Increasing dietary linoleic acid does not increase tissue ...

Linoleic acid (LA, 18:2 n-6) is the major dietary polyunsaturated fatty acid (PUFA) in the Western diet and is a metabolic precursor to AA, ... Skiptomaincontent Advertisement SearchallBMCarticles Search DownloadPDF DownloadePub Research OpenAccess Published:10June2011 IncreasingdietarylinoleicaciddoesnotincreasetissuearachidonicacidcontentinadultsconsumingWestern-typediets:asystematicreview BrianSRett1&JayWhelan1  Nutrition&Metabolism volume 8,Article number: 36(2011) Citethisarticle 14kAccesses 109Citations 43Altmetric Metricsdetails AbstractBackgroundLinoleicacid,withaDRIof12-17g/d,isthemosthighlyconsumedpolyunsaturatedfattyacidintheWesterndietandisfoundinvirtuallyallcommonlyconsumedfoods.Theconcernwithdietarylinoleicacid,beingthemetabolicprecursorofarachidonicacid,isitsconsumptionmayenrichtissueswitharachidonicacidandcontributetochronicandoverproductionofbioactiveeicosanoids.However,nosystematicreviewofhumantrialsregardinglinoleicacidconsumptionandsubsequentchangesintissuelevelsofarachidonicacidhasbeenundertaken.ObjectiveInthisstudy,wereviewedthehumanliteraturethatreportedchangesindietarylinoleicacidanditssubsequentimpactonchangingtissuearachidonicacidinerythrocytesandplasma/serumphospholipids.DesignWeidentified,reviewed,andevaluatedallpeer-reviewedpublishedliteraturepresentingdataoutliningchangesindietarylinoleicacidinadulthumanclinicaltrialsthatreportedchangesinphospholipidfattyacidcomposition(specificallyarachidonicacid)inplasma/serumanderythrocyteswithintheparametersofourinclusion/exclusioncriteria.ResultsDecreasingdietarylinoleicacidbyupto90%wasnotsignificantlycorrelatedwithchangesinarachidonicacidlevelsinthephospholipidpoolofplasma/serum(p=0.39).Similarly,whendietarylinoleicacidlevelswereincreaseduptosixfold,nosignificantcorrelationswitharachidonicacidlevelswereobserved(p=0.72).However,therewasapositiverelationshipbetweendietarygamma-linolenicacidanddietaryarachidonicacidonchangesinarachidoniclevelsinplasma/serumphospholipids.ConclusionsOurresultsdonotsupporttheconceptthatmodifyingcurrentintakesofdietarylinoleicacidhasaneffectonchanginglevelsofarachidonicacidinplasma/serumorerythrocytesinadultsconsumingWestern-typediets. BackgroundArachidonicacid(AA,20:4n-6)isapotentbioactivemolecule.Whenreleasedfrommembranephospholipids,itisconvertedtoavarietyofbioactivecompounds,calledeicosanoids.Theseoxidizedlipidmoleculesarerelatedtoanumberofchronicdiseasesincludingcardiovasculardisease,cancerandinflammation[1–4].EnrichmentofAAintissuesispositivelycorrelatedwiththeproductionofeicosanoids.Linoleicacid(LA,18:2n-6)isthemajordietarypolyunsaturatedfattyacid(PUFA)intheWesterndietandisametabolicprecursortoAA,linkedbiochemicallyviatwodesaturasesandanelongase.TypicalintakesofLAare12-17gramsperdayforwomenandmen,respectively[5],orapproximately6%ofenergy.Intheabsenceofotheromega-6(n-6)PUFA(includingdietaryAA),dietaryLAisthesolecontributortotissueAA.ThisrelationshiphadbeenestablishedinexperimentalrodentmodelswheredietaryLAwascorrelatedwithtissueAAcontentinanon-linearrelationshipinratsprovidedfat-freebackgrounddiets[6]andlipid-richdiets[7].RecentreviewssuggestthisrelationshipmayexistinadulthumansconsumingatypicalWestern-typediet[8,9]andsomehaverecommendedlimitingLAintakeasawaytohelpreducetissueAAlevels[10,11].Certainly,thisrelationshiphadbeenreportedinsubjectsconsumingdietscontainingLAatlevelslessthan2%ofenergy[12].Thereare,however,anumberofrecentpaperssuggestingthatincreasingdietaryLAdoesnotincreasetissueAAlevels,butinfactmayhaveaninverserelationship[13,14].Tocompoundthecomplexityofthisrelationship,thefamilyofn-6PUFAare,ingeneral,synonymouslyidentifiedtodietaryLA,whileseeminglyignoringothermemberswhocancontributetotissueAA,i.e.,dietarygamma-linolenicacid(GLA,18:3n-6)andAA.ThisstudywasdesignedtoexploretherelationshipofdietaryLAandtissueAA,viz.,phospholipidpoolsofplasma/serumanderythrocytes.Toourknowledge,thisisthefirststudytoreviewtheliteratureastowhetherincreasingdietaryLAispositivelycorrelatedwithincreasingtissueAAcontent,andwhetherreducingdietaryLAhastheoppositeeffectinadultsconsumingWestern-typediets.Wefurtherinvestigatedwhatpotentialcontributionsotherdietaryn-6PUFAmayhaveontissueAAcontent.ThisstudywaslimitedinscopeanddidnotaddressothercontroversialissuesrelatedtodietaryLAorotherPUFAortheireffectsonissuesrelatedtohealth.MethodsTheaimofthispaperwastoidentify,review,andevaluateallpeer-reviewedpublishedliteraturepresentingdataoutliningchangesindietaryLAinadulthumanclinicaltrialswhichreportphospholipidfattyacidcomposition(specificallyAA)inplasma/serumanderythrocytes.Wechosethephospholipidpoolinplasma/serumbecausehereiswhereamajorityofthehumandatais,itrepresentsmembranesoflipoproteinsderivedfromthesurfaceofhepaticendoplasmicreticulum[15](ithelpstocontrolforpotentialvariationsinothercomponents,suchascirculatingtriglycerides).Thestudiesreportingthefattyacidcompositionoferythrocytephospholipidsdosobecausefattyacidsinerythrocytesarealmosttotallyesterifiedinphospholipids.FurtherrefinementstothesearchstrategyincludedreportedchangesintissueAAlevelsfollowingdietaryintakeofAAanditsvariousn-6PUFAprecursors,i.e.,LAandGLA.Publishedarticlesmeetingeligibilitycriteriafrom1970topresentwerereviewed,ofwhich4336articleswereretrievedfromMay2009-November2009(Figure1).TheprimarysearchengineusedwasPubMed.gov(TheNationalLibraryofMedicine,NationalInstitutesofHealth),alongwithseveralprominentnutrition-basedclinicaljournals,i.e.,AmericanJournalofClinicalNutrition,BritishJournalofNutrition,andanyadditionalcitationsinarticlesreviewed.Thesearchtermsincludedlinoleicacid,γ-linolenicacid,gamma-linolenicacid,arachidonicacid,omega-6,n-6,oliveoil,soybeanoil,sunfloweroil,saffloweroil,cornoil,omega-3,n-3,plasma,erythrocyte,redbloodcellandphospholipid.Figure1Schematicoutliningthesystematicreview.FullsizeimageThefollowingeligibilitycriteriaappliedtoallacceptedarticles.Subjectshadtobe18yearsorolderwithnoknownmetabolicdisorderthatwouldinfluencetissueAAcontent.SufficientdataonLA,GLAand/orAAconsumption(pre-andpost-intervention)wasrequired.Thenatureoftheintervention(i.e.,capsules,oilsordietarymodifications)hadtobepresented.Thefattyaciddata(plasma/serumand/orerythrocyte)hadtobedeterminedfromfastingpatients,pre-andpost-supplementation.Baselineandpost-treatmentoftissuephospholipidfattyacidcompositionhadtobeprovided.Onoccasion,percentchangesintissuefattyacidcompositionwereprovidedandthisdatawasused.Onlythosepaperspublishedafter1970duetoimprovedgaschromatographicmethodswereaccepted.Articleswereautomaticallyexcludedifsubjectswerelessthan18yearsold,pregnantornursing,consumingsupplementscontaininglongchainn-3fattyacidsorsupplementedfishintakeaboveandbeyondtheirtypicaldietaryregimen,orusingknowninhibitorsofAAmetabolism,suchasnon-steroidalanti-inflammatorydrugs(NSAIDs).Afteraninitialreviewofthepapers,4043wereexcludedbecauseofinsufficientdataorstudiesthatdidnotinvestigateourparameters.Ofthe293papersthatpassedtheinitialreviewprocess,eachwasreviewedbytwoindependentinvestigators(BRandJW)andthirty-sixwereacceptablebybothreviewers.Thosepapersthatwerenotaccepted(n=249)wererejectedbecausebaselinedatawasnotsufficientlyreported,datafortargettissueswasnotpresented,insufficientdatawaspresentanddidnotallowforappropriatecalculations,backgrounddietswerenotsufficientlydescribed,ortheyincludedsupplementationofrestrictedfooditems(i.e.,longchainn-3PUFA).Thirty-sixarticleswerefoundtomeetalloftheinclusion-exclusioncriteria.Onceaccepted,dataondietaryn-6fattyacidintake(%ofcaloriesorg/d)andtissueAAcontentwereextracted.Studydesign,numberandgenderofsubjects,methodofsupplementation(i.e.,typeofoil,capsulesorfoodcomponentused)wererecorded.ThosestudiesinvolvingdietaryLAaspercentageofcaloriesorg/danditseffectsonchangesintissueAAcontentaresummarizedinTables1,2,&3.Similarly,thosestudiesinvolvingdietaryGLA(0.36-6.00g/d)andAA(0.50-6.00g/d)aresummarizedinTables4and5.Ifastudymettheeligibilitycriteriaandcontainedmorethanonecomparison,eachcomparisonwasreportedasaseparatedatapoint.Table1Studiesoutliningtheeffectsofdecreasingdietarylinoleicacidlevels(%energy)frombaselineonchangesinplasma/serumphospholipidarachidonicacidlevelFullsizetableTable2Studiesoutliningtheeffectsofincreasingdietarylinoleicacidlevels(%energy)frombaselineonchangesinplasma/serumphospholipidarachidonicacidlevelFullsizetableTable3Studiesoutliningtheeffectsofsupplementingdietarylinoleicacidlevels(g/day)onchangesinplasma/serumphospholipidarachidonicacidlevelFullsizetableTable4Studiesoutliningtheeffectsofsupplementingdietarygamma-linolenicacidonchangesinplasma/serumphospholipidarachidonicacidlevelFullsizetableTable5Studiesoutliningtheeffectsofsupplementingdietaryarachidonicacidonchangesinplasma/serumphospholipidarachidonicacidlevelFullsizetableBaselinetissueAAlevelsweredefinedasrelativeabundanceofAAintissuephospholipidspriortodietarysupplementation(orreduction)ofthecorrespondingdietaryn-6PUFAofinterest(i.e.,LA,GLAorAA).Inthecaseofcross-overdesigns,baselinefattyacidcompositionwasestablishedfollowingawashoutperiodoraftersupplementationofacontroldietiftherewerenooronlyminorchangesinthedietaryn-6PUFAcontent.Forexample,asupplementrichinoleicacid(amonounsaturatedfattyacidtypicallyusedasacontrolandknowntohaveaneutraleffectontissueAAcontent)couldbeusedasacontrollipid(oroil)priortosupplementationofanequalamountofalipid(oroil)richinLA.Percentchangeforeachdietaryn-6fattyacidofinterestwasusedtostandardizetherelativedifferencesbetweenbaselineintakesandinterventionintakesfollowingtheexperimentalperiodusingthefollowingformula:Thelevelsofintakewerebasedontherelativecaloricamount(%ofcalories),andwhenthisdatawasnotavailableabsoluteintakelevels(g/d)wereused.PercentchangefortissueAAcontentwasusedtostandardizetherelativedifferencesbetweenbaselinelevelsandinterventionlevelsfollowingtheexperimentalperiodusingthefollowingformula:StatisticalAnalysisTheoveralllinearcorrelationbetweenpercentchangeofdietaryn-6fattyacidsandpercentchangeoftissueAAwascomputedusingtheProcCorrprocedureinSAS9.2(SASInstituteInc.SASCampusDrive,Cary,NorthCarolina).ThecorrelationmatrixandtheTstatistictestedforcorrelationandstatisticalsignificance,respectively.Forthelinearcorrelations,theequationofthelinewascomputed,andrepresentedbyy=mxforthosethatexhibitedlinearity.Datanotresemblingalinearrelationship(i.e.dietaryGLAandAA)utilizedapolynomialgrowthcurvefromSASGeneralLinearModelandt-testsformodelparameterstestedforsignificance.P-valueslessthanorequalto0.05wereconsideredsignificant.TheYvaluesrepresentchangesofAA(%frombaseline)andtheXvaluesrepresentthechangesofthevariousdietaryn-6PUFA(%frombaselineorg/dsupplemented).Inadditiontotheoverallcorrelationtest,thestatisticalsignificanceforeachindividualdatapoint(forchangesintissueAA),asreportedbytheauthorsintheirrespectivemanuscripts,wasidentifiedineachgraph.Ifthechangesfrombaselineweresignificantlydifferentthedatawasrepresentedbytriangle.Ifthechangesfrombaselinewerenotstatisticallydifferent,theywererepresentedbyadiamond.ResultsElevencomparisonsreporteddecreasesinLAintakes(-12%to-90%)andnosignificantcorrelationswereassociatedwithchangesinplasma/serumphospholipidAAcontent(r2=0.07,p=0.44,y=0.026x)(Table1andFigure2).Onlyonestudyoftheelevenreportedasignificantchange,a4.1%increaseinAAcontent,followinga29%reductioninLAintake[16].Figure2Effectsofdecreasingdietarylinoleicacid(LA)intake(%change)basedonenergyonchangesinplasma/serumphospholipidarachidonicacid(AA)content.Significantchanges(p<0.05)inAAasreportedintheoriginalpapersaredesignatedastriangles.Non-significantAAchangesasreportedintheoriginalpapersaredesignatedasdiamonds.Abbreviations:AA,arachidonicacid;LA,linoleicacid;PL,phospholipid.FullsizeimageIncreasesindietaryLA,rangingfrom12%-550%,wasnotsignificantlycorrelatedwithchangesinplasma/serumphospholipidAAcontent(r2=0.074,p=0.45,y=-0.0053x)(Table2andFigure3).Ofthesixteencomparisons,onlyfourstudiesreportedsignificantchangesinAAlevelswhendietaryLAlevelswereincreased;threestudiesreported3-20%reductionsfollowing12%-110%increasesinLAconsumption[16–18]andonlyonestudyreportedasignificantincreaseinAAcontent(10%)followingan86%increaseinLAintake[19].Sub-dividingthestudiesbydesign(crossoverversusnon-crossover)hadnoeffectontheresults(datanotshown).Similarly,inthosestudiesthatonlyreportedabsolutelevelsofLAsupplementation(g/d),increasingLAsupplementationwasnotsignificantlycorrelatedwithchangesinplasma/serumphospholipidAAcontent(r2=0.092,p=0.64,y=0.969x)(Table3andFigure4).Oftheseventeencomparisons,onlytwoweresignificantlydifferent,oneresultedinanincreaseinAAcontentby3%followingsupplementationof2.24g/dofLA[20]andtheotherresultedinareductionofAAcontentby7%followingsupplementationof0.86g/d[21].Figure3Effectsofincreasingdietarylinoleicacid(LA)intake(%change)basedonenergyonchangesinplasma/serumphospholipidarachidonicacid(AA)content.Significantchanges(p<0.05)inAAasreportedintheoriginalpapersaredesignatedastriangles.Non-significantAAchangesasreportedintheoriginalpapersaredesignatedasdiamonds.Abbreviations:AA,arachidonicacid;LA,linoleicacid;PL,phospholipid.FullsizeimageFigure4Effectsofincreasingdietarylinoleicacid(LA)intake(g/d)onchangesinplasma/serumphospholipidarachidonicacid(AA)content.Significantchanges(p<0.05)inAAasreportedintheoriginalpapersaredesignatedastriangles.Non-significantAAchangesasreportedintheoriginalpapersaredesignatedasdiamonds.Abbreviations:AA,arachidonicacid;LA,linoleicacid;PL,phospholipid.FullsizeimageSimilarcomparisonsweremadeinerythrocyteswithincreasinganddecreasingintakesofLA,althoughthenumberofstudiesweremorelimited.IncreasesindietaryLA,rangingfrom12%-100%,werenotsignificantlycorrelatedwithchangesintissueAAcontent(r2=0.06,p=0.75,y=-0.1479x)(Figure5).ReducingdietaryLAintake(-12%to-70%)wasnotsignificantlycorrelatedwithchangesintissueAAcontent(r2=0.017,p=0.77,y=-0.0174x)(Figure6).Inaddition,outofthesevenstudies,onlyonestudyreportedasignificantchangewheredecreasingdietaryLAintakeby29%resultedina4%increaseinAAcontent[16].Figure5Effectsofincreasingdietarylinoleicacid(LA)(%change)intakebasedonenergyonchangesinerythrocyte(RBC)phospholipidarachidonicacid(AA)content.Significantchanges(p<0.05)inAAasreportedintheoriginalpapersaredesignatedastriangles.Non-significantAAchangesasreportedintheoriginalpapersaredesignatedasdiamonds.Abbreviations:AA,arachidonicacid;LA,linoleicacid;PL,phospholipid.FullsizeimageFigure6Effectsofdecreasingdietarylinoleicacid(LA)(%change)basedonenergyonchangesinerythrocyte(RBC)phospholipidarachidonicacid(AA)content.Significantchanges(p<0.05)inAAasreportedintheoriginalpapersaredesignatedastriangles.Non-significantAAchangesasreportedintheoriginalpapersaredesignatedasdiamonds.Abbreviations:AA,arachidonicacid;LA,linoleicacid;PL,phospholipid.FullsizeimageSevenstudiesmetourcriteriafortheeffectsofGLAsupplementationonchangesinplasma/serumphospholipidAAcontent(Table4andFigure7).ThereappearedtobeadosedependentincreaseinAAcontentwithincreasingintakesofGLA(rangingfrom0.36g/dto6.00g/day).Thispositivecorrelation(r2=0.75,p=0.03,y=0.004x+7.36)wassignificantwithalinearregressionmodel,andapproachedsignificancewithanon-linear(quadratic)regressionmodel(r2=0.56,y=-1.4x2+13.76x,p=0.079).Thenumberofavailabledatamaybeafactorintheseresults.OfthesixGLAdatapoints,fourofthemreportedstatisticallysignificantincreasesinAA.Figure7Effectsofincreasingdietarygamma-linolenicacid(GLA)(g/d)onchangesinplasma/serumphospholipidarachidonicacid(AA)content.Significantchanges(p<0.05)inAAasreportedintheoriginalpapersaredesignatedastriangles.Non-significantAAchangesasreportedintheoriginalpapersaredesignatedasdiamonds.Abbreviations:AA,arachidonicacid;GLA,gamma-linolenicacid;PL,phospholipid.FullsizeimageSimiliarly,increasingdietaryAA(0.50g/dto6.00g/day)waspositivelycorrelatedwithincreasesinplasma/serumphospholipidAAcontentusingaquadraticregressionmodel(r2=0.79,y=-8.7x2+74.87x,p=0.013)(Figure8).Alldatapointswerereportedassignificantlydifferent(Table5).Figure8Effectsofincreasingdietaryarachidonicacid(AA)(g/d)basedonenergyonchangesinplasma/serumphospholipidAAcontent.Significantchanges(p<0.05)inAAasreportedintheoriginalpapersaredesignatedastriangles.Non-significantAAchangesasreportedintheoriginalpapersaredesignatedasdiamonds.Abbreviations:AA,arachidonicacid;PL,phospholipid.FullsizeimageDiscussionArachidonicacidisarguablythemostimportantPUFAassociatedwithmembranephospholipids.Uponrelease,AAcanbeenzymaticallymetabolizedtoamyriadofbioactivederivatives,eicosanoids,knowntocontributetoavarietyofchronicdiseases,butarealsoknowntobeinvolvedintissuehomeostasisandtheresolutionofinflammation[1–4,22].TherelativeabundanceofAAinmembranephospholipidspositivelyinfluenceseicosanoidproduction[23].ItiswellknownthatdietaryPUFAcanaffecttissueAAlevels;however,whatisuncertainandcontroversialiswhethermodifyingcurrentintakesofdietaryLAwillresultinconcomitantchangesintissueAAcontent,i.e.,increasingLAintakeresultsinanincreaseintissueAAcontentanddecreasingLAhastheoppositeeffect[8].ThegoalofthispaperwastoascertaintherelationshipbetweendietaryLAandtissueAAcontent(phospholipidpoolsofplasma/serumanderythrocytes)inadultsconsumingaWestern-stylebackgrounddiet.Itwasnotdesignedtoaddressothercontroversiessurroundingtheissuesofdietaryn-6orn-3PUFAorinotherpopulationgroups.Manypapersinterchangethemoregeneraltermn-6PUFAfordietaryLA,buttherearetwomajorn-6PUFA,LAandAA,thataredistributedunevenlyintheWesterndiet.WhileLAisthemajorPUFAinmostcommonlyconsumedfoods,AAisexclusivelyfoundinanimalproducts,suchas,muscle,organmeatsandeggs[24].Theyhavedistinctbiologicalactivitiesthatarebiochemicallylinkedviadesatuationandelongation,andassuch,LAistheconditionallyessentialfattyacid.LinoleicacidisspecificallyrequiredintheskintomaintaintheintegrityoftheepidermalwaterbarrierandAAistheimmediateprecursortoeicosanoids,aswellasbeingthen-6PUFAselectivelyincorporatedintothemembranesofcertaintissues,i.e.,brain[25].Whenconsumed(LAvs.AA),theyappeartohavedifferentialeffectsontissuefattyacidcomposition,whereAAappearstomorerobustlymodifytissueAAlevelsandeicosanoids[14,26].ThedatapresentedinthispapersuggeststhatadoseresponsebetweendietaryLAandtissueAAdoesnotexistswithinthebackdropofindividualsconsumingaWestern-typediet.IncreasingLAbyasmuchas551%frombaselineandreducingLAbyasmuchas90%frombaselinefailedtoyieldcompellingevidencesupportingtheconceptthatanyconversionofdietaryLAtodownstreammetabolitesresultsintissueenrichmentofAA,anotioncommonlyassumed.Forexample,"However,thehigherconcentrationsofLAtypicallyfoundintheWesterndietresultsinagreaterconversionofLAtoarachidonicacid"[8]and"Excessiven-6precursorspromotesformationofAA"[9],suggestingenrichmentofAAintissueswithincreasesinLAintake.WechosetoevaluatethedatabylookingatchangesfrombaselineintissueAAcontenttostandardizethedatafromonestudytothenext.Eachstudybeganwithabaselinevalueandwereportedpercentchangesfromthatbaseline.SupplementalintakesofLAwerereportedbasedonenergyandwhenthatvaluecouldnotbedetermined,wereportedabsolutesupplementedvalues,andthesedatawerereportedseperately.Asobservedfromthedistributionoftheresponses,therewaswidevariability.SomepapersshowedsmallincreasesintissueAAlevelswhendietaryLAchanged,whileotherpapersshowedsmalldecreases,butmostofthesechangeslackedsignificance.Whentherewassignificance,thechangeswereminimalandthedistributionpatternofthedatadidnotfavoranincreaseoradecrease.Wechoseplasma/serumanderythrocytesasthetissuesofchoicebecausehereiswherethebulkofdataexistsinthehumanliterature.Erythrocytesrepresentamorestablepoolofdietarylipids,containverylittleneutrallipidsandthusrepresentsamembranefractionofAA.Fastingplasma/serumphospholipidlevelsprimarily(butnotexclusively)representsinpartphospholipidsoflipoproteinsthatarederivedfromhepaticendoplasmicreticulum[15],andthispoolismoreresponsivetomorerecentdietaryPUFAintakes.InanefforttoidentifywhydietaryLAmaynotmodifytissueAAlevels,wereviewedtheliteraturefordietaryGLAusingthesamesearchstrategy.WastheconversionofLAtoAArate-limiting,orweretissuelevelsofAAsaturated?Delta-6desaturaseistherate-limitingenzymeinthemetabolismofLAtoAA.GLAisadietaryn-6PUFAthatentersthemetabolicpathwayafterthedelta-6desaturasestep.Ifdelta-6desaturaseisrate-limitingandtissueAAcontentisnotsaturated,thenthereshouldbeevidencethatincludingGLAinthedietincreasestissueAAlevels.WhenGLAwassupplementedasthetriacylglycerolformorasacomponentofadietaryoilcontainingGLA(i.e.,blackcurrant,eveningprimroseorborageoil),tissueAAcontentincreasedinadoseresponsivemanner.Theseeffectsappearedtobelessprominentinthosestudies[27–29]thatusedoilscontainingappreciableamountsofthemorehighlyunsaturatedn-3PUFAstearidonicacid,i.e.,blackcurrant[30].WhenAAwassupplementedinthediet,therewasfurtherenrichmentintissueAAcontentabovethatobservedwitheitherLAorGLA.Theseresultssuggestthatdelta-5desaturasepotentiallybecomesratelimitingwhenGLAissupplemented.Thereactionmediatedbydelta-5desaturaseisanintermediatestepbetweenGLAandAAandby-passingthatstepwithdietaryAAleadstofurtherenrichment.ThesedataseemtosuggestthatwhiledietaryLAmaybeametabolicprecursorforAA,itsinfluenceontissuelevelsinpopulationsconsumingWesterndietsarelimitedbytheenzymaticconversionthroughdelta-6desaturaseandnotduetotissuesaturationofAA.Thesedataaresupportedbythepoorratesofconversionofplasma/serumLAtoAAinadults.Intracerstudiesinvolvingstableisotopes,theestimatedfractionalconversionofLAtoAAwasbetween0.3%and0.6%[31].ThelevelsofLAinthedietrequiredtoachieveessentialitycouldbeaslowas0.5-2.0%ofenergyininfants[32,33]andithasbeenreportedthattissuelevelsofAAnolongerrespondtodietaryLAintakesabove2%energyinadults[12].OurstudywasdesignedtochosestudiesthatincorporatedaWestern-typedietwhereLAisnottypicallylimiting,reflectiveofthegeneralpublic.ThismeansafullcomplimentofPUFAswerebeingconsumedalongwithLAsupplementation.TheDRIsforLAandalpha-linolenicacid(ALA,18:3n-3)are12g-17g/dand1.1g-1.6g,respectively(womenthelowerfigure,menthehigherfigure).Thiswouldbeequivalenttointakesapproximating6%and0.7%ofcaloriesperdayforLAandALA,respectively.ItisnotunreasonabletothinkthatwithabackgrounddietcontainingLA,ALA,AA,andlong-chainn-3PUFAs,i.e.eicosapentaenoicacid(EPA,20:5n-3)anddocosahexaenoicacid(DHA,22:6n-3)attypicalintakes,thatmodifyingdietaryLAlevelsmaynotinfluencetissueAAlevels.ItispossiblethatasLAincreasesinthedietitmaybecompetingwithAAforreacylationintophospholipids[13,14,16–18,21,34].AsmallnumberofstudiesmodifiedLAintakesbyusingoilsthatalsocontainedsomeALA,suchassoybeanandcanolaoil[17,35,36],buttheresultsfromthesestudieswerenotsignificantandweresimilartotheotherresults.TherecouldbesomeconcernthatsomeofthesupplementedoilscontainALA,suchassoybeanoil.ItmustberememberedthatsoybeanoilhasaLA:ALAratiosimilar(8:1)tothatfoundintheUSdiet(10:1)andifyouincludedorexcludedthesepaperstheresultswereunaffected.WealsoincludedtwostudiesthatsupplementedLAwithrecommendedfishrestrictions(becausetheymetourinclusion/exclusioncriteria)[19,37].Onestudy(+176%LA)reportednochangesinAAlevels,whiletheother(+86%LA)reporteda10%increaseinAA.Someoftheweaknessesofthisreviewarereflectedinthestudiesthatqualifiedforourevaluation.Mostwerenotdesignedtospecificallyaddressourresearchquestion;however,thosethatwerespecificallydesignedtoevaluatetheeffectofdietaryLAontissueAAcontentyieldedresultsthatweresimilartotheoverallresults[13].Eachstudyusedadifferentpopulationwithpotentiallydifferentbackgrounddiets,butoverallthiswouldbetterreflecttheconsumptionpatternsofthegeneralpublic.Notallstudieswereblinded(61%wereblinded)anddietaryLAwasnotexclusivelymodified.ThemethodsformodifyingLAintakeswerevariedandotherdietaryPUFAwerenotcontrolledforwiththeexceptionsidentifiedpreviously,anddataforonlytwotissueswereevaluated.WhenLAwasmodified,itwasdonesobytypicallychangingthelevelsofanoilrichinLA(i.e.,cornoil,saffloweroil,sunfloweroil)orfoodscontainingLA(asopposedtoaddingpureLA),reflectinghowLAwouldbeconsumedbythegeneralpublic.Therewerenostandardlengthtothestudies.Forexample,studiesinvolvingplasma/serumrangedbetween14days-5months,andthoselookingaterythrocytedatarangedbetween14-180days.Importantly,thesubjectswereusedastheirowncontrols,thestudiesaddressedchangesinLAinrelationshiptoWestern-typediets,andtheresultswerenotdifferentbetweenthosestudiesthatweredouble-blindrandomizedplacebocontrolledtrials(1/3)andthosethatwerenot.Despitetheseweaknesses,positiveresultswerestillidentifiedwithintakesofGLAandAA,helpingtosupportthoseresultsreportedwithLA.ConclusionsElevatedtissueAAlevelsarebelievedtobepositivelyassociatedwitheicosanoidformationandriskforavarietyofchronicdiseases,includingcardiovasculardisease,cancerandinflammation.TheliteratureexpressesconcernoverthefactthatincreasingdietaryLAcanpotentiallyenrichtissueswithAAduetotheirmetaboliclink.Theresultsofthisstudydonotsupportthisconcern.WhereasAAlevelsinbloodphospholipidsisincreasedbyGLAorAAsupplements,interventionstudiesbringnoevidencetosuggestthatchangesindietaryLAwillmodifytissueAAcontentinanadultpopulationconsumingaWestern-typediet. AbbreviationsAA: arachidonicacid ALA: alpha-linolenicacid DHA: docosahexaenoicacid DRI: DietaryReferenceIntake EPA: eicosapentaenoicacid GLA: gamma-linolenicacid LA: linoleicacid NSAIDs: non-steroidalanti-inflammatorydrugs PL: phospholipid PUFA: polyunsaturatedfattyacids. ReferencesCalderPC:n-3Polyunsaturatedfattyacids,inflammation,andinflammatorydiseases.AmJClinNutr.2006,83:S1505-1519. 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GoogleScholar  DownloadreferencesAcknowledgementsandfundingThisresearchwasassociatedwiththeUSDAMultistateRegionalResearchProjectNC1039,andfundedinpartbytheTennesseeAgriculturalExperimentStation(JW).AuthorinformationAffiliationsDepartmentofNutrition,UniversityofTennessee,Knoxville,Tennessee,37996-1900,USABrianSRett & JayWhelanAuthorsBrianSRettViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarJayWhelanViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarCorrespondingauthorCorrespondenceto JayWhelan.AdditionalinformationCompetinginterestsTheauthorsdeclarethattheyhavenocompetinginterests.Authors'contributionsBRconductedtheresearchandco-wrotemanuscript,andJWformulatedanddesignedresearch,co-wrotemanuscriptandhadfinalresponsibilityforallpartsofthemanuscript.Allauthorshavereadandapprovedthefinalmanuscript.Authors’originalsubmittedfilesforimagesBelowarethelinkstotheauthors’originalsubmittedfilesforimages.Authors’originalfileforfigure1Authors’originalfileforfigure2Authors’originalfileforfigure3Authors’originalfileforfigure4Authors’originalfileforfigure5Authors’originalfileforfigure6Authors’originalfileforfigure7Authors’originalfileforfigure8Rightsandpermissions ThisarticleispublishedunderlicensetoBioMedCentralLtd.ThisisanOpenAccessarticledistributedunderthetermsoftheCreativeCommonsAttributionLicense(http://creativecommons.org/licenses/by/2.0),whichpermitsunrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalworkisproperlycited. ReprintsandPermissionsAboutthisarticleCitethisarticleRett,B.S.,Whelan,J.IncreasingdietarylinoleicaciddoesnotincreasetissuearachidonicacidcontentinadultsconsumingWestern-typediets:asystematicreview. NutrMetab(Lond)8,36(2011).https://doi.org/10.1186/1743-7075-8-36DownloadcitationReceived:04March2011Accepted:10June2011Published:10June2011DOI:https://doi.org/10.1186/1743-7075-8-36SharethisarticleAnyoneyousharethefollowinglinkwithwillbeabletoreadthiscontent:GetshareablelinkSorry,ashareablelinkisnotcurrentlyavailableforthisarticle.Copytoclipboard ProvidedbytheSpringerNatureSharedItcontent-sharinginitiative KeywordsPhospholipidFattyAcidCompositionDietaryLinoleicAcidTissueFattyAcidCompositionBackgroundDietPhospholipidPool DownloadPDF DownloadePub Advertisement Nutrition&Metabolism ISSN:1743-7075 Contactus Submissionenquiries:[email protected] Generalenquiries:[email protected]