Abnormalities in Lipoproteinemia

Normal Physiology of Lipoproteins
Types of lipoproteins
Abnormalities related to lipoproteins

1. Abnormalitiesin Lipoproteinemia
Mr. Jaineel Dharod
Dept. of Pharmacology

2. Index
Introduction
Definition
Ranges
Structure
Classification
Functions
Abnormalities

3. Lipoprotein:
➢Lipidsabsorbedfromthedietandsynthesizedbytheliverand
adiposetissuemustbetransportedbetweenvariouscellsandorgans
forutilizationandstorage.
➢Lipidsareinsolubleinwater,theproblemoftransportationinthe
aqueousplasmaissolvedbyassociatingnonpolarlipids
(triacylglycerol'sandcholesterylesters)withamphipathiclipids
(phospholipidsandcholesterol)andproteinstomakewater-
misciblelipoproteins.

4. Definition:
Alipoproteinisabiochemicalassemblythatcontainsbothproteins
andlipids,boundtotheproteins,whichallowfatstomovethrough
thewaterinsideandoutsidecells.
Theproteinsservetoemulsifythelipidmolecules.
Manyenzymes,transporters,structuralproteins,antigens,andtoxins
arelipoproteins.

5. Ranges:

6. Structure
Lipoproteinsconsistofanonpolarcoreandasinglesurfacelayerof
amphipathiclipids
Thenonpolarlipidcoreconsistsofmainlytriacylglycerolandcholesteryl
esterandissurroundedbyasinglesurfacelayerofamphipathic
phospholipidandcholesterolmolecules
Theseareorientedsothattheirpolargroupsfaceoutwardtotheaqueous
medium
Theproteinmoietyofalipoproteinisknownasanapolipoproteinor
apoprotein.

8. Classification
Lipoproteinscanbeclassifiedinthreeways-
1)Basedondensity-
TheyareseparatedbyUltracentrifugation.
Dependinguponthefloatationconstant(Sf),Fivemajorgroupsof
lipoproteinshavebeenidentifiedthatareimportantphysiologically
andinclinicaldiagnosis.
✓Chylomicrons,
✓VLDL
✓IDL
✓LDL
✓HDL

9. (i)Chylomicrons,
-derivedfromintestinalabsorptionoftriacylglycerolandotherlipids;
-Density<0.95while
-meandiameter100-500nm
(ii)Verylowdensitylipoproteins(VLDL),
-derivedfromtheliverfortheexportoftriacylglycerol;
-density0.95-1.006
-meandiameter30-80nm.
(iii)Intermediatedensitylipoproteins(IDL)
-derivedfromthecatabolismofVLDL,
-density1.006-1.019
-mean25-50nm.

10. iv)Low-densitylipoproteins(LDL),
-representingafinalstageinthecatabolismofVLDL;
-density1.019-1.063
-meandiameter18-28nm
(iv)High-densitylipoproteins(HDL),
-involvedincholesteroltransportandalsoinVLDLandchylomicron
metabolism.
-Density1.063-1.121
-meandiameter5-15nm.

12. 2)Basedonelectrophoreticmobilities
➢Lipoproteinsmaybeseparatedaccordingtotheirelectrophoretic
propertiesinto-preβ,β,andbroadbetalipoproteins.
➢Themobilityofalipoproteinismainlydependentuponprotein
content.
➢Thosewithhigherproteincontentwillmovefastertowardsthe
anodeandthosewithminimumproteincontentwillhave
minimummobility.

13. ▪HDLare-α,VLDLpre-β,LDL-β,andIDLarebroadbeta
lipoproteins.
▪Freefattyacidandalbumincomplexalthoughnotalipoproteinis
animportantlipidfractioninserumandisthefastestmoving
fraction.
▪Chylomicronsremainattheoriginsincetheyhavemorelipid
content.
▪VLDLswithlessproteincontentthanLDLmovefasterthan
LDL,thisisduetonatureofapoproteinpresent.

14. 3)BasedonnatureofApo-proteincontent
❑Oneormoreapolipoproteins(proteinsorpolypeptides)arepresent
ineachlipoprotein.
❑ThemajorapolipoproteinsofHDL(α-lipoprotein)aredesignatedA.
❑ThemainapolipoproteinofLDL(β-lipoprotein)isapolipoproteinB(B-
100),whichfoundalsoinVLDL.
❑ChylomicronscontainatruncatedformofapoB(B-48)thatis
synthesizedintheintestine,whileB-100issynthesizedintheliver.
❑ApoEisfoundinVLDL,HDL,Chylomicrons.

16. LDL–Low Density Lipoproteins

17. ✓They are products of VLDL and IDL metabolism, and the most
cholesterolrich of alllipoproteins.
Low density lipoprotein is sometimes called "bad cholesterol“
LDL are the principal cholesterol and fat transporter in human
blood thatcarries cholesterol from the liver to the body tissues
andcells.
Function of LDLs:

18. Despitecholesterol'snegativereputation,it'sneverthelessan
importantbiomoleculethatservesanumberofvitalpurposesin
thebody.
AppropriatelevelsofLDLcholesterolcanpositivelyimpacthealthin
manyways.
Inmetabolismtheirfunctionismediatingbycellularuptakevia
receptor-mediatedendocytosisfollowedbylysosomaldegradation,
andisstronglydependentonthelipiddistribution.

19. Apartfromtheirwell-establishedroleaslipidtransporter,
LDLparticlesareintimatelyinvolvedintheprogressionof
cardiovasculardiseasessuchasatherosclerosisorstroke,whichare
amongthemostprevalentcausesofdeath.
RaisedplasmalevelsofLDLarelinkedtoanincreasedriskfordisease.

20. Metabolism of LDL
➢About40to60%ofallLDLareclearedbytheliverinaprocess
mediatedbyapoBandhepaticLDLreceptors.
➢TherestaretakenupbyeitherhepaticLDLornon-hepaticnon-
LDL(scavenger)receptors.
HepaticLDLreceptorsaredown-regulatedby:
deliveryofcholesteroltotheliverbychylomicrons,andby
increaseddietarysaturatedfat.
Theycanbeup-regulatedbydecreaseddietaryfatandcholesterol.

21. Non-hepaticscavengerreceptors
mostnotablyonmacrophages.
takeupexcessoxidizedcirculatingLDLnotprocessedbyhepatic
receptors.
MonocytesrichinoxidizedLDLmigrateintothesub-endothelial
spaceandbecomemacrophages.
ThesemacrophagesarethentakeupmoreoxidizedLDLand
formfoamcellswithinatheroscleroticplaques.

22. HDL–High Density Lipoproteins

23. HDLtypeisthesmallestofthelipoproteinparticles.
Itisthedensestbecauseitcontainsthehighestproportionofprotein
tolipids.
Itsmostabundantapolipoproteins.

24. FUNCTION OF HDL:
Highdensitylipoprotein(HDL)particlesareprotectiveparticlesthat
havefunctionsinthebody.
They:
➢Playakeyroleinprotectingagainstheartdiseaseviatheirrolein
reversecholesteroltransport,orthetransportofexcess
cholesteroloutofthebody.
➢Arealsopartoftheinnateimmunesystemduetotheirabilityto
bindanumberoftoxicsubstancesintheblood.

25. HDLissynthesizedandsecretedfrombothliverandintestine.
However,apoCandapoEaresynthesizedintheliverand
transferredfromliverHDLtointestinalHDLwhenthelatterenters
theplasma.
AmajorfunctionofHDListoactasarepositoryfortheapoCand
apoErequiredforthemetabolismofchylomicronsandVLDL.
Synthesis ofHDL

26. LCATandtheLCATactivatorapoA-I—bindtothediscoidal
particles,andthesurfacephospholipidandfreecholesterolare
convertedintocholesterylestersandlysolecithin.
Thenonpolarcholesterylestersmoveintothehydrophobicinterior
ofthebilayer,whereaslysolecithinistransferredtoplasma
albumin.
Thus,anonpolarcoreisgenerated,formingaspherical,
pseudomicellarHDLcoveredbyasurfacefilmofpolarlipids
andapolipoproteins.
Thisaidstheremovalofexcessunesterifiedcholesterolfrom
lipoproteinsandtissues.

27. Chylomicron
Chylomicron(fromtheGreekchylø,meaningjuiceormilky
fluid,andmicron,meaningsmallparticle)arelipoproteinparticles
thatconsistof:
Triglycerides(85–92%),
Phospholipids(6–12%),
Cholesterol(1–3%),
Proteins(1–2%).

28. Function ofchylomicron
✓Chylomicronstransportlipidsabsorbedfromtheintestinetoadipose,
cardiacandskeletalmuscletissue,wheretheirtriglyceridecomponentsare
hydrolyzedbytheactivityoflipoproteinlipaseandthereleasedfreefatty
acidsareabsorbedbythetissue.
✓Whenalargeportionofthetriacylglycerolcorehavebeenhydrolyzed,
chylomicronremnantsareformedandaretakenupbytheliver,hereby
transferringdietaryfatalsototheliver.
✓Ittransportsdietaryfatsandcholesterolfromintestinestotissues.

29. Metabolism ofchylomicron
Theenzymelipoproteinlipase,withapolipoprotein(apo)C-IIasaco-factor,
hydrolyzeschylomicrontriglycerideallowingthedeliveryoffreefattyacids
tomuscleandadiposetissue.
Asaresult,anewparticlecalledachylomicronremnantisformed.This
particleisenrichedincholesterylesterandfat-solublevitaminsandcontains
apoB-48andapoE.
Itisrapidlyremovedfromthecirculationbytheliver.ApoEisthemoiety
requiredforrapidhepaticremoval.
ItsactivityisinhibitedbyCapolipoproteins,especiallyapoC-I.

30. Theparticlemustfirstachieveasizethatallowsittobe"sieved"throughthe
endothelialfenestre
Here,itmay
1)beremoveddirectlybyLDLreceptors.
2)acquireadditionalapoEthatissecretedfreeintothespace,andthenbe
removeddirectlybytheLDLreceptor-relatedprotein(LRP);
3)itmaybesequesteredinthespace.Sequestrationoccursbybindingof
apoEtoheparansulfateproteoglycansand/orbindingofapoBtohepatic
lipase.

31. Very-low-density lipoprotein(VLDL)
Itisatypeoflipoproteinmadebytheliver.

32. Function ofVLDL
•VLDLtransportsendogenoustriglycerides,phospholipids,cholesterol,and
cholesterylesters.
•Itfunctionsasthebody'sinternaltransportmechanismforlipids.
•Inadditionitservesforlong-rangetransportofhydrophobicintercellular
messengers,likethemorphogen.

33. Metabolism ofVLDL
VLDLmetabolismisverysimilartoChylomicronsmetabolism.
ThemainlipidfoundinVLDLisalsotriacylglycerol,butinthiscasetriacylglycerolscome
fromexcessfattyacidsondietoranincreaseinthehepaticsynthesisoffattyacidsasa
consequenceofexcesscarbohydratesindiet.
FatscomingfromthehepatocytesuptakeofChylomicronsremnantsarealsoasourceof
triacylglycerolsforVLDL.
Additionallytotriacylglycerols,VLDLcontainsaround35%offreeandesterified
cholesterol,35%ofphospholipids,andvariousapoproteins,includingApoB-100.
VLDL,inthesamewaythanChylomicrons,acquiresinthebloodstreamApoC-IIandApoE.
ThefunctionsoftheseapoproteinsinVLDLaresimilartotheirfunctionsinChylomicrons:
ApoC-IIactivatesLipoproteinLipaseandasaconsequence,VLDLtriacylglycerolsare
hydrolyzed,sotheproportionofcholesterolincreases.

34. IDL (intermediate densitylipoprotein)
-It’sformedfromthedegradationofverylow-densitylipoproteins.
Theirsizeis,ingeneral,25to35nmindiameter,andtheycontainprimarily
arangeoftriacylglycerolsandcholesterolesters.

35. Function ofIDL
Itenablesfatsandcholesteroltomovewithinthewater-based
solutionofthebloodstream.
EachnativeIDLparticleconsistsofproteinthatencirclesvarious
fattyacids,enabling,asawater-solubleparticle,thesefatty
acidstotravelintheaqueousbloodenvironmentaspartofthefat
transportsystemwithinthebody.
Ingeneral,IDL,somewhatsimilartolow-densitylipoprotein(LDL),
transportsavarietyoftriglyceridefatsandcholesteroland,like
LDL,canalsopromotethegrowthofatheroma.

37. Abnormalities
✓Hypolipoproteinemia
✓Hyperlipoproteinemia

38. Hypolipoproteinemia

39. Hyperlipoproteinemia

40. Hyperlipoproteinemia

41. Hyperlipoproteinemia
Itisalsoknownashyperlipidaemiaorhyperlipoproteinemia
Inthiscaseitisdefinedasapresenceofraisedorabnormallevelsof
lipidsand/orlipoproteinsintheblood
Thisisabnormalityiscommoninthegeneralpopulation,andisoneofthe
mostimportantmodifiableriskfactorsforcoronaryheartdisease(CHD).
Dyslipidaemiaisgenerallycharacterizedbyincreasedfasting
concentrationsoftotalcholesterol(TC),LDLcholesterol(LDL-C),and
triglycerides(TG),inconjunctionwithdecreasedconcentrationsofHDL
cholesterol(HDL-C)

42. Ondiagnosinghyperlipoproteinemia,hyperlipidaemicstatus
shouldbeevaluatedtodeterminewhetheritisprimarylipoprotein
disorderorsecondarytoanyofavarietyofmetabolicdiseases.
Thediagnosisofprimaryhyperlipoproteinemiaismadeafter
secondarycauseshavebeenexcluded.

43. HereditaryHyperlipoproteinemia's
✓FamilialLipoproteinlipasedeficiency(TypeIHyperlipoproteinemia).
✓Characterizedbyhighlevelsofchylomicronsandtriglyceridesanda
deficiencyoflipoproteinlipase,anenzymethatacceleratesthe
breakdownoflipoproteins.
✓Diseaseonsetisusuallyininfancy.
✓Type1hasapureelevationoftriglyceridesinthechylomicronfraction.
✓Thesepeoplesometimesgetpancreatitisandabdominalpains,butthey
donotseemtohaveanincreaseinvasculardisease

44. TypeII,brokenintotwosubtypes,typeII-aandtypeII-b.
Haveelevatedcholesterol.
Somehaveelevatedtriglyceridesalso.
Thefamilial(genetic)versionsofType2oftendevelop
xanthomas,whichareyellowfattydepositsundertheskinofthe
knuckles,elbows,buttocksorheels.
Theymayalsohavesmalleryellowpatchesontheeyelids.
Bothsubtypesdisplayhighlevelsofbloodcholesterol.
PeoplewithtypeII-balsohavehighlevelsoftriglyceridesintheir
blood.Diseaseonsetisusuallyafterage20.
Type II Familialhypercholesterolemia

46. DYSBETALIPOPROTEINEMIA
▪alsocalledbroadbetadisease.
▪AccumulationofIDL,VLDLandchylomicronremnant.
▪Elevatedleveloftotalcholesterolandtriglycerides
▪ThedisordercausedbyApo-EorApo-Ereceptor.
▪Diabetes,hypothyroidismareassociatedwithtypeIII
disorders.
▪Type3appearsinonein10,000peopleandelevatesboth
triglyceridesandcholesterolwithconsequentvasculardisease,
▪Diseaseonsetisusuallyinadults.

47. Abetalipoproteinemia
✓Elevatesonlytriglyceridesanddoesnotincreasetheriskofvascular
disease
✓GeneticdefectinthesynthesisofApo-B.
✓BothchylomicronandVLDLareaffected.
✓Fatmalabsorptionoccursbecausechylomicroncannotbeformedby
intestine.
✓Diseaseonsetisusuallyduringpubertyorearlyadulthood.

48. Secondaryhyperlipoproteinemia
Diabetesmellitus,becauseitaltersthewaythebodyhandlesitsenergy
needs,alsoaffectsthewayithandlesfats.Theresultiselevatedtriglycerides
andreducedHDLcholesterol.Thiseffectisamplifiedbyobesity
Hypothyroidismsacommoncauseoflipidabnormalities.Thethyroidhormone
affectstherateofmanychemicalprocessesinthebody,includingtheclearingof
fatsfromtheblood.Theconsequenceisusuallyanelevationofcholesterol
Kidneydiseaseaffectstheblood'sproteinsandconsequentlythecomposition
ofthefatpackages.ItusuallyraisestheLDLs
Liverdisease,dependingonitsstageandseverity,canraiseorloweranyofthe
bloodfats
Alcoholraisestriglycerides
CigarettessmokinglowersHDLcholesterol,asdoesmalnutritionandobesity.

49. ➢Usuallyhighlipidlevelsareasymptomatic
➢Occasionallywhenfatlevelsarehigh,itcanbedepositedinskinand
tendonsformingbumpscalledxanthomas(eyesandAchillestendon)
➢Veryhightriglyceridelevelsmaycauselivertoenlarge
➢Highlipidsincreasetheriskofdevelopingpancreatitis,whichcauses
severeabdominalpainandissometimesfatal
➢Humancoronaryatherosclerosisisachronicinflammatorydiseasethatis
superimposedonabackgroundoflipidabnormalities.
➢Inhumans,oxidizedLDLinplasmaandwithinatheroscleroticlesionsis
stronglyassociatedwithcoronaryarterydisease,acutecoronary
syndromes,andvulnerableplaques

50. Factors
Levelsoflipoproteinsandlipids(LDL)increaseslightlywithage.
Otherfactorsassociatedwithincreaseoftheseare:
familialhistory
Obesity
diethighinsaturatedfat
Inactivity
alcoholconsumption

51. Thank You