Physicians' Academy for Cardiovascular Education

HDL mediated efflux of cholesterol from the arterial wall

Slides (presentation) - Oct. 18, 2011

Prof. John Chapman
INSERM, Hôpital de la Pitié
Paris, France

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HDL mediated efflux of cholesterol from the arterial wall: Can HDL promote removal of cholesterol from atherosclerotic lesions?
Current Model of HDL-C Metabolism: Reverse Cholesterol Transport
An appropriate model of cholesterol efflux from the atherosclerotic plaque should reflect the complex structure of the lesion itself.
What is the predominant form of cholesterol present in the vulnerable atherosclerotic plaque ?
Lipid accounts for 40% of surface area of vulnerable plaques
In what physical forms is cholesterol present within vulnerable plaques ?
Cholesterol is differentially distributed between plaque components
FC -rich microdomains are present in regions of human aortic tissue with lipid-containing foam cells
Slide 9
Incubation of human monocyte-derived macrophage cultures with AcLDL generates extracellular unesterified cholesterol-rich microdomains
Unesterified cholesterol-rich microdomains can be removed by cholesterol acceptors
Cholesterol is differentially distributed between plaque components
Zhao et al, Curr Opin Lipidol 2010
HDL-Mediated Cholesterol Efflux From Cholesterol-Rich Macrophages
Stimulation of cellular cholesterol efflux by LDR agonists in human macrophages
ABCG1 is highly expressed in human foam cells upon stimulation by LXR agonists
Cellular cholesterol efflux to HDL in human macrophages is ABCG1 independent
Stimulation of cholesterol efflux to HDL by LXR agonists requires the ABCA1 transporter in human macrophages
Cellular cholesterol efflux to HDL in human macrophages requires the CLA-1 receptor
In human macrophages
HDL: New Dimensions
Mechanisms of Cellular Cholesterol Efflux to HDL particles
Proteolytic inactivation of pre-HDL impairs ABCA1-dependent initiation of reverse cholesterol transport in the atherosclerotic plaque
Summary
What is the evidence that HDL/apoAI mediate cholesterol efflux from the plaque?
Long history of HDL infusion reducing atheroma burden
HDL Infusions
Impact of HDL on Plaque Evolution: Experimental Evidence for Plaque Regression
Reconstituted HDL (CSL111) reduced atheroma in man
Impact of Reconstituted HDL infusion on Peripheral Arterial disease
Accumulation of lipids and macrophage size in the lesions.
Impact of rHDL infusion on atherosclerotic lesions in the SFA
Can the cholesterol cargo in HDLpotentially contribute to plaque cholesterol accumulation and thence progression ?
apoE-HDL and Reverse Cholesterol Transport
ApoE- HDL
Are these observations relevant to emerging therapeutic approaches to raise HDL-C and normalise its function in dyslipidemic, high risk metabolic states ?
HDL metabolism: Impact of CETP inhibition

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