Curs4 Lipoprot Prot

7/26/2019 Curs4 Lipoprot Prot

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LipoproteinsLipoproteins



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)



Lipoprotein structure



LDLmolecule



The Players – Lipids

Triacylglycerol

Phospholipids

CholesterolCholesteryl esters



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



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.



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.



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



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.



$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



$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



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.




ApoC- activates

lipoprotein lipase which

catalyses the hydrolysis

of triacylglycerols




Apolipoproteins are

transferred bac! to "#L




$he chylomicron

remnant is ta!en up by

the apoB48%remnant

receptor in the liver



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



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-

())



2LDLetabolism

Apo C*s and apo+ and

cholesteryl ester are

ac,uired from "#L in

circulation



8atty 5cid Transport

ApoC- activates

lipoprotein lipase which

catalyses the hydrolysis

of $&



2LDLetabolism

Apolipoproteins are

transferred bac! to "#L

$he end product is a

'L#L remnant #L.



>emnant@ptaAe

$he remnant particle #L./

if it contains apo+/ can be

ta!en up by the

apo+%remanant receptor



2LDLCon!ersion to

LDL0urther action on #L by

hepatic lipase loses

additional apolipoproteins

apo+. becomes and is

converted to L#L



Surface MonolayerSurface Monolayer Phospholipids (2'!Phospholipids (2'!

"ree Cholesterol (1'!"ree Cholesterol (1'!

Protein (22!Protein (22!


$ri%lyceride ('!$ri%lyceride ('!

Cholesteryl stersCholesteryl sters(*'!(*'!

C3 >ich: LDL

Cholesterol and5therosclerosis%



LDL etabolism

$epaticLipaseCholesterylester transferprotein

L#L is removed by

apoB()) receptors

which are mainly

e1pressed in the

liver



LDL @ptaAe by Tissues

#efects in the L#L receptor leads to familial hypercholesterolemia

2 2



Corneal arcus



Tendon xanthoma



Surface MonolayerSurface Monolayer Phospholipids (2'!Phospholipids (2'!

"ree Cholesterol (+!"ree Cholesterol (+!

Protein (#'!Protein (#'!


$ri%lyceride ('!$ri%lyceride ('!

Cholesteryl stersCholesteryl sters(1)!(1)!

C3 >ich: $DL




$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



$DLaturation


"#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



$DL etabolism

5ascent "#L lipid-poor apoA-. is produced by the liver and intestine



$DL etabolism

0ree cholesterol is ac,uired from peripheral tissues



$DL etabolism

LCA$ converts free cholesterol to cholesteryl



$DL etabolism

A variety of enzymes interconvert "#L subspecies



Cholesterol

$omeostasis



$epaticCholesterol

etabolism



$epatic Cholesterol #ynthesis

>ate Limitingnlypath"ay forcholesteroldegradation

+nergetically e1pensive; prefer

to conserve what is already

made%ac,uired 6 L#L receptor

pathway



LDL Cellular etabolism

L#L are ta!en up by the L#L 7eceptor into clathrin-coated pits



L#L dissociates from the receptor; the receptor recycles to the membrane



n the lysosome/ lipids are deseterified; proteins are hydrolyzed



ncrease in free cholesterol regulates decrease cholesterol synthesis

and upta!e; increase cholesterol esterification



$epaticCholesterol

etabolism

hen cholesterol accumulates



>ole of LB> and 8B>

hen cholesterol accumulates

in cells/ cholesterol is o1idized

to create o1ysterols



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



3ndothelial Dysfunction

7oss/ 5+9:; (



8ormation of 8atty #treaA



D l f @ bl



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



Pla<ue >upture "ith Thrombus

$hrombus "ibrous cap

1 mmLipid core

.llustration courtesy of "rederic 3 Schoen M D Ph D

Curs4 Lipoprot Prot

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