5/25/2017 Introduction to Lipids and Lipoproteins - Endotext - NCBI Bookshelf

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

De Groot LJ, Chrousos G, Dungan K, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000-.

IntroductiontoLipidsandLipoproteins
KennethRFeingold,MD
ProfessorofMedicine,UniversityofCaliforniaSanFranciscoStaffPhysicianandChiefoftheEndocrineClinicSanFranciscoVAMedicalCenter,
Metabolism111F,VAMedicalSanFrancisco,CA94121

CarlGrunfeld,MD,PhD
ProfessorofMedicine,UniversityofCaliforniaSanFranciscoChiefoftheMetabolismandEndocrineSectionandAssociateChiefofStaffforResearch
andDevelopmentSanFranciscoVAMedicalCenter,Metabolism111F,VAMedicalCenter,4150ClementSt,SanFrancisco,CA94121

LastUpdate:June10,2015.

ABSTRACT
Cholesterolandtriglyceridesareinsolubleinwaterandthereforetheselipidsmustbetransportedinassociationwith
proteins.Lipoproteinsarecomplexparticleswithacentralcorecontainingcholesterolestersandtriglycerides
surroundedbyfreecholesterol,phospholipids,andapolipoproteins.Plasmalipoproteinscanbedividedintoseven
classesbasedonsize,lipidcomposition,andapolipoproteins(chylomicrons,chylomicronremnants,VLDL,IDL,
LDL,HDL,andLp(a)).Chylomicronremnants,VLDL,IDL,LDL,andLp(a)areproatherogenicwhileHDLis
antiatherogenic.Apolipoproteinshavefourmajorfunctionsincluding1)servingastructuralrole,2)actingasligands
forlipoproteinreceptors,3)guidingtheformationoflipoproteins,and4)servingasactivatorsorinhibitorsof
enzymesinvolvedinthemetabolismoflipoproteins.

Theexogenouslipoproteinpathwaystartswiththeincorporationofdietarylipidsintochylomicronsintheintestine.In
thecirculationthetriglyceridescarriedinchylomicronsaremetabolizedinmuscleandadiposetissuebylipoprotein
lipaseandchylomicronremnantsareformed.Thechylomicronremnantsarethentakenupbytheliver.The
endogenouslipoproteinpathwaybeginsintheliverwiththeformationofVLDL.ThetriglyceridescarriedinVLDL
aremetabolizedinmuscleandadiposetissuebylipoproteinlipaseandIDLareformed.TheIDLarefurther
metabolizedtoLDL,whicharetakenupbyviatheLDLreceptorinnumeroustissuesincludingtheliver,whichisthe
predominantsiteofuptake.ReversecholesteroltransportbeginswiththeformationofnascentHDLbytheliverand
intestine.ThesesmallHDLcanthenacquirecholesterolandphospholipidsthatareeffluxedfromcells,aprocess
mediatedbyABCA1resultingintheformationofmatureHDL.MatureHDLcanacquireadditioncholesterolfrom
cellsviaABCG1,SRB1,orpassivediffusion.TheHDLthentransportsthecholesteroltothelivereitherdirectlyby
interactingwithhepaticSRB1orindirectlybytransferringthecholesteroltoVLDLorLDL,aprocessfacilitatedby
CETP.CholesteroleffluxfrommacrophagestoHDLplaysanimportantroleinprotectingfromthedevelopmentof
atherosclerosis.

INTRODUCTION
Becauselipids,suchascholesterolandtriglycerides,areinsolubleinwatertheselipidsmustbetransportedin
associationwithproteinsinthecirculation.Largequantitiesoffattyacidsfrommealsmustbetransportedas
triglyceridestoavoidtoxicity.Theselipoproteinsplayakeyroleintheabsorptionandtransportofdietarylipidsby
thesmallintestine,inthetransportoflipidsfromthelivertoperipheraltissues,andthetransportoflipidsfrom
peripheraltissuestotheliverandintestine(reversecholesteroltransport).Asecondaryfunctionistotransporttoxic
foreignhydrophobicandamphipathiccompounds,suchasbacterialendotoxin,fromareasofinvasionandinfection
[1].

STRUCTUREOFLIPOPROTEINS
Lipoproteinsarecomplexparticlesthathaveacentralhydrophobiccoreofnonpolarlipids,primarilycholesterol
estersandtriglycerides.Thishydrophobiccoreissurroundedbyahydrophilicmembraneconsistingofphospholipids,
freecholesterol,andapolipoproteins(Figure1).Plasmalipoproteinsaredividedintosevenclassesbasedonsize,lipid
composition,andapolipoproteins(Table1andFigure2).

https://www.ncbi.nlm.nih.gov/books/NBK305896/?report=printable 1/17
5/25/2017 Introduction to Lipids and Lipoproteins - Endotext - NCBI Bookshelf

Figure1 LipoproteinStructure(figuremodifiedfromBiochemisty39:9763,2000)

Table1 LipoproteinClasses

Lipoprotein Density Size MajorLipids MajorApoproteins

(g/ml) (nm)
Chylomicrons <0.930 751200 Triglycerides ApoB48,ApoC,ApoE,ApoAI,AII,
AIV
Chylomicron 0.9301.006 3080 Triglycerides ApoB48,ApoE
Remnants Cholesterol
VLDL 0.9301.006 3080 Triglycerides ApoB100,ApoE,ApoC
IDL 1.0061.019 2535 Triglycerides ApoB100,ApoE,ApoC
Cholesterol
LDL 1.0191.063 1825 Cholesterol ApoB100
HDL 1.0631.210 512 Cholesterol ApoAI,ApoAII,ApoC,ApoE
Phospholipids
Lp(a) 1.0551.085 ~30 Cholesterol ApoB100,Apo(a)

https://www.ncbi.nlm.nih.gov/books/NBK305896/?report=printable 2/17
5/25/2017 Introduction to Lipids and Lipoproteins - Endotext - NCBI Bookshelf

Figure2 ClassesofLipoproteins(figuremodifiedfromAdvancesProteinChemistry45:303,
1994)

Chylomicrons:Thesearelargetriglyceriderichparticlesmadebytheintestine,whichareinvolvedinthetransportof
dietarytriglyceridesandcholesteroltoperipheraltissuesandliver.TheseparticlescontainapolipoproteinsAI,AII,
AIV,AV,B48,CII,CIII,andE.ApoB48isthecorestructuralproteinandeachchylomicronparticlecontains
oneApoB48molecule.Thesizeofchylomicronsvariesdependingontheamountoffatingested.Ahighfatmeal
leadstotheformationoflargechylomicronparticlesduetotheincreasedamountoftriglyceridebeingtransported
whereasinthefastingstatethechylomicronparticlesaresmallcarryingdecreasedquantitiesoftriglyceride.

Chylomicronremnants:Theremovaloftriglyceridefromchylomicronsresultsinsmallerparticlescalledchylomicron
remnants.Comparedtochylomicronstheseparticlesareenrichedincholesterolandareproatherogenic.

Verylowdensitylipoproteins(VLDL):Theseparticlesareproducedbytheliverandaretriglyceriderich.They
containapolipoproteinB100,CI,CII,CIII,andE.ApoB100isthecorestructuralproteinandeachVLDL
particlecontainsoneApoB100molecule.SimilartochylomicronsthesizeoftheVLDLparticlescanvary
dependingonthequantityoftriglyceridecarriedintheparticle.Whentriglycerideproductionintheliverisincreased,
thesecretedVLDLparticlesarelarge.

Intermediatedensitylipoproteins(IDLVLDLremnants):TheremovaloftriglyceridesfromVLDLresultsinthe
formationofIDLparticleswhichareenrichedincholesterol.TheseparticlescontainapolipoproteinB100andE.
TheseIDLparticlesareproatherogenic.

Lowdensitylipoproteins(LDL):TheseparticlesarederivedfromVLDLandIDLparticlesandtheyareevenfurther
enrichedenrichedincholesterol.LDLcarriesthemajorityofthecholesterolthatisinthecirculation.The
predominantapolipoproteinisB100andeachLDLparticlecontainsoneApoB100molecule.LDLconsistsofa
spectrumofparticlesvaryinginsizeanddensity.AnabundanceofsmalldenseLDLparticlesareseeninassociation
withhypertriglyceridemia,lowHDLlevels,obesity,type2diabetes(i.e.patientswiththemetabolicsyndrome)and
infectiousandinflammatorystates.ThesesmalldenseLDLparticlesareconsideredtobemoreproatherogenicthan
largeLDLparticlesforanumberofreasons.SmalldenseLDLparticleshaveadecreasedaffinityfortheLDL
receptorresultinginaprolongedperiodoftimeinthecirculation.Additionally,theymoreeasilyenterthearterialwall

https://www.ncbi.nlm.nih.gov/books/NBK305896/?report=printable 3/17
5/25/2017 Introduction to Lipids and Lipoproteins - Endotext - NCBI Bookshelf

andbindmoreavidlytointraarterialproteoglycans,whichtrapstheminthearterialwall.Finally,smalldenseLDL
particlesaremoresusceptibletooxidation,whichcouldresultinanenhanceduptakebymacrophages.

Highdensitylipoproteins(HDL):Theseparticlesplayanimportantroleinreversecholesteroltransportfrom
peripheraltissuestotheliver,whichisonepotentialmechanismbywhichHDLmaybeantiatherogenic.Inaddition
HDLparticleshaveantioxidant,antiinflammatory,antithrombotic,andantiapoptoticproperties,whichmayalso
contributetotheirabilitytoinhibitatherosclerosis.HDLparticlesareenrichedincholesterolandphospholipids.
ApolipoproteinsAI,AII,AIV,CI,CII,CIII,andEareassociatedwiththeseparticles.ApoAIisthecore
structuralproteinandeachHDLparticlemaycontainmultipleApoAImolecules.HDLparticlesarevery
heterogeneousandcanbeclassifiedbasedondensity,size,charge,orapolipoproteincomposition(Table2).

Table2 ClassificationofHDL

Methodofclassification TypesofHDL
Densitygradientultracentrigugation HDL2,HDL3,VeryhighdensityHDL
Nuclearmagneticresonance large,medium,andsmall
Gradientgelelectrophoresis HDL2a,2b,3a,3b,3c
2dimensionalgelelectrophoresis prebeta1and2,alpha1,2,3,4
Apolipoproteincomposition AIparticles,AI:AIIparticles,AI:Eparticles

Lipoprotein(a)(Lp(a)):Lp(a)isanLDLparticlethathasapolipoprotein(a)attachedtoApoB100viaadisulfide
bond.Thisparticleisproatherogenic.Thephysiologicfunctionofthislipoproteinisunknown.

APOLIPOPROTEINS
Apolipoproteinshavefourmajorfunctionsincluding1)servingastructuralrole,2)actingasligandsforlipoprotein
receptors,3)guidingtheformationoflipoproteins,and4)servingasactivatorsorinhibitorsofenzymesinvolvedin
themetabolismoflipoproteins(Table3).Apolipoproteinsthusplayacrucialroleinlipoproteinmetabolism.

ApolipoproteinAI:ApoAIissynthesizedintheliverandintestineandisthemajorstructuralproteinofHDL
accountingforapproximately70%ofHDLprotein.ItalsoplaysaroleintheinteractionofHDLwithATPbinding
cassetteproteinA1(ABCA1),ABCG1,andclassB,typeIscavengerreceptor(SRB1).ApoAIisanactivatorof
lecithin:cholesterolacyltransferase(LCAT).

ApolipoproteinAII:ApoAIIissynthesizedintheliverandisthesecondmostabundantproteinonHDLaccounting
forapproximately20%ofHDLprotein.

ApolipoproteinAIV:ApoAIVissynthesizedintheintestineduringfatabsorption.ApoAIVisassociatedwith
chylomicronsandhighdensitylipoproteins,butisalsofoundinthelipoproteinfreefraction.Itspreciserolein
lipoproteinmetabolismremainstobedeterminedbutstudieshavesuggestedaroleforApoAIVinregulatingfood
intake.

ApolipoproteinAV:ApoAVissynthesizedintheliverandassociateswithtriglyceriderichlipoproteins.Itisan
activatorofLPLmediatedlipolysisandtherebyplaysanimportantroleinthemetabolismoftriglyceriderich
lipoproteins.

ApolipoproteinB48:ApoB48issynthesizedintheintestineandisthemajorstructuralproteinofchylomicronsand
chylomicronremnants.ThereisasinglemoleculeofapoB48perchylomicronparticle.Thereisasingle
apolipoproteinBgenethatisexpressedinboththeliverandintestine.Theintestineexpressesaproteinthatis
approximatelythesizeoftheliverduetomRNAediting.Theapobec1editingcomplexisexpressedinthe
intestineandeditsaspecificcytidinetoauracilintheapoBmRNAintheintestinecreatingastopcodonthatresults
inthecessationofproteintranslationandashorterApoB(ApoB48).NotablyApoB48isnotrecognizedbythe
LDLreceptor.

ApolipoproteinB100:ApoB100issynthesizedintheliverandisthemajorstructuralcomponentofVLDL,IDL,
andLDL.ThereisasinglemoleculeofApoB100perVLDL,IDL,andLDLparticle.ApoB100isaligandforthe
LDLreceptorandthereforeplaysanimportantroleintheclearanceoflipoproteinparticles.

https://www.ncbi.nlm.nih.gov/books/NBK305896/?report=printable 4/17
5/25/2017 Introduction to Lipids and Lipoproteins - Endotext - NCBI Bookshelf

ApolipoproteinC:TheCapolipoproteinsaresynthesizedprimarilyintheliverandfreelyexchangebetween
lipoproteinparticlesandthereforearefoundinassociationwithchylomicrons,VLDL,andHDL.

ApoCIIisacofactorforlipoproteinlipase(LPL)andthusstimulatestriglyceridehydrolysis.Lossoffunction
mutationsinApoCIIresultinmarkedhypertriglyceridemiaduetoafailuretometabolizetriglyceriderich
lipoproteins.

ApoCIIIisaninhibitorofLPL.Additionally,ApoCIIIinhibitstheinteractionoftriglyceriderichlipoproteinswith
theirreceptors.RecentstudieshaveshownthatlossoffunctionmutationsinApoCIIIleadtodecreasesinserum
triglyceridelevelsandareducedriskofcardiovasculardisease.Interestingly,inhibitionofApoCIIIexpression
resultsinadecreaseinserumtriglyceridelevelseveninpatientsdeficientinlipoproteinlipaseindicatingthatthe
abilityofApoCIIItomodulateserumtriglyceridelevelsisnotdependentsolelyonregulatinglipoproteinlipase
activity.

ApolipoproteinE:ApolipoproteinEissynthesizedinmanytissuesbuttheliverandintestinearetheprimarysource
ofcirculatingApoE.ApoEexchangesbetweenlipoproteinparticlesandisassociatedwithchylomicrons,
chylomicronremnants,VLDL,IDL,andasubgroupofHDLparticles.Therearethreecommongeneticvariantsof
ApoE(ApoE2,E3,andE4).ApoE2differsfromthemostcommonisoform,ApoE3,byasingleaminoacid
substitutionwherecysteinesubstitutesforarginineatresidue158.ApoE4differsfromApoE3atresidue112,where
argininesubstitutesforcysteine.ApoE3andE4areligandsfortheLDLreceptorwhileApoE2ispoorlyrecognized
bytheLDLreceptor.PatientswhoarehomozygousforApoE2candevelopfamilialdysbetalipoproteinemia.ApoE4
isassociatedwithanincreasedriskofAlzheimersdiseaseandanincreasedriskofatherosclerosis.

Apolipoprotein(a):Apo(a)issynthesizedintheliver.Thisproteinisahomologofplasminogenanditsmolecular
weightvariesfrom300,000to800,000.ItisattachedtoApoB100viaadisulfidebond.HighlevelsofApo(a)are
associatedwithanincreasedriskofatherosclerosis.Apo(a)isaninhibitoroffibrinolysisandcanalsoenhancethe
uptakeoflipoproteinsbymacrophages,bothofwhichcouldincreasetheriskofatherosclerosis.Thephysiologic
functionofApo(a)isunknown.Interestinglythisapolipoproteinisfoundinprimatesbutnotinotherspecies.

Table3 Apolipoproteins

Apolipoprotein MW Primary LipoproteinAssociation Function

Source
ApoAI 28,000 Liver, HDL,chylomicrons StructuralproteinforHDL,Activates
Intestine LCAT
ApoAII 17,000 Liver HDL,chylomicrons StructuralproteinforHDL,Activates
hepaticlipase
ApoAIV 45,000 Intestine HDL,chylomicrons Unknown
ApoAV 39,000 Liver VLDL,chylomicrons,HDL PromotesLPLmediatedTGlipolysis
ApoB48 241,000 Intestine Chylomicrons Structuralproteinforchylomicrons
ApoB100 512,000 Liver VLDL,IDL,LDL,Lp(a) Structuralprotein,LigandforLDL
receptor
ApoCI 6,600 Liver Chylomicrons,VLDL, ActivatesLCAT
HDL
ApoCII 8,800 Liver Chylomicrons,VLDL, CofactorforLPL
HDL
ApoCII 8,800 Liver Chylomicrons,VLDL, InhibitsLPLanduptakeoflipoproteins
HDL
ApoE 34,000 Liver Chylomicronremnants, LigandforLDLreceptor
IDL,HDL
Apo(a) 250,000 Liver Lp(a) Inhibitsplasminogenactivation
800,00

LIPOPROTEINRECEPTORSANDLIPIDTRANSPORTERS
https://www.ncbi.nlm.nih.gov/books/NBK305896/?report=printable 5/17
5/25/2017 Introduction to Lipids and Lipoproteins - Endotext - NCBI Bookshelf

LIPOPROTEINRECEPTORSANDLIPIDTRANSPORTERS
Thereareanumberofreceptorsandtransportersthatplayacrucialroleinlipoproteinmetabolism.

LDLreceptor[2]:TheLDLreceptorispresentintheliverandmostothertissues.ItrecognizesApoB100andApoE
andhencemediatestheuptakeofLDL,chylomicronremnants,andIDL,whichoccursviaendocytosis(Figure3).
Afterinternalizationthelipoproteinparticleisdegradedinlysosomesandthecholesterolisreleased.Thedeliveryof
cholesteroltothecelldecreasestheactivityofHMGCoAreductase,akeyenzymeinthebiosynthesisofcholesterol,
andtheexpressionofLDLreceptors.LDLreceptorsintheliverplayamajorroleindeterminingplasmaLDLlevels
(alownumberofreceptorsisassociatedwithhighplasmaLDLlevelswhileahighnumberofhepaticLDLreceptors
isassociatedwithlowplasmaLDLlevels).ThenumberofLDLreceptorsisregulatedbythecholesterolcontentof
thecell[3].WhencellularcholesterollevelsaredecreasedthetranscriptionfactorSREBPistransportedfromthe
endoplasmicreticulumtothegolgiwhereproteasescleaveandactivateSREBP,whichthenmigratestothenucleus
andstimulatestheexpressionofLDLreceptors(Figure4).Conversely,whencellularcholesterollevelsarehigh
SREBPremainsintheendoplasmicreticuluminaninactiveformandtheexpressionofLDLreceptorsislow.

Figure3 LDLReceptorPathway(figuremodifiedfromAnnualReviewofBiochemistry46:897,
1977)

https://www.ncbi.nlm.nih.gov/books/NBK305896/?report=printable 6/17
5/25/2017 Introduction to Lipids and Lipoproteins - Endotext - NCBI Bookshelf

Figure4 SREBPPathway(figuremodifiedfromJournalofLipidResearch50:SuppS15,2009)

LDLreceptorrelatedprotein(LRP):LRPisamemberoftheLDLreceptorfamily.Itisexpressedinmultipletissues
includingtheliver.LRPrecognizesApoEandmediatestheuptakeofchylomicronremnantsandIDL.

ClassBscavengerreceptorB1(SRB1):SRB1isexpressedintheliver,adrenalglands,ovaries,testes,macrophages,
andothercells.IntheliverandsteroidproducingcellsitmediatestheselectiveuptakeofcholesterolestersfromHDL
particles.InmacrophagesandothercellsitfacilitatestheeffluxofcholesterolfromthecelltoHDLparticles.

ATPbindingcassettetransporterA1(ABCA1):ABCA1isexpressedinmanycellsincludinghepatocytes,
enterocytes,andmacrophages.Itmediatesthetransportofcholesterolandphospholipidsfromthecelltolipidpoor
HDLparticles(prebetaHDL).

ATPbindingcassettetransporterG1(ABCG1):ABCG1isexpressedinmanydifferentcelltypesandmediatesthe
effluxofcholesterolfromthecelltoHDLparticles.

ATPbindingcassettetransporterG5andG8(ABCG5/ABCG8):ABCG5andABCG8areexpressedintheliverand
intestineandformaheterodimer.Intheintestinethesetransportersmediatethemovementofplantsterolsand
cholesterolfrominsidetheenterocyteintotheintestinallumentherebydecreasingtheirabsorption.Intheliverthese
transportersplayaroleinthemovementofcholesterolandplantsterolsintothebile.

NiemannPickC1like1(NPC1L1):NPC1L1isexpressedintheintestineandmediatestheuptakeofcholesteroland
plantsterolsfromtheintestinallumenintotheenterocyte.

ENZYMESANDTRANSFERPROTEINSINVOLVEDINLIPOPROTEINMETABOLISM
Thereareanumberofenzymesandtransferproteinsthatplayakeyroleinlipoproteinmetabolism.

Lipoproteinlipase(LPL):LPLissynthesizedinmuscle,heart,andadiposetissue,thensecretedandattachedtothe
endotheliumoftheadjacentbloodcapillaries.Thisenzymehydrolyzesthetriglyceridescarriedinchylomicronsand
VLDLtofattyacids,whichcanbetakenupbycells.Thecatabolismoftriglyceridesresultsintheconversionof
chylomicronsintochylomicronremnantsandVLDLintoIDL.ThisenzymerequiresApoCIIasacofactor.ApoAV
alsoplaysakeyroleintheactivationofthisenzyme.IncontrastApoCIIIandApoAIIinhibittheactivityofLPL.

https://www.ncbi.nlm.nih.gov/books/NBK305896/?report=printable 7/17
5/25/2017 Introduction to Lipids and Lipoproteins - Endotext - NCBI Bookshelf

InsulinstimulatesLPLexpressionandLPLactivityisreducedinpatientswithpoorlycontrolleddiabetes,whichcan
impairthemetabolismoftriglyceriderichlipoproteinsleadingtohypertriglyceridemia.

Hepaticlipase:Hepaticlipaseislocalizedtothesinusoidalsurfaceoflivercells.Itmediatesthehydrolysisof
triglyceridesandphospholipidsinIDLandLDLleadingtosmallerparticles(IDLisconvertedtoLDLLDLis
convertedfromlargeLDLtosmallLDL).ItalsomediatesthehydrolysisoftriglyceridesandphospholipidsinHDL
resultinginsmallerHDLparticles.

Endothelialcelllipase:ThislipaseplaysamajorroleinhydrolyzingthephospholipidsinHDL.

Lecithin:cholesterolacyltransferase(LCAT):LCATismadeintheliver.Intheplasmaitcatalyzesthesynthesisof
cholesterolestersinHDLbyfacilitatingthetransferofafattyacidfromposition2oflecithintocholesterol.This
allowsforthetransferofthecholesterolfromthesurfaceoftheHDLparticle(freecholesterol)tothecoreoftheHDL
particle(cholesterolester),whichfacilitatesthecontinueduptakeoffreecholesterolbyHDLparticlesbyreducingthe
concentrationofcholesterolonthesurfaceofHDL.

Cholesterylestertransferprotein(CETP):Thisproteinissynthesizedintheliverandintheplasmamediatesthe
transferofcholesterolestersfromHDLtoVLDL,chylomicrons,andLDLandthetransferoftriglyceridesfrom
VLDLandchylomicronstoHDL.InhibitionofCETPactivityleadstoanincreaseinHDLcholesterolandadecrease
inLDLcholesterol.

EXOGENOUSLIPOPROTEINPATHWAY(CHYLOMICRONS)

Figure5 ExogenousLipoproteinPathway

FatAbsorption
[4]

Theexogenouslipoproteinpathwaystartsintheintestine.Dietarytriglycerides(approximately100gramsperday)
arehydrolyzedtofreefattyacidsandmonoacylglycerolbyintestinallipasesandemulsifiedwithbileacids,
cholesterol,plantsterols,andfatsolublevitaminstoformmicelles.Whilethefattyacidsintheintestineare
https://www.ncbi.nlm.nih.gov/books/NBK305896/?report=printable 8/17
5/25/2017 Introduction to Lipids and Lipoproteins - Endotext - NCBI Bookshelf

overwhelminglyaccountedforbydietaryintakethecholesterolintheintestinallumenisprimarilyderivedfrombile
(approximately8001200mgofcholesterolfrombilevs.300500mgfromdiet).Plantsterolsaccountfor
approximately25%ofdietarysterolintake(approximately100150mg/day).Thecholesterol,plantsterols,fatty
acids,monoacylglycerol,andfatsolublevitaminscontainedinthemicellesarethentransportedintotheintestinal
cells.Theuptakeofcholesterolandplantsterolsfromtheintestinallumenintointestinalcellsisfacilitatedbyasterol
transporter,NiemannPickC1like1protein(NPC1L1)(Figure6).Ezetimibe,adrugwhichinhibitsintestinal
cholesterolandplantsteroluptake,bindstoNPC1L1andinhibitsitsactivity.Onceintheintestinalcellthecholesterol
andplantsterolsmaybetransportedbackintotheintestinallumen,aprocessmediatedbyABCG5andABCG8,or
convertedtosterolestersbyacylCoAcholesterolacyltransferase(ACAT),whichattachesafattyacidtothesterol.
Comparedtocholesterol,plantsterolsarepoorsubstratesforACATandthereforetheformationofplantsterolesters
doesnotoccurasefficientlyastheformationofcholesterolesters.Inhumansonly<5%ofdietaryplantsterolsare
absorbedandthevastmajorityaretransportedoutoftheintestinecell,aprocessmediatedbyABCG5andABCG8,
whichareveryefficientateffluxingplantsterolsfromtheintestinalcellintotheintestinallumen.Patientswith
sitosterolemiahavemutationsineitherABCG5orABCG8andnetabsorptionofdietaryplantsterolsisincreased(20
30%absorbedvs.<5%innormalsubjects).Thus,ABCG5andABCG8alongwithACATserveasgatekeepersand
blocktheuptakeofplantsterolsandlikelyalsoplayanimportantroleindeterminingtheefficiencyofcholesterol
absorption(humanstypicallyabsorbonlyapproximately50%ofdietarycholesterolwitharangeof2575%).

Figure6 IntestinalCellandSterolMetabolism

Thepathwayofabsorptionoffreefattyacidsisnotwellunderstoodbutitislikelythatbothpassivediffusionand
specifictransportersplayarole.ThefattyacidtransporterCD36isstronglyexpressedintheproximalthirdofthe
intestineandislocalizedtothevilli.Whilethistransporterlikelyplaysaroleinfattyaciduptakebyintestinalcells,
thistransporterisnotessentialashumansandmicedeficientinthisproteindonothavefatmalabsorption.However,
inmicedeficientinCD36thereisashiftintheabsorptionoflipidtothedistalintestine,suggestingpathwaysthatcan
compensatefortheabsenceofCD36.Fattyacidtransportprotein4(FATP4)isalsohighlyexpressedintheintestine.
However,micedeficientinFATP4donothaveabnormalitiesinfatabsorption.Thepathwaysbywhich
monoacylglycerolsareabsorbedbyintestinalcellsremaintobedefined.

FormationofChylomicrons
[4]
https://www.ncbi.nlm.nih.gov/books/NBK305896/?report=printable 9/17
5/25/2017 Introduction to Lipids and Lipoproteins - Endotext - NCBI Bookshelf

Theabsorbedfattyacidsandmonoacylglcerolsareutilizedtosynthesizetriglycerides.Thekeyenzymesrequiredfor
triglyceridesynthesisaremonoacylglycerolacyltransferase(MGAT)anddiacylglyceroltransferase(DGAT).MGAT
catalyzestheadditionofafattyacidtomonoacylglycerolwhileDGATcatalyzestheadditionofafattyacidto
diacylglycerolresultingintriglycerideformation.Asnotedabove,themajorityofthecholesterolabsorbedbythe
intestineisesterifiedtocholesterolestersbyACAT.Thetriglyceridesandcholesterolestersarepackagedinto
chylomicronsintheendoplasmicreticulum.Thesizeandcompositionofthechylomicronsformedintheintestineare
dependentontheamountoffatingestedandabsorbedbytheintestineandthetypeoffatabsorbed.Increasedfat
absorptionresultsinlargerchylomicrons.Theformationofchylomicronsintheendoplasmicreticulumrequiresthe
synthesisofApoB48bytheintestinalcell(Figure6).Microsomaltriglyceridetransferprotein(MTP)isrequiredfor
themovementoflipidfromtheendoplasmicreticulumtotheApoB48.TheabsenceofMTPresultsintheinability
toformchylomicrons(Abetalipoproteinemia).LomitipideinhibitsMTPfunctionandisusedtotreatpatientswith
homozygousFamilialHypercholesterolemia.

ChylomicronMetabolism
[5]

Chylomicronsaresecretedintothelymphanddeliveredviathethoracicducttothecirculation.Itshouldbenotedthat
thisresultsinthenewlyformedchylomicronsbeingdeliveredtothesystemiccirculationandnotdelivereddirectlyto
theliverviatheportalcirculation.Thisfacilitatesthedeliveryofthenutrientscontainedinthechylomicronsto
muscleandadiposetissue.Inmuscleandadiposetissuelipoproteinlipase(LPL)isexpressedathighlevels.LPLis
synthesizedinmuscleandadipocytesandtransportedtotheluminalsurfaceofcapillaries.Lipasematurationfactor1
playsakeyroleinthestabilizationandmovementofLPLfrommusclecellsandadipocytestothecapillary
endothelialcellsurface.Glycosylphosphatidylinisitolanchoredhighdensitylipoproteinbindingprotein1(GPIHBP1)
anchorsLPLtothecapillaryendothelium.ActivationofLPLbyApoCII,carriedonthechylomicrons,leadstothe
hydrolysisofthetriglyceridesthatarecarriedinthechylomicronsresultingintheformationoffreefattyacids,which
canbetakenupbytheadjacentmusclecellsandadipocytesforeitherenergyproductionorstorage.Fattyacid
transportproteins(FATPs)andCD36facilitatetheuptakeoffattyacidsintoadipocytesandmusclecells.Someofthe
freefattyacidsreleasedfromchylomicronsbindtoalbuminandcanbetransportedtoothertissues.ApoAValso
playsanimportantroleinactivatingLPLactivity.LossoffunctionmutationsinLPL,ApoCII,GPIHPB1,lipase
maturationfactor1,andApoAVcanresultinmarkedhypertriglyceridemia(chylomicronemia).Inaddition,thereare
proteinsthatinhibitLPLactivity.ApoCIIIinhibitsLPLactivityandlossoffunctionmutationsinthisgeneare
associatedwithincreasesinLPLactivityanddecreasesinplasmatriglyceridelevels.Similarly,angiopoetinlike
protein3and4,whichtargetLPLforinactivation,regulateLPLactivity.Lossoffunctionmutationsintheseproteins
alsoareassociatedwithdecreasesinplasmatriglyceridelevels.FinallytheexpressionofLPLbymusclecellsand
adipocytesisregulatedbyhormones(particularlyinsulin),nutritionalstatus,andinflammation.

Themetabolismofthetriglyceridescarriedinthechylomicronsresultsinamarkeddecreaseinthesizeofthese
particlesleadingtotheformationofchylomicronremnants,whichareenrichedincholesterolestersandacquireApo
E.Astheseparticlesdecreaseinsizephospholipidsandapolipoproteins(ApoAandC)onthesurfaceofthe
chylomicronsaretransferredtootherlipoproteins,mainlyHDL.ThetransferofApoCIIfromchylomicronstoHDL
decreasestheabilityofLPLtofurtherbreakdowntriglycerides.Thesechylomicronremnantsareclearedfromthe
circulationbytheliver.TheApoEonthechylomicronremnantsbindstotheLDLreceptorandotherhepatic
receptorssuchasLRPandsyndecan4andtheentireparticleistakenupbythehepatocytes.ApoEiscrucialforthis
processandmutationsinApoE(forexampletheApoE2isoform)canresultindecreasedchylomicronclearanceand
elevationsinplasmacholesterolandtriglyceridelevels(Familialdysbetalipoproteinemia).

Theexogenouslipoproteinpathwayresultsintheefficienttransferofdietaryfattyacidstomuscleandadiposetissue
forenergyutilizationandstorage.Thecholesterolisdeliveredtotheliverwhereitcanbeutilizedfortheformationof
VLDL,bileacids,orsecretedbacktotheintestineviasecretionintothebile.Innormalindividualsthispathwaycan
handlelargeamountsoffat(100gramsormoreperday)withoutresultinginmarkedincreasesinplasmatriglyceride
levels.Infact,inanormalindividual,amealcontaining75gramsoffatresultsinonlyaverymodestincreasein
postprandialtriglyceridelevels.

ENDOGENOUSLIPOPROTEINPATHWAY(VLDLANDLDL)

https://www.ncbi.nlm.nih.gov/books/NBK305896/?report=printable 10/17
5/25/2017 Introduction to Lipids and Lipoproteins - Endotext - NCBI Bookshelf

Figure7 EndogenousLipoproteinPathway

FormationofVLDL
[6]

InthelivertriglyceridesandcholesterolestersaretransferredintheendoplasmicreticulumtonewlysynthesizedApo
B100.SimilartotheintestinethistransferismediatedbyMTP.Theavailabilityoftriglyceridesistheprimary
determinantoftherateofVLDLsynthesis.IfthesupplyoftriglycerideislimitedthenewlysynthesizedApoBis
rapidlydegraded.Thus,incontrasttomanyproteinstherateofsynthesisoftheApoB100isnotthemajor
determinantoftherateofsecretion.RathertheamountoflipidavailabledetermineswhetherApoB100isdegraded
orsecreted.MTPisrequiredfortheearlyadditionoflipidtoApoB100particlesbutadditionallipidisaddedvia
pathwaysthatdonotrequireMTP.LossoffunctionmutationsineitherApoB100orMTPresultinthefailureto
produceVLDLandmarkeddecreasesinplasmatriglycerideandcholesterollevels(Familialhypobetalipoproteinemia
orabetalipoproteinemia).TheprecisepathwaybywhichthenewlysynthesizedVLDLparticlesaresecretedfromthe
hepatocyteintothecirculationisnotresolved.

VLDLMetabolism
VLDLparticlesaretransportedtoperipheraltissueswherethetriglyceridesarehydrolyzedbyLPLandfattyacidsare
released.Thisprocessisverysimilartothatdescribedaboveforchylomicronsandthereiscompetitionbetweenthe
metabolismofchylomicronsandVLDL.HighlevelsofchylomicronscaninhibittheclearanceofVLDL.The
removaloftriglyceridesfromVLDLresultsintheformationofVLDLremnants(Intermediatedensitylipoproteins
(IDL)).TheseIDLparticlesarerelativelyenrichedincholesterolestersandacquireApoEfromHDLparticles.Ina
pathwayanalogoustotheremovalofchylomicronremnantstheseIDLparticlescanberemovedfromthecirculation
bytheliverviabindingofApoEtoLDLandLRPreceptors.However,whilethevastmajorityofchylomicron
remnantsarerapidlyclearedfromthecirculationbytheliver,onlyafractionofIDLparticlesarecleared
(approximately50%butvaries).TheremainingtriglyceridesintheIDLparticlesarehydrolyzedbyhepaticlipase
leadingtoafurtherdecreaseintriglyceridecontentandtheexchangeableapolipoproteinsaretransferredfromtheIDL

https://www.ncbi.nlm.nih.gov/books/NBK305896/?report=printable 11/17
5/25/2017 Introduction to Lipids and Lipoproteins - Endotext - NCBI Bookshelf

particlestootherlipoproteinsleadingtotheformationofLDL.TheseLDLparticlespredominantlycontain
cholesterolestersandApoB100.Thus,LDLisaproductofVLDLmetabolism.

LDLMetabolism
ThelevelsofplasmaLDLaredeterminedbytherateofLDLproductionandtherateofLDLclearance,bothofwhich
areregulatedbythenumberofLDLreceptorsintheliver.TheproductionrateofLDLfromVLDLispartially
determinedbyhepaticLDLreceptoractivitywithahighLDLreceptoractivityresultinginadecreaseinLDL
productionduetoanincreaseinIDLuptake.Conversely,lowLDLreceptoractivityresultsinanincreaseinLDL
productionformationduetoadecreaseinIDLuptake.WithregardstoLDLclearance,approximately70%of
circulatingLDLisclearedviahepatocyteLDLreceptormediatedendocytosiswiththeremaindertakenupby
extrahepatictissues.AnincreaseinthenumberofhepaticLDLreceptorsthereforeincreasesLDLclearanceleadingto
adecreaseinplasmaLDLlevels.Conversely,adecreaseinhepaticLDLreceptorsslowsLDLclearanceleadingtoan
increaseinplasmaLDLlevels.ThusthelevelofhepaticLDLreceptorsplaysakeyroleinregulatingplasmaLDL
levels.

ThelevelsofLDLreceptorsintheliveraremainlyregulatedbythecholesterolcontentofthecell.Ascholesterol
levelsinthecelldecrease,inactivesterolregulatoryelementbindingproteins(SREBPs),whicharetranscription
factorsthatmediatetheexpressionofLDLreceptorsandotherkeygenesinvolvedincholesterolandfattyacid
metabolism,aretransportedfromtheendoplasmicreticulumtothegolgiwhereproteasescleavetheSREBPsinto
activetranscriptionfactors(Figure4).TheseactiveSREBPsmovetothenucleuswheretheystimulatethe
transcriptionoftheLDLreceptorandothergenes,includingHMGCoAreductase,theratelimitingenzymein
cholesterolsynthesis.IfcholesterollevelsinthecellarehighthentheSREBPsremainintheendoplasmicreticulum
inaninactiveformanddonotstimulateLDLreceptorsynthesis.Inaddition,cholesterolinthecellisoxidizedand
oxidizedsterolsactivateLXR,anuclearhormonereceptorthatisatranscriptionfactor,whichstimulatesthe
transcriptionofE3ubiquitinligasethatmediatestheubiquitinationanddegradationofthelowdensitylipoprotein
receptor(Inducibledegraderofthelowdensitylipoproteinreceptor(IDOL)).Thus,thecellcansensetheavailability
ofcholesterolandregulateLDLreceptoractivity.IfthecholesterolcontentofthecellisdecreasedLDLreceptor
activityisincreasedtoallowfortheincreaseduptakeofcholesterol.Conversely,ifthecholesterolcontentofthecell
isincreasedLDLreceptoractivityisdecreasedandtheuptakeofLDLbythecellisdiminished.Finally,theLDL
receptoristargetedfordegradationbyPCSK9,asecretedproteinthatbindstotheLDLreceptorandenhancesLDL
receptordegradationinthelysosomes.LossoffunctionmutationsinPCSK9resultinincreasedLDLreceptoractivity
anddecreasedLDLlevelswhilegainoffunctionmutationsinPCSK9leadtodecreasedLDLreceptoractivityand
elevationsinLDLlevels.

Thus,theendogenouslipoproteinpathwayfacilitatesthemovementoftriglyceridessynthesizedinthelivertomuscle
andadiposetissue.Additionally,italsoprovidesapathwayforthetransportofcholesterolfromthelivertoperipheral
tissues.

HDLMETABOLISMANDREVERSECHOLESTEROLTRANSPORT
[7,8]

https://www.ncbi.nlm.nih.gov/books/NBK305896/?report=printable 12/17
5/25/2017 Introduction to Lipids and Lipoproteins - Endotext - NCBI Bookshelf

Figure8 HDLMetabolism

HDLformation
AnumberofstepsarerequiredtogeneratematureHDLparticles.Thefirststepinvolvesthesynthesisofthemain
structuralproteincontainedinHDL,ApoAI.ApoAIissynthesizedpredominantlybytheliverandintestine.After
ApoAIissecreted,itacquirescholesterolandphospholipidsthatareeffluxedfromhepatocytesandenterocytes.The
effluxofcholesterolandphospholipidstothenewlysynthesizedApoAI(prebetaHDL)isfacilitatedbyABCA1.
PatientswithlossoffunctionmutationsinABCA1(Tangiersdisease)failtolipidatethenewlysecretedApoAI
leadingtotherapidcatabolismofApoAIandverylowHDLlevels.UsingmicewithtargetedknockoutofABCA1
ithasbeenshownthatHDLcholesterollevelsarereducedby80%inmicelackingABCA1intheliverand30%in
micelackingABCA1intheintestine.Whileinitiallycholesterolandphospholipidsareobtainedfromtheliverand
intestine,HDLalsoacquireslipidfromothertissuesandfromotherlipoproteins.Musclecells,adipocytes,andother
tissuesexpressABCA1andareabletotransfercholesterolandphospholipidstolipidpoorApoAIparticles.
Additionally,asnotedabove,newlyformedHDLcanalsoobtaincholesterolandphospholipidsfromchylomicrons
andVLDLduringtheirlipolysisbyLPL.Thisaccountsfortheobservationthatpatientswithhighplasmatriglyceride
levelsduetodecreasedclearancefrequentlyhavelowHDLcholesterollevels.Additionally,phospholipidtransfer
protein(PLTP)facilitatesthemovementofphospholipidsbetweenlipoproteinsmicelackingPLTPhaveamarked
reductioninHDLcholesterolandApoAIlevels.Finally,thelipolysisoftriglyceriderichlipoproteinsalsoresultsin
thetransferofapolipoproteinsfromtheseparticlestoHDL.

HDLCholesterolEsterification
AsnotedearlierthecholesterolinthecoreofHDLisesterified(cholesterolesters).Thecholesterolthatiseffluxed
fromcellstoHDLisfreecholesterolandislocalizedtothesurfaceofHDLparticles.Inordertoformmaturelarge
sphericalHDLparticleswithacoreofcholesterolestersthefreecholesteroltransferredfromcellstothesurfaceof
HDLparticlesmustbeesterified.LCAT,anHDLassociatedenzymecatalyzesthetransferofafattyacidfrom
phospholipidstofreecholesterolresultingintheformationofcholesterolesters.Thecholesterolesterformedisthen
abletomovefromthesurfaceoftheHDLparticletothecore.ApoAIisanactivatorofLCATandfacilitatesthis
https://www.ncbi.nlm.nih.gov/books/NBK305896/?report=printable 13/17
5/25/2017 Introduction to Lipids and Lipoproteins - Endotext - NCBI Bookshelf

esterificationprocess.LCATactivityisrequiredfortheformationoflargeHDLparticles.LCATdeficiencyinhumans
resultsindecreasedHDLcholesterolandApoAIlevelsandahigherpercentageofsmallHDLparticles.

HDLMetabolism
LipasesandtransferproteinsplayanimportantroleindeterminingthesizeandcompositionofHDLparticles.The
cholesterolestercarriedinthecoreofHDLparticlesmaybetransferredtoApoBcontainingparticlesinexchangefor
triglyceride.ThistransferismediatedbyCETPandresultsinHDLenrichedintriglycerideswhichmaythenbe
metabolizedbylipases.HumansdeficientinCETPactivityhaveveryhighHDLcholesterollevelsandlargeHDL
particles.CETPalsoimpactsLDLcholesterollevelsandtheabsenceofCETPresultsinadecreaseinLDL
cholesterol.MicedonothaveCETPandhaverelativelyhighHDLcholesterollevelsandlowLDLcholesterollevels.
HepaticlipasehydrolyzesbothtriglyceridesandphospholipidsinHDL.ThetriglyceridesthataretransferredtoHDL
byCETPactivityarecatabolizedbyhepaticlipaseresultingintheformationofsmallHDLparticles,thereleaseof
ApoAI,andincreasedApoAIdegradation.Geneticdeficiencyofhepaticlipaseresultsinamodestelevationin
HDLcholesterollevelsandlargerHDLparticles.Hepaticlipaseactivityisincreasedininsulinresistantstatesandthis
isassociatedwithreducedHDLcholesterollevels.Endothelialcelllipaseisaphospholipasethathydrolyzesthe
phospholipidscarriedinHDLparticles.InmiceincreasedendotheliallipaseactivityresultsindecreasedHDL
cholesterollevelswhiledecreasedendotheliallipaseactivityincreasesHDLcholesterollevels.

ThecholesterolcarriedonHDLisprimarilydeliveredtotheliver.TheuptakeofHDLcholesterolbytheliveris
mediatedbySRBI,whichpromotestheselectiveuptakeofHDLcholesterol.TheHDLparticlebindstoSRBIand
thecholesterolinHDListransportedintotheliverwithoutinternalizationoftheHDLparticle.Asmallercholesterol
depletedHDLparticleisformed,whichisthenreleasedbackintothecirculation.InSRBIdeficientmicethereisa
markedincreaseinHDLcholesterollevels.InterestinglytheriskofatherosclerosisisincreasedintheseSRBI
deficientdespiteanincreaseinHDLcholesterollevels.Notably,whileHDLcholesterollevelsareincreasedinSRB1
deficientmicethereversecholesteroltransportpathwayisactuallyreduced.Whileinmicethephysiological
importanceofthehepaticSRBIpathwayisclear,theroleinhumansisuncertain.Inhumanspolymorphismsinthe
SRBIgeneinfluenceHDLcholesterollevelsbuttheeffectonatherosclerosisisminimal.Inmicethemovementof
cholesterolfromperipheraltissuestotheliverisdependentsolelyonSRBIwhileinhumansCETPcanfacilitatethe
transportofcholesterolfromHDLtoApoBcontaininglipoproteins,whichservesasanalternativepathwayforthe
transportcholesteroltotheliver.

ApoAIismetabolizedindependentlyofHDLcholesterol.MostoftheApoAIiscatabolizedbythekidneyswiththe
remaindercatabolizedbytheliver.LipidfreeorlipidpoorApoAIisfilteredbythekidneysandthentakenupbythe
renaltubules.ThesizeoftheApoAIparticledetermineswhetheritcanbefilteredbythekidneysandhencethe
degreeoflipidationofApoAIdeterminestherateofcatabolism.Conditionsordiseasestates(forexampleTangiers
disease,whichisduetoamutationinABCA1orLCATdeficiency)thatresultinlipidpoorHDLleadtothe
acceleratedcatabolismofApoAIbythekidney.ApoAIbindstocubilin,whichinconjunctionwithmegalin,a
memberoftheLDLreceptorgenefamily,leadstotheuptakeanddegradationoffilteredApoAIbyrenaltubular
cells.WhiletheliverisalsoinvolvedinthecatabolismofApoAI,themechanismsarepoorlyunderstood.HDL
particlesmaycontainApoEanditisthereforepossiblethatApoEcontainingHDLparticlesaretakenupviathe
LDLreceptorandotherApoEreceptorsintheliveranddegraded.

ReverseCholesterolTransport
[9]

Peripheralcellsaccumulatecholesterolthroughtheuptakeofcirculatinglipoproteinsanddenovocholesterol
synthesis.Mostcellsdonothaveamechanismforcatabolizingcholesterol.Cellsthatsynthesizesteroidhormones
canconvertcholesteroltoglucocorticoids,estrogen,testosterone,etc.Intestinalcells,sebocytes,andkeratinocytescan
secretecholesterolintotheintestinallumenorontotheskinsurfacetherebyeliminatingcholesterol.However,in
orderformostcellstodecreasetheircholesterolcontentreversecholesteroltransportisrequired.Fromaclinicalpoint
ofview,theabilityofmacrophagestoefficientlyeffluxcholesterolintothereversecholesteroltransportpathwaymay
playanimportantroleinthepreventionofatherosclerosis.

AsnotedearlierABCA1playsanimportantroleintheeffluxofcholesteroltolipidpoorprebetaApoAIparticles
(Figure9).ABCG1playsanimportantroleintheeffluxofcholesterolfromcellstomatureHDLparticles.Insome
studies,SRB1alsoplaysaroleintheeffluxofcholesteroltomatureHDLparticles.Additionally,passivediffusionof
https://www.ncbi.nlm.nih.gov/books/NBK305896/?report=printable 14/17
5/25/2017 Introduction to Lipids and Lipoproteins - Endotext - NCBI Bookshelf

cholesterolfromtheplasmamembranetoHDLmayalsocontributetocholesterolefflux.ThelevelsofbothABCA1
andABCG1areincreasedbyLXRactivation.LXRisanuclearhormonetranscriptionfactorthatisactivatedby
oxysterols.Asthecholesterollevelsinacellincreasetheformationofoxysterolsincreasesleadingtotheactivationof
LXRresultinginanincreaseinABCA1andABCG1expression,whichwillresultintheenhancedeffluxof
cholesterolfromthecelltoHDL.Additionally,ABCA1andABCG1mRNAsaretargetedfordegradationbymiR33,
amicroRNAthatisembeddedwithintheSREBP2gene.Anincreaseincellularcholesteroldecreasestheexpression
ofSREBP2leadingtoadecreaseinmiR33resultinginenhancedLXRexpression.Thus,thedecreaseinSREBP2
transcriptionwillleadtoadecreaseinLDLreceptoractivityandareductionincholesteroluptake,while
simultaneously,adecreaseinmiR33willleadtoanincreaseinLXRactivitystimulatingtheexpressionofABCA1
andABCG1resultingindecreasedcholesterolefflux.Converselyadecreaseincellularcholesterollevelswill
increaseSREBP2expressionresultinginanincreaseinLDLreceptoractivityandanincreaseinmiR33,whichwill
resultinanincreaseinLXRactivity,increasedexpressionofABCA1andABCG1,andenhancedcholesterolefflux.
TogetherchangesincholesteroluptakemediatedbytheLDLreceptorandcholesteroleffluxmediatedbyABCA1and
ABCG1willmaintaincellularcholesterolhomeostasis.

Figure9
CholesterolEffluxfromMacrophages(modifiedfromJ.ClinicalInvestigation116:3090,2006)

OncecholesterolistransferredfromcellstoHDLtherearetwopathwaysforthecholesteroltobetakenupbythe
liver.Asdiscussedearlier,HDLcaninteractwithhepaticSRBIreceptorsresultingintheselectiveuptakeof
cholesterolfromHDLparticles.Alternatively,CETPcantransfercholesterolfromHDLparticlestoApoBcontaining
particleswiththesubsequentuptakeofApoBcontaininglipoproteinsbytheliver.Afterthedeliveryofcholesterolto
theliverthereareanumberofpathwaysbywhichthecholesterolcanbeeliminated.Cholesterolcanbeconvertedto
bileacidsandsecretedinthebile.Alternatively,cholesterolcanbedirectlysecretedintothebile.ABCG5and
ABCG8promotethetransportofcholesterolintothebileandtheexpressionofthesegenesisenhancedbyLXR
activation.ThusanincreaseinhepaticcholesterollevelsleadingtoincreasedoxysterolproductionwillactivateLXR
resultingintheincreasedexpressionofABCG5andABCG8facilitatingthesecretionofcholesterolinthebile.

Evidencesuggeststhatreversecholesteroltransportplaysanimportantroleinprotectingfromthedevelopmentof
atherosclerosis.ItshouldbenotedthatHDLcholesterollevelsmaynotbeindicativeoftherateofreversecholesterol
https://www.ncbi.nlm.nih.gov/books/NBK305896/?report=printable 15/17
5/25/2017 Introduction to Lipids and Lipoproteins - Endotext - NCBI Bookshelf

transport.AsdescribedabovereversecholesteroltransportinvolvesanumberofstepsandthelevelofHDL
cholesterolmaynotaccuratelyreflectthesesteps.Forexample,studieshaveshownthattheabilityofHDLto
promotecholesteroleffluxfrommacrophagescanvary.Thus,thesamelevelofHDLcholesterolmaynothave
equivalentabilitiestomediatetheinitialstepofreversecholesteroltransport.

LIPOPROTEIN
(a)[10]

Figure10 Lp(a)

Lp(a)consistsofanLDLmoleculeandauniqueapolipoprotein(a),whichisattachedtotheApoB100oftheLDL
viaasingledisulfidebound.Lp(a)containApo(a)andApoB100ina1:1molarratio.SimilartoApoB100,apo(a)
isalsomadebyhepatocytes.Apo(a)containsmultiplekringlemotifsthataresimilartothekringlerepeatsin
plasminogen.Thenumberofkringlerepeatscanvaryandthusthemolecularweightofapo(a)canrangefrom
250,000to800,000.ThelevelsofLp(a)inplasmacanvarymorethana1000foldrangingfromundetectableto
greaterthan100mg/dl.Lp(a)levelsprimarilyreflectLp(a)productionrates,whichareprimarilygenetically
regulated.IndividualswithhighmolecularweightApo(a)proteinstendtohavelowerlevelsofLp(a)while
individualswithlowmolecularweightApo(a)tendtohavehigherlevels.Itishypothesizedthattheliverisless
efficientinsecretinghighmolecularweightApo(a).ThemechanismofLp(a)clearanceisuncertainbutdoesnot
appeartoinvolveLDLreceptors.TherapiesthataccelerateLDLclearanceandlowerLDLlevelsdonotlowerLp(a)
levels(forexamplestatintherapy).ThekidneyappearstoplayanimportantroleinLp(a)clearanceaskidneydisease
isassociatedwithdelayedclearanceandelevationsinLp(a)levels.

REFERENCES

1.Feingold,K.R.andC.Grunfeld,Lipids:akeyplayerinthebattlebetweenthehostandmicroorganisms.JLipid
Res,2012.53(12):p.24879.

2.Goldstein,J.L.andM.S.Brown,TheLDLreceptor.ArteriosclerThrombVascBiol,2009.29(4):p.4318.

https://www.ncbi.nlm.nih.gov/books/NBK305896/?report=printable 16/17
5/25/2017 Introduction to Lipids and Lipoproteins - Endotext - NCBI Bookshelf

3.Goldstein,J.L.,R.A.DeBoseBoyd,andM.S.Brown,Proteinsensorsformembranesterols.Cell,2006.124(1):
p.3546.

4.Abumrad,N.A.andN.O.Davidson,Roleofthegutinlipidhomeostasis.PhysiolRev,2012.92(3):p.106185.

5.DallingaThie,G.M.,etal.,Themetabolismoftriglyceriderichlipoproteinsrevisited:newplayers,newinsight.
Atherosclerosis,2010.211(1):p.18.

6.Tiwari,S.andS.A.Siddiqi,IntracellulartraffickingandsecretionofVLDL.ArteriosclerThrombVascBiol,
2012.32(5):p.107986.

7.Rosenson,R.S.,etal.,Cholesteroleffluxandatheroprotection:advancingtheconceptofreversecholesterol
transport.Circulation,2012.125(15):p.190519.

8.Rye,K.A.andP.J.Barter,CardioprotectivefunctionsofHDLs.JLipidRes,2014.55(2):p.16879.

9.Zhao,Y.,T.J.VanBerkel,andM.VanEck,Relativerolesofvariouseffluxpathwaysinnetcholesterolefflux
frommacrophagefoamcellsinatheroscleroticlesions.CurrOpinLipidol,2010.21(5):p.44153.

10.HooverPlow,J.andM.Huang,Lipoprotein(a)metabolism:potentialsitesfortherapeutictargets.Metabolism,
2013.62(4):p.47991.

Copyright 2000-2017, MDText.com, Inc.

This electronic version has been made freely available under a Creative Commons (CC-BY-NC-ND) license. A copy of the license can be viewed at
http://creativecommons.org/licenses/by-nc-nd/2.0/.

Bookshelf ID: NBK305896 PMID: 26247089

https://www.ncbi.nlm.nih.gov/books/NBK305896/?report=printable 17/17