1、Lipid MetabolismLipid Transport in BloodnLipids are not water solublenBlood is mainly waternPack lipids in proteinnChylomicronsnMade in the enterocytes(small intestine)nLipoproteins(lipids and proteins)nVLDL,LDL,HDL made in liverGroff&Gropper,1999Release of Lipids From LipoproteinsnLipoprotein lipas
2、e(LPL)nEnzyme anchored on the cell membranes in blood vessels nReleases glycerol and free fatty acids from chylomicrons and lipoproteinsnGlycerol and free fatty acids absorbed by cellsnMuscle(oxidized as a source of energy)Release of LipidsnChylomicrons chylomicron remnantsnCholesterol-richnTaken up
3、 by liver and fatty acids are metabolizedRepackaging in the LivernLipid is repackaged in the liver to VLDL or very low density lipoproteinnLipoproteins are classified by densitynLipoproteins transport lipid to the rest of the bodyVLDLTGLDLTGHDLLipoproteinsnClassified by densitynProtein:lipid ratio n
4、More protein,increased densitynMore lipid,decreased densitynFour classes of lipoproteinsnChylomicronsnVLDLnLDLnHDLFormed in liverLipoproteinsnDiffer according to the lipid:protein rationDensitynChylomicronsnVery-lowdensity lipoproteins(VLDL)nHigh lipid contentnLow-density lipoproteins(LDL)nMain chol
5、esterol transportnHigh-density lipoproteins(HDL)nLow lipid contentLowHighComplexSourceDensity(g/ml)%Protein%TGa%PLb%CEc%Cd%FFAeChylomicronIntestine1.281990000100aTriacylglycerols,bPhospholipids,cCholesteryl esters,dFree cholesterol,eFree fatty acids*HDL2 and HDL3 derived from nascent HDL as a result
6、 of the acquisition of cholesteryl esters Low Density LipoproteinsnVLDL LDLnCholesterol-richnConverted to bile salts nCarries cholesterol to tissuesnUsed for membrane synthesisnLDL bad cholesterolnAssociated with plaque formation in blood vesselsnHigh triglyceride and cholesterol contentHigh Density
7、 LipoproteinsnRemoves cholesterol from:nCellsnLipoproteinsnDeliver cholesterol to liver for excretionnConverted to bile salts and excreted in fecesnHDL good cholesterolnIs cholesterol bad for you?nCell membranes,bile salts,synthesis of steroid hormonesnRatio of LDL:HDL vs.total cholesterolLipid Tran
8、sportnFree fatty acids transported as complex with albumin in bloodnLipids rapidly removed from bloodnLivernFat depotsnOther tissueAdipose TissuenAdipocytes are the major storage site for triglyceridesnAdipose tissue(stored for later use,or immediately oxidized as a source of energy)nContains up to
9、approximately 85%lipidnContains approximately 90%DMnWhat is the DM content of muscle?nOnly 20-25%DM!nSize=amount of fat storednObesity=increase in both size and numbernMS,Lupus&other diseases=normal tissue dies,replaced by fibroblasts,become adipocytesAdipose TissueGroff&Gropper,1999Fed state.Adipos
10、e TissuenFasted statenBlood glucose level decreases insulin levels decrease and glucagon levels increasenLipolytic activity increasesnHormone-sensitive lipasenRelease of fatty acidsnFree fatty acids released into bloodnFree fatty acidalbumin complexnLiver takes up free fatty acidsnOxidation or forma
11、tion of ketone bodiesLeptinnProtein hormone produced by adipocytesnLarger cells=more leptin producednEffects on many tissuesnHypothalamusnRegulates eating behaviornNegative-feedback mechanismLeptin-deficient mutants(left)fail to limit their eating and becomes 3 times the weight of normal mouse(right
12、)Lipolysis Monogastric&RuminantnMobilization of body triglycerides for use as energyTriglycerideGlycerol3 FFA+Lipoprotein LipaseGlycolysisGluconeogenesis-oxidation*Free fatty acids bind to albumin to form non-esterified fatty acids that are soluble in blood*Triglyceride CatabolismnHydrolysis of trig
13、lycerides yieldsn One glyceroln Three FFAnGlycerol is used for energy or gluconeogenesisn Glycerol enters glycolytic pathwaysnFFA are oxidized to CO2 and H2On-Oxidationn Takes place in mitochondrianFAs cannot be used for gluconeogenesisBeta Oxidation-oxidation Saturated Fatty AcidsnFatty acids are a
14、 rich energy sourcenOxidation occurs only in mitochondria of specific tissuesnSkeletal&cardiac musclenLiver nAdipose tissue-oxidation Saturated Fatty AcidsnCleaves two carbons at a time from the carboxyl endnProduces NADH,FADH2 and acetyl-CoAnAcetyl-CoA enters TCA cyclenNADH and FADH2 enter electron
15、 transport chainnYield ATPOCH3CCoA=1st Step in Beta-OxidationActivation:Use 2 ATP equivalents to attach CoAOxidation:FAD takes H,Creates new double bond between C 2&3Hydration:add water across double bondOxidation:NAD takes Hs,new O=formedAddition&Cleavage:Add new CoA,cleave off acetyl-CoA.Lose 2 CC
16、1C2C3C4C5C6C7C8C9C10C11C12C13C14C15C16CoAOO-OxidationnPalmitate(16:0)nCarboncarbon cleavagen1 FADH2+1 NADH 5 ATP(via electron transport chain)n7 cleavage points x 5 ATP=35 ATP nOxidation of acetylCoAn8 acetyl-CoA units entering TCA cycle x 12 ATP=96 ATP nTotal ATP 35+96=131 2 ATP=129 ATPn2 ATP used
17、for fatty acid activation and entry into mitochondria1st2nd3rd4th5th6thlastSummary of-oxidationEnergy yieldThe ATP yield for every oxidation cycle is 14 ATP,broken down as follows:1 FADH2 x 1.5 ATP=1.5 ATP 1 NADH x 2.5 ATP=2.5 ATP 1 acetyl CoA x 10 ATP=10 ATP For instance,the ATP yield of palmitatep
18、almitate is:7 FADH2 x 1.5 ATP=10.5 ATP 7 NADH x 2.5 ATP=17.5 ATP 8 acetyl CoA x 10 ATP=80 ATP ATP equivalent used during activation=-2 Total:106 ATPSpecial ConsiderationsnWhy doesnt muscle utilize fatty acids during exercise?nRequires oxygen available for oxidationnUse anaerobic fermentation of gluc
19、ose to lactate preferentiallynWhy dont red blood cells utilize fatty acids for their energy metabolism?nNo mitochondria in RBCsUnsaturated Fatty AcidsnUnsaturated fatty acids must be saturated before beta-oxidationnIsomerase converts cis to trans and moves double bond to the 2 positionnIn polyunsatu
20、rated:need reductasenAdd Hs to second double bondOdd Chain Fatty AcidsnMinor species,odd chains made by microbes,degradation of AAsnB-oxidation occurs to end:nLeft with 3 carbon+CoA(propionyl CoA)nVitamin B12 cobalamin co-enzymenCatalyzes conversion of propionyl CoA(3 C)to succinyl-CoA(4 C)nTCA cycl
21、e intermediateKetone Bodies(Ketogenesis)nAcetone,acetoacetate,-hydroxybutyratenProduced in liver from incomplete oxidation of fatty acidsnUsed by extra-hepatic(non-liver)tissue in preference to fatty acids as energynTurned into acetyl-CoAnExcess spills over into urine or exhaled as acetoneFatty Acid
22、 SynthesisnIn fed state-lots of glucosenGlycogen stores fill upnATP and citrate inhibit glycolysis pathwaysnGlucose diverted through the pentose-phosphate pathwaynNADPH formed and used in fatty acid synthesisnPyruvate is formedFatty Acid Synthesis-MonogastricsnWhat are the advantages of storing exce
23、ss feed or energy as fat?nHigh energy density tissue,low water contentnMajor producers of fatty acidsnLivernAdipose tissuenMammary glandnCan animals synthesize all fatty acids?nNO essential fatty acids MUST come from dietn18:2,18:3nCats cannot synthesize 20:4Lipogenesis-MonogastricsnMechanism of fat
24、ty acid synthesis is similar between different species,but the contribution of tissue types varies with speciesnMouse&rat-50%livernChicken-mostly livernPig-mostly adiposeFatty Acid Biosynthesis-MonogastricnOccurs in endoplasmic reticulumnOccurs when:nEnergy needs are met(ATP ADP)nGlycogen stores ful
25、lnExcess nutrients presentFatty Acid Biosynthesis-MonogastricnBegins with acetyl-CoA from:nCarbohydrate metabolism(glucose)nSpecific amino acidsnDegraded lipidsnFatty acid chains are createdn2C units added from carboxyl to methyl end nEster bondsnUp to 16C(palmitate)fatty acids can be synthesizednNA
26、DPH required as“energy source”MitochondriaCytosolAcetyl CoATCA CycleCitrateCitrateOxaloacetate(2C)Acetyl CoAAcetyl CoA Carboxylase(biotin)HCO3 ATP(3C)Malonyl CoACO2NADPH4C Butyryl CoA2C Acetyl CoA3C Malonyl CoA6C Caprayl CoACO2NADPHFatty Acid SynthaseFatty Acid Biosynthesis-MonogastricnCycle continu
27、es by continued addition of malonyl CoA and loss of CO2nPalmitate(16C)is final product after 7 cyclesnDesaturation and elongation occur elsewhere:ERFatty Acid ModificationsnPalmitate an be elongatednAddition of two-carbon units at COOH-end of fatty acidnDesaturationn16:0 and 18:0 can be converted to
28、 16:1 and 18:1,respectivelyWhy are w-3&w-6 Essential?nMammals lack enzyme to add double bonds beyond C-9nChain elongation and double bond addition yield arachidonic acid(C20:4)from linoleic acid(C18:2)Metabolism of natural C20 cis fatty acids produces powerful eicosanoids Metabolism of FatsLipid Synthesis in MonogastricsFigure 25.10Lipogenesis-RuminantsnSimilar to monogastrics except for:nMain site nAdipose tissue,livernSources of carbon(acetyl-CoA)nAcetatenLactatenBeta-hydroxy-butyratenDietary fatty acidsUnable to convert glucose to fatty acids
