HDL Pictures2

8/3/2019 HDL Pictures2

1/47

LDL

LDL

Modified LDL Induces Macrophages to ReleaseCytokines That Stimulate Adhesion Molecule

Expression in Endothelial Cells

Nathan CF.J Clin Invest1987;79:319-326.

Endothelium

Vessel LumenMonocyte

Modified LDL

Macrophage

MCP-1

AdhesionMolecules

Cytokines

Intima


2/47


3/47


4/47

LDL

LDL

Cockerill GW et al.Arterioscler Thromb Vasc Biol1995;15:1987-1994.

Endothelium

Vessel Lumen

Monocyte

Modified LDL

Macrophage

MCP-1AdhesionMolecules

Cytokines

Inhibition of Adhesion Molecules

Intima

HDL InhibitOxidation

of LDL

HDL Inhibit Adhesion Molecule Expression

FoamCell

HDL Promote Cholesterol Efflux


5/47

Endothelium

Vessel Lumen

MCP-1

E-

Selectin

Charo IF. Curr Opin Lipidol1992;3:335-343.

Recruitment of Blood Monocytes byEndothelial Cell Adhesion Molecules

Intima

VCAM-1ICAM-1

StickingMonocyte Rolling

Transmigration


6/47

Heterogeneity of HDL

Rye KA et al.Atherosclerosis 1999;145:227-238.

Apolipoprotein Composition

A-I HDL A-I/A-IIHDL

A-II HDL

Particle Shape

Discoidal

Spherical

Lipid Composition

TG, CE, and PL

Particle Size

HDL2b HDL2a HDL3a HDL3b

HDL3c


7/47

Inhibition of Endothelial Cell

VCAM-1 Expression by HDL:Effect of HDL Composition

Inhibition unaffected by replacing apoA-I with apoA-II

Inhibition unaffected by replacing apoA-I with SAA

Inhibition unaffected by varying the cholesteryl ester

or triglyceride content of HDL

Inhibition IS affected by varying HDL phospholipids

Baker PW et al.J Lipid Res 1999;40:345-353.


8/47

Atherosclerosis is anInflammatory Disease

Ross R. N Engl J Med1999;340:115-126.

Endothelium

Vessel Lumen

IntimaFoam Cell

Monocyte

Cytokines

Growth FactorsMetalloproteinases

Cell ProliferationMatrix Degradation Macrophage


9/47

LDL

LDL

Modified LDL Stimulate Expression ofMCP-1 in Endothelial Cells

Navab M et al.J Clin Invest1991;88:2039-2046.

Endothelium

Vessel Lumen

Intima

Monocyte

Modified LDL

MCP-1


10/47

LDL

LDL

Differentiation of Monocytesinto Macrophages

Steinberg D et al. N Engl J Med1989;320:915-924.

Endothelium

Vessel Lumen

Intima

Monocyte

Modified LDL

Modified LDL PromoteDifferentiation ofMonocytes intoMacrophages

MCP-1

Macrophage


11/47

LDL

LDLEndothelium


Macrophage

MCP-1

AdhesionMolecules


Macrophages Express ReceptorsThat Take up Modified LDL

Foam Cell

Modified LDL

Taken up byMacrophage

Intima


12/47

LDL

LDLEndothelium


Macrophage

AdhesionMolecules

Macrophages and Foam Cells ExpressGrowth Factors and Proteinases

Foam Cell

IntimaModified

LDLCytokines

Cell ProliferationMatrix Degradation

Growth Factors

Metalloproteinases

Ross R. N Engl J Med1999;340:115-126.

MCP-1


13/47

Structure of HDL

Rye KA et al.Atherosclerosis 1999;145:227-238.

Hydrophobic

Coreof Triglycerideand Cholesteryl

Esters

apoA-II

SurfaceMonolayer of

Phospholipidsand Free

CholesterolapoA-I


14/47

Role of HDL Apolipoproteins inRemoving Oxidized Lipids from LDL

CETP transfers oxidized lipids fromLDL to HDL

The oxidized lipids in HDL are reducedby HDL apolipoproteins

The liver takes up reduced lipids fromHDL more rapidly than from LDL

Christison JK et al.J Lipid Res 1995;36:2017-2026;

Gardner B et al.J Biol Chem 1998;273:6088-6095.


15/47

Role of LDL in Inflammation


Endothelium

Vessel Lumen

LDL

LDL Readily Enter the Artery Wall Where They May be Modified

LDL

Intima

Modified LDL

Modified LDL are Proinflammatory

Hydrolysis of Phosphatidylcholineto Lysophosphatidylcholine

Other Chemical Modifications

Oxidation of Lipidsand ApoB

Aggregation


16/47

Structure of HDL Particle

A-IA-I

A-II

A-I, A-II = apolipoprotein A-I, A-II;

CE = cholesteryl ester; TG = triglycerides

CETG


17/47

Production of HDL by Liverand Intestine

A-I A-I

A-II

A-I, A-II = apolipoprotein A-I, A-II

Liver Intestine

HDL HDL


18/47

HDL Metabolism andReverse Cholesterol

Transport

A-I

Liver

CE

CE

CEFC

FC

LCATFC

Bile

SR-BI

A-I

ABC1 = ATP-binding cassette protein 1; A-I = apolipoprotein A-I;CE = cholesteryl ester; FC = free cholesterol;LCAT = lecithin:cholesterol acyltransferase;

SR-BI = scavenger receptor class BI

ABC1

MacrophageMature

HDL

NascentHDL


19/47

Role of CETP in HDL Metabolism

A-I

Liver

CE

CEFCF

C

LCATFC

Bile

SR-BI

A-I

ABC1

Macrophage

CE B

CETP = cholesteryl ester transfer proteinLDL = low-density lipoproteinLDLR = low-density lipoprotein receptor

VLDL = very-low-density lipoprotein

LDLR

VLDL/LDL

CETP

Mature

HDL Nascent HDL

CE

SRA


20/47

Role of Hepatic Lipase andLipoprotein Lipase in HDL Metabolism

CM = chylomicron; CMR = chylomicron remnant; HDL = high-density lipoprotein;HL = hepatic lipase; IDL = intermediate-density lipoprotein;

LPL = lipoprotein lipase; PL = phospholipase; TG = triglyceride

B

Kidney

Endothelium B

TG

CMR/IDL

C-II

CM/VLDL

HL

LPL

A-I

CETG

HDL2

PL

A-I

CE

HDL3

PL


21/47

Lipoprotein Classes and Inflammation

HDLLDLChylomicrons,

VLDL, andtheir catabolic

remnants

> 30 nm 20

22 nmPotentially proinflammatory

9

15 nmPotentiallyanti-

inflammatory


22/47

Structure of LDL

Murphy HC et al. Biochemistry2000;39:9763-970.

Hydrophobic Core

of Triglycerideand CholesterylEsters

apoB

SurfaceMonolayer ofPhospholipidsand FreeCholesterol


23/47


24/47


25/47


26/47


27/47


28/47


29/47


30/47


31/47


32/47


33/47


34/47


35/47


36/47


37/47


38/47

Reverse Cholesterol Transport


39/47


40/47


41/47


42/47


43/47


44/47


45/47

Normal Endothelium


46/47


47/47

Documents

HDL Pictures2