Slide 1Slide 2Slide 3Slide 4Slide 5Slide 6Slide 7Slide 8Slide 9Slide 10Slide 11Slide 12Slide 13Slide 14Slide 15LIPOLYSIS:FATOXIDATION&KETONESBIOC460-DR.TISCHLERLECTURE33OBJECTIVES1. Lipolysisa)describethepathway; b)locationc)principalenzyme d)rolee)roleofalbuminandFABPintransport/metabolismofFFA2. DegradationoffattyacylCoAa)rolesofacylCoAsynthetase,CPT-IandCPT-II,andCATb)relationshipof-oxidationproductstoenergyproduction.c)degradationofodd-vseven-chainFAd)vitaminsformetabolizingpropionylCoAtosuccinylCoA3. Ketonebodymetabolisma)whereketogenesisoccursb)whenketogenesisoccursc)roleofkeotgenesisd)whynormalindividualsdonotusuallydevelopketacidosisevenwhenproducingketonebodies.FATFACTSfat(lipid)makesup37%ofthecaloriesintheAmericandietenergyrichandprovides9kcal/gmdietarylipids90%triacylglycerols(TAGs)alsoincludecholesterolesters,phospholipids,essential unsaturatedfattyacids;fat-solublevitaminsmostdietaryfattransportedtoadiposeforstoragedietaryTAGshydrolyzedintheintestinebypancreaticlipases;thenreassembledintheintestinalcellsdietaryfatstransportedtotissuesasTAGorcholesterolviachylomicronsatperipheraltissues(e.g.,adiposeormuscle),FAremovedfromtheTAGbyalipoproteinlipaseinthecapillarywalls;releasedfattyacidsdiffuseintothecellsaturatedfattyacid: CH3-(CH2)n-COOHunsaturatedfattyacid: CH3-CH=CH-(CH2)n-COOHpolyunsaturatedfattyacid: CH3-CH=CH-CH2-CH=CH-(CH2)n-COOH CH2----OOC-R1CH2OH HOOC-R1| |R2-COO----CH CHOHHOOC-R2||CH2----OOC-R3CH2OHHOOC-R3Figure1.Generalstructuresoffattyacidsandtriacylglycerol.Lipolysisofstoredtriacylglycerolbylipasesproducesfattyacidsplusglycerol.LipolysisTriacylglycerolGlycerolFattyacidsLIPOLYSISfattyacidshydrolyticallycleavedfromtriacylglycerollargelyinadiposetoreleasefattyacidsasafuelmayalsooccurinmuscleorliver-smalleramountsoffattyacidsarestoredhormone-sensitive(cyclicAMP-regulated)lipaseinitiateslipolysis–cleavesfirstfattyacidthislipaseandothersremoveremainingfattyacidsfattyacids/glycerolreleasedfromadiposetothebloodhydrophobicfattyacidsbindtoalbumin,intheblood,fortransportMITOCHONDRIONcellmembraneFA=fattyacidLPL=lipoproteinlipaseFABP=fattyacidbindingproteinACSFABPFABPFA[3]FABPacyl-CoA[4]CYTOPLASMCAPILLARYFAalbuminFAFAFAfromfatcellFA[1]acetyl-CoATCAcycle-oxidation[6][7]carnitinetransporteracyl-CoA[5]Figure2.OverviewoffattyaciddegradationACS=acylCoAsynthetaseLPLLipoproteins(Chylomicrons or VLDL)[2]Figure3(top).ActivationofpalmitatetopalmitoylCoA(step4,Fig.2)andconversiontopalmitoylcarnitineIntermembraneSpaceOUTERMITOCHONDRIALMEMBRANEpalmitoyl-carnitineCoApalmitoyl-CoAcarnitineCytoplasmpalmitoyl-CoAAMP + PPiATP + CoA palmitateCPT-I [2]ACS[1]Figure3(bottom).Mitochondrialuptakeviaofpalmitoyl-carnitineviathecarnitine-acylcarnitinetranslocase(CAT)(step5inFig.2).MatrixINNERMITOCHONDRIALMEMBRANEIntermembrane Spacepalmitoyl-carnitinecarnitineCoApalmitoyl-CoACAT[3]palmitoyl-carnitineCPT-IIcarnitineCoApalmitoyl-CoA[4]CPT-ICATIntermembraneSpaceOUTERMITOCHONDRIALMEMBRANEpalmitoyl-carnitineCoAcarnitineCytoplasmpalmitoyl-CoAAMP + PPiATP + CoA palmitatepalmitoyl-CoAMatrixINNERMITOCHONDRIALMEMBRANE[3]palmitoyl-carnitinecarnitineCoApalmitoyl-CoA[4]CPT-I [2]ACS[1]CPT-IIFigure4.Processingand-oxidationofpalmitoylCoAmatrix side inner mitochondrialmembrane2 ATP3 ATPrespiratory chainrecycle6 timesCarnitinetranslocasePalmitoylcarnitinePalmitoylcarnitinePalmitoyl-CoA+ Acetyl CoACH3-(CH)12-C-S-CoAOoxidationFADFADH2hydrationH2OcleavageCoAoxidationNAD+NADHCitricacid cycle2 CO2propionylCoAcarboxylase:(biotin-dependent)propionylCoA+ATP+CO2methylmalonylCoA+AMP+PPimethylmalonylCoAmutase:(adenosylcobalamin-dependent)methylmalonylCoAsuccinylCoAFigure5.ReactionsinthemetabolismofpropionylCoAderivedfromodd-chainfattyacidsOXIDATIONOFODD-CHAINFATTYACIDSFinalstepof-oxidationproduces:propionylCoA+acetylCoAFigure6.Ketonebodyformation(ketogenesis)inlivermitochondriafromexcessacetylCoAderivedfromthe-oxidationoffattyacidsMITOCHONDRION(excess acetyl CoA)Hydroxymethylglutaryl CoAHMG-CoAsynthaseacetyl CoACoAAcetoacetateHMG-CoA-lyaseacetyl CoA-Hydroxybutyrate-HydroxybutyratedehydrogenaseNAD+NADHAcetone(non-enzymatic)2 Acetyl CoAFatty acid-oxidationCitric acid cycleoxidation to CO2Acetoacetyl CoACoAThiolasehighratesoflipolysis(e.g.,long‑termstarvationorinuncontrolleddiabetes)producesufficientketonesinthebloodtobeeffectiveasafuelketonesarethepreferredfuel
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