Post on 02-Mar-2018
7/26/2019 Curs4 Lipoprot Prot
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LipoproteinsLipoproteins
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Lipoproteins
• particles found in plasma that transport lipids includingcholesterol
• Lipoproteins are ordinates mixtures of lipids with proteins
• lipoprotein classes• chylomicrons: take lipids from small intestine through lymph cells
• very low density lipoproteins (VLDL)
• intermediate density lipoproteins (IDL)
•
low density lipoproteins (LDL)
• high density lipoproteins (HDL)
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Lipoprotein structure
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LDLmolecule
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The Players – Lipids
Triacylglycerol
Phospholipids
CholesterolCholesteryl esters
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The apolipoproteins
• maor components of lipoproteins
• often referred to as aproteins
•
classified !y alpha!etical designation (" thru #)• the use of roman numeral suffix descri!es the order
in which the apolipoprotein emerge from achromatographic column
• responsi!le for recognition of particle !y receptors
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Apolipoprotein Structure:
Amphipathic -helices (polar along one surface of ahelix and hydrophobic along the other side) are
common structural motifs.
ne !ie" is that these -helices may foat on the
phospholipid surface of the lipoprotein.#ome domains of apolipoproteins ha!e roles ininteraction of lipoproteins with cell surace
receptors.
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Apolipoprotein A-I (apoA-I) of human$DL% in the absence of lipid% is found
consist of an N&terminal antiparallel 4-helixbundle ' a C&terminal domain that is also
α&helical.
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HDLHDLLDLLDLChylomicrons,Chylomicrons,VLDL, andVLDL, and
their catabolictheir catabolicremnantsremnants
> 30 nm> 30 nm 20–22 nm20–22 nm 9–15 nm9–15 nm
D.**+ g,mlD-.*&.*+/g,mlD-.*+/&.0 g,ml
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There is special interest in the structure andstability of apolipoprotein E.
1n addition to being a constituent of !ariouslipoproteins% e.g. 2LDL ' $DL% a variant of
apolipoprotein 3% designated apoE4% is
implicated in Alzheimer's disease and otherneurological conditions.
$a!ing the apoE4 isoform is a ma4or risactor for 5l6heimer7s disease.
8ragments of apo39 are found to generateintracellular deposits resembling theneuro!brillar" tan#les seen in 5l6heimer7s
disease.
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$hylomicron
• formed through extrusion of resynthesi%edtriglycerides from the mucosal cells into theintestinal lacteals
• flow through the thoracic ducts into thesuclavian veins
• degraded to remnants !y the action oflipoprotein lipase (LpL) which is located oncapillary endothelial cell surface
•
remnants are taken up !y liver parenchymalcells due to apo#&III and apo#&IV isoformrecognition sites
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$h"lomicron %etabolism
Long-chain fattyacids are re-
esterified into
triacylglycerols in
the gut and
transferred;chylomicrons
which contain
apoB48 are
synthesized and
secreted into the
blood via thelymphatic
circulation
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Chylomicron etabolism
5poC;s% apo3 andcholesteryl esters areac<uired from $DL in
circulation.
5po5&1 and apo5&12may be ac<uired fromeither the intestine orfrom $DL incirculation.
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Chylomicron etabolism
ApoC- activates
lipoprotein lipase which
catalyses the hydrolysis
of triacylglycerols
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Chylomicron etabolism
Apolipoproteins are
transferred bac! to "#L
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Chylomicron etabolism
$he chylomicron
remnant is ta!en up by
the apoB48%remnant
receptor in the liver
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Surface MonolayerSurface Monolayer Phospholipids (12!Phospholipids (12!
"ree Cholesterol (1#!"ree Cholesterol (1#!
Protein (#!Protein (#!
Hydrophobic CoreHydrophobic Core
$ri%lyceride (&'!$ri%lyceride (&'!Cholesteryl sters ()!Cholesteryl sters ()!
T= >ich: 2LDL
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2LDL ?iogenesis
icrosomal T= transferprotein(TP)
8acilitates thetranslocation%folding of apo?
and addition oflipids to lipidbinding domains
$& and
cholesterol are
synthesized in
the liver as
'L#L whichcontains apoB-
())
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2LDLetabolism
Apo C*s and apo+ and
cholesteryl ester are
ac,uired from "#L in
circulation
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8atty 5cid Transport
ApoC- activates
lipoprotein lipase which
catalyses the hydrolysis
of $&
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2LDLetabolism
Apolipoproteins are
transferred bac! to "#L
$he end product is a
'L#L remnant #L.
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>emnant@ptaAe
$he remnant particle #L./
if it contains apo+/ can be
ta!en up by the
apo+%remanant receptor
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2LDLCon!ersion to
LDL0urther action on #L by
hepatic lipase loses
additional apolipoproteins
apo+. becomes and is
converted to L#L
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Surface MonolayerSurface Monolayer Phospholipids (2'!Phospholipids (2'!
"ree Cholesterol (1'!"ree Cholesterol (1'!
Protein (22!Protein (22!
Hydrophobic CoreHydrophobic Core
$ri%lyceride ('!$ri%lyceride ('!
Cholesteryl stersCholesteryl sters(*'!(*'!
C3 >ich: LDL
Cholesterol and5therosclerosis%
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LDL etabolism
$epaticLipaseCholesterylester transferprotein
L#L is removed by
apoB()) receptors
which are mainly
e1pressed in the
liver
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LDL @ptaAe by Tissues
#efects in the L#L receptor leads to familial hypercholesterolemia
2 2
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Corneal arcus
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Tendon xanthoma
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Tendon xanthoma
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Surface MonolayerSurface Monolayer Phospholipids (2'!Phospholipids (2'!
"ree Cholesterol (+!"ree Cholesterol (+!
Protein (#'!Protein (#'!
Hydrophobic CoreHydrophobic Core
$ri%lyceride ('!$ri%lyceride ('!
Cholesteryl stersCholesteryl sters(1)!(1)!
C3 >ich: $DL
Cholesterol and5therosclerosis%
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$DL #ubpopulations
polipoprotein Compositionpolipoprotein Composition
-. HDL-. HDL -./-.. HDL-./-.. HDL -.. HDL-.. HDL
Particle ShapeParticle Shape
DiscoidalDiscoidal
SphericalSpherical
Lipid CompositionLipid Composition
$0, C, and PL$0, C, and PL
Particle SieParticle Sie
HDLHDL2b2b HDLHDL2a2a HDLHDL*a*a HDLHDL*b*b HDLHDL*c*c
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$DLaturation
Cholesterol and5therosclerosis%
"#L is secreted in adiscoidal form from the liver
and gut3
As it ac,uires cholesterol
from tissues in the
circulation/ it matures into a
spherical form through the
action of lecithincholesterol
acyl transferase
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$DL etabolism
5ascent "#L lipid-poor apoA-. is produced by the liver and intestine
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$DL etabolism
0ree cholesterol is ac,uired from peripheral tissues
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$DL etabolism
LCA$ converts free cholesterol to cholesteryl
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$DL etabolism
A variety of enzymes interconvert "#L subspecies
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Cholesterol
$omeostasis
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$epaticCholesterol
etabolism
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$epatic Cholesterol #ynthesis
>ate Limitingnlypath"ay forcholesteroldegradation
+nergetically e1pensive; prefer
to conserve what is already
made%ac,uired 6 L#L receptor
pathway
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LDL Cellular etabolism
L#L are ta!en up by the L#L 7eceptor into clathrin-coated pits
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L#L dissociates from the receptor; the receptor recycles to the membrane
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n the lysosome/ lipids are deseterified; proteins are hydrolyzed
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ncrease in free cholesterol regulates decrease cholesterol synthesis
and upta!e; increase cholesterol esterification
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$epaticCholesterol
etabolism
hen cholesterol accumulates
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>ole of LB> and 8B>
hen cholesterol accumulates
in cells/ cholesterol is o1idized
to create o1ysterols
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Intimal Injury
Fatty Streak
Lipid-Rich
Plaque
Plaque
Disruption Thrombus Lysis Response
Fibromuscular
Occlusion
Occlusie
Thrombus
! "! #! $! %!
&'e (years)
&thero'enic Risk Factors Thrombo'enic Risk Factors
3!olution and Progression of Coronary 5therosclerosis
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3ndothelial Dysfunction
7oss/ 5+9:; (
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8ormation of 8atty #treaA
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D l f @ bl
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De!elopment of @nstable8ibrous Pla<ue
>upture or ulceration ofbrous cap rapidly leads to
thrombosis. ccurs primarily at sites of
thinning of the brous cap.
Thinning is a result ofcontinuing inEux of and
acti!ation of macrophages"hich release
metalloproteinases and other
proteolytic en6ymes. These en6ymes degrade the
matrix "hich can lead tohemorrhage and thrombus
formation
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Pla<ue >upture "ith Thrombus
$hrombus "ibrous cap
1 mmLipid core
.llustration courtesy of "rederic 3 Schoen M D Ph D