaturation16:0and18:0canbeconvertedto
16:1and18:1,respectivelyFattyAcidModificationsPalmitWhyarew-3&w-6Essential?MammalslackenzymetoadddoublebondsbeyondC-9Chainelongationanddoublebondadditionyieldarachidonicacid(C20:4)fromlinoleicacid(C18:2)Whyarew-3&w-6Essential?Ma
MetabolismofnaturalC20cisfattyacidsproducespowerfuleicosanoids
Metabolism
ofFats
LipidSynthesisinMonogastricsFigure25.10LipidSynthesisinMonogastricLipogenesis-RuminantsSimilartomonogastricsexceptfor:MainsiteAdiposetissue,liverSourcesofcarbon(acetyl-CoA)AcetateLactateBeta-hydroxy-butyrateDietaryfattyacidsUnabletoconvertglucosetofattyacidsLipogenesis-RuminantsSimilarLipidMetabolismLipidMetabolismLipidTransportinBloodLipidsarenot
watersolubleBloodismainlywater…PacklipidsinproteinChylomicronsMadeintheenterocytes(smallintestine)Lipoproteins
(lipidsandproteins)VLDL,LDL,HDLmadeinliverGroff&Gropper,1999LipidTransportinBloodLipidsReleaseofLipidsFromLipoproteinsLipoproteinlipase(LPL)Enzymeanchoredonthecellmembranes
inbloodvesselsReleasesglycerolandfreefattyacidsfromchylomicronsandlipoproteinsGlycerolandfreefattyacidsabsorbedbycellsMuscle(oxidizedasasourceofenergy)ReleaseofLipidsFromLipoproReleaseofLipidsChylomicronschylomicronremnantsCholesterol-richTakenupbyliverandfattyacidsaremetabolizedReleaseofLipidsChylomicronsRepackagingintheLiverLipidisrepackagedinthelivertoVLDLorverylowdensitylipoproteinLipoproteinsareclassifiedbydensityLipoproteinstransportlipidtotherestofthebodyVLDLTGLDLTGHDLRepackagingintheLiverLipidLipoproteinsClassifiedbydensityProtein:lipidratioMoreprotein,increaseddensityMorelipid,decreaseddensityFourclassesoflipoproteinsChylomicronsVLDLLDLHDLFormedinliverLipoproteinsClassifiedbydensLipoproteinsDifferaccordingtothelipid:proteinratioDensityChylomicronsVery-low–densitylipoproteins(VLDL)HighlipidcontentLow-densitylipoproteins(LDL)MaincholesteroltransportHigh-densitylipoproteins(HDL)LowlipidcontentLowHighLipoproteinsDifferaccordingtComplexSourceDensity(g/ml)%Protein%TGa%PLb%CEc%Cd%FFAeChylomicronIntestine<0.951-285-888310VLDLLiver0.95-1.0067-1050-5518-2012-158-101IDLVLDL1.006-1.01910-1225-3025-2732-358-101LDLVLDL1.019-1.06320-2210-1520-2837-488-101*HDL2Intestine,liver(chylomicronsandVLDLs)
1.063-1.12533-355-1532-4320-305-100*HDL3Intestine,liver(chylomicronsandVLDLs)
1.125-1.2155-573-1326-4615-302-66Albumin-FFAAdiposetissue>1.281990000100aTriacylglycerols,bPhospholipids,cCholesterylesters,dFreecholesterol,eFreefattyacids
*HDL2andHDL3derivedfromnascentHDLasaresultoftheacquisitionofcholesterylesters
ComplexSourceDensity(g/ml)%PrLowDensityLipoproteinsVLDLLDLCholesterol-richConvertedtobilesaltsCarriescholesteroltotissuesUsedformembranesynthesisLDL~‘badcholesterol’AssociatedwithplaqueformationinbloodvesselsHightriglycerideandcholesterolcontentLowDensityLipoproteinsVLDLHighDensityLipoproteinsRemovescholesterolfrom:CellsLipoproteinsDelivercholesteroltoliverforexcretionConvertedtobilesaltsandexcretedinfecesHDL~‘goodcholesterol’Ischolesterol‘bad’foryou?Cellmembranes,bilesalts,synthesisofsteroidhormonesRatioofLDL:HDLvs.totalcholesterolHighDensityLipoproteinsRemovLipidTransportFreefattyacidstransportedascomplexwithalbumininbloodLipidsrapidlyremovedfrombloodLiverFatdepotsOthertissueLipidTransportFreefattyacidAdiposeTissueAdipocytesarethemajorstoragesitefortriglyceridesAdiposetissue(storedforlateruse,orimmediatelyoxidizedasasourceofenergy)Containsuptoapproximately85%lipidContainsapproximately90%DMWhatistheDMcontentofmuscle?Only20-25%DM!!!AdiposeTissueAdipocytesaretSize=amountoffatstoredObesity=increaseinbothsizeandnumberMS,Lupus&otherdiseases=normaltissuedies,replacedbyfibroblasts,becomeadipocytesSize=amountoffatstoredAdiposeTissueGroff&Gropper,1999Fedstate...AdiposeTissueGroff&Gropper,AdiposeTissueFastedstateBloodglucoseleveldecreases
insulinlevelsdecreaseand
glucagonlevelsincreaseLipolyticactivityincreasesHormone-sensitivelipaseReleaseoffattyacidsFreefattyacidsreleasedintobloodFreefattyacid–albumincomplexLivertakesupfreefattyacidsOxidationorformationofketonebodiesAdiposeTissueFastedstateLeptinProteinhormoneproducedbyadipocytesLargercells=moreleptinproducedEffectsonmanytissuesHypothalamusRegulateseatingbehaviorNegative-feedbackmechanismLeptinProteinhormoneproducedLeptin-deficientmutants(left)failtolimittheireatingandbecomes3timestheweightofnormalmouse(right)Leptin-deficientmutants(leftLipolysis–Monogastric&RuminantMobilizationofbodytriglyceridesforuseasenergyTriglycerideGlycerol3FFA+LipoproteinLipaseGlycolysisGluconeogenesisΒ-oxidation*Freefattyacidsbindtoalbumintoformnon-esterifiedfattyacidsthataresolubleinblood*Lipolysis–Monogastric&RumiTriglycerideCatabolismHydrolysisoftriglyceridesyieldsOneglycerolThreeFFAGlycerolisusedforenergyorgluconeogenesisGlycerolentersglycolyticpathwaysFFAareoxidizedtoCO2andH2O
-OxidationTakesplaceinmitochondriaFA’scannotbeusedforgluconeogenesisTriglycerideCatabolismHydrolyBetaOxidationBetaOxidationβ-oxidation–SaturatedFattyAcidsFattyacidsarearichenergysourceOxidationoccursonlyinmitochondriaofspecifictissuesSkeletal&cardiacmuscleLiverAdiposetissueβ-oxidation–SaturatedFattyβ-oxidation–SaturatedFattyAcidsCleavestwocarbonsatatimefromthecarboxylendProducesNADH,FADH2andacetyl-CoAAcetyl-CoAentersTCAcycleNADHandFADH2enterelectrontransportchainYieldATPOCH3–C–CoA=β-oxidation–SaturatedFatty1stStepinBeta-OxidationActivation:Use2
ATPequivalentstoattachCoAOxidation:FADtakesH,CreatesnewdoublebondbetweenC2&3Hydration:addwateracrossdoublebondOxidation:NADtakesH’s,newO=formedAddition&Cleavage:AddnewCoA,cleaveoffacetyl-CoA.Lose2C1stStepinBeta-OxidationActi-OxidationPalmitate(16:0)Carbon–carboncleavage1FADH2+1NADH5ATP(viaelectrontransportchain) 7cleavagepointsx5ATP=35ATP Oxidationofacetyl–CoA8acetyl-CoAunitsenteringTCAcyclex12ATP=96ATP TotalATP35+96=131–2ATP=129ATP2ATPusedforfattyacidactivationandentryintomitochondria1st2nd3rd4th5th6thlast-OxidationPalmitate(16:0)1stSummaryofβ-oxidationSummaryofβ-oxidationEnergyyieldTheATPyieldforeveryoxidationcycleis14ATP,brokendownasfollows:1FADH2x1.5ATP=1.5ATP1NADHx2.5ATP=2.5ATP1acetylCoAx10ATP=10ATPForinstance,theATPyieldofpalmitateis:7FADH2x1.5ATP=10.5ATP7NADHx2.5ATP=17.5ATP8acetylCoAx10ATP=80ATPATPequivalentusedduringactivation=-2Total:106ATPEnergyyieldSpecialConsiderationsWhydoesn’tmuscleutilizefattyacids
duringexercise?RequiresoxygenavailableforoxidationUseanaerobicfermentationofglucosetolactatepreferentiallyWhydon’tredbloodcellsutilizefattyacidsfortheirenergymetabolism?NomitochondriainRBC’sSpecialConsiderationsWhydoesUnsaturatedFattyAcidsUnsaturatedfattyacidsmustbesaturatedbeforebeta-oxidationIsomeraseconvertscistotransandmovesdoublebondtothe2positionInpolyunsaturated:needreductaseAddH’stoseconddoublebondUnsaturatedFattyAcidsUnsaturOddChainFattyAcidsMinorspecies,oddchainsmadebymicrobes,degradationofAA’sB-oxidationoccurstoend:Leftwith3carbon+CoA(propionylCoA)VitaminB12cobalaminco-enzymeCatalyzesconversionofpropionylCoA(3C)tosuccinyl-CoA(4C)TCAcycleintermediateOddChainFattyAcidsMinorspeKetoneBodies(Ketogenesis)Acetone,acetoacetate,β-hydroxybutyrateProducedinliverfromincompleteoxidationoffattyacidsUsedbyextra-hepatic(non-liver)tissueinpreferencetofattyacidsasenergyTurnedintoacetyl-CoAExcessspillsoverintourineorexhaledasacetoneKetoneBodies(Ketogenesis)AceFattyAcidSynthesisInfedstate-lotsofglucoseGlycogenstoresfillupATPandcitrate
inhibitglycolysispathwaysGlucosedivertedthroughthe
pentose-phosphatepathwayNADPHformedandusedinfattyacidsynthesisPyruvateisformedFattyAcidSynthesisInfedstaFattyAcidSynthesis-MonogastricsWhataretheadvantagesof
storingexcessfeedorenergyasfat?Highenergydensitytissue,lowwatercontentMajorproducersoffattyacidsLiverAdiposetissueMammaryglandCananimalssynthesizeallfattyacids?NO–essentialfattyacidsMUSTcomefromdiet18:2,18:3Catscannotsynthesize20:4FattyAcidSynthesis-MonogasLipogenesis-MonogastricsMechanismoffattyacidsynthesisissimilarbetweendifferentspecies,butthecontributionoftissuetypesvarieswithspeciesMouse&rat-50%liverChicken-
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