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HDL mediated efflux of cholesterol from the arterial wall: Can HDL promote removal of cholesterol from atherosclerotic lesions?
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Current Model of HDL-C Metabolism: Reverse Cholesterol Transport
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An appropriate model of cholesterol efflux from the atherosclerotic plaque should reflect the complex structure of the lesion itself.
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What is the predominant form of cholesterol present in the vulnerable atherosclerotic plaque ?
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Lipid accounts for 40% of surface area of vulnerable plaques
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In what physical forms is cholesterol present within vulnerable plaques ?
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Cholesterol is differentially distributed between plaque components
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FC -rich microdomains are present in regions of human aortic tissue with lipid-containing foam cells
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Slide 9
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Incubation of human monocyte-derived macrophage cultures with AcLDL generates extracellular unesterified cholesterol-rich microdomains
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Unesterified cholesterol-rich microdomains can be removed by cholesterol acceptors
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Cholesterol is differentially distributed between plaque components
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Zhao et al, Curr Opin Lipidol 2010
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HDL-Mediated Cholesterol Efflux From Cholesterol-Rich Macrophages
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Stimulation of cellular cholesterol efflux by LDR agonists in human macrophages
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ABCG1 is highly expressed in human foam cells upon stimulation by LXR agonists
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Cellular cholesterol efflux to HDL in human macrophages is ABCG1 independent
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Stimulation of cholesterol efflux to HDL by LXR agonists requires the ABCA1 transporter in human macrophages
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Cellular cholesterol efflux to HDL in human macrophages requires the CLA-1 receptor
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In human macrophages
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HDL: New Dimensions
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Mechanisms of Cellular Cholesterol Efflux to HDL particles
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Proteolytic inactivation of pre-HDL impairs ABCA1-dependent initiation of reverse cholesterol transport in the atherosclerotic plaque
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Summary
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What is the evidence that HDL/apoAI mediate cholesterol efflux from the plaque?
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Long history of HDL infusion reducing atheroma burden
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HDL Infusions
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Impact of HDL on Plaque Evolution: Experimental Evidence for Plaque Regression
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Reconstituted HDL (CSL111) reduced atheroma in man
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Impact of Reconstituted HDL infusion on Peripheral Arterial disease
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Accumulation of lipids and macrophage size in the lesions.
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Impact of rHDL infusion on atherosclerotic lesions in the SFA
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Can the cholesterol cargo in HDLpotentially contribute to plaque cholesterol accumulation and thence progression ?
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apoE-HDL and Reverse Cholesterol Transport
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ApoE- HDL
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Are these observations relevant to emerging therapeutic approaches to raise HDL-C and normalise its function in dyslipidemic, high risk metabolic states ?
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HDL metabolism: Impact of CETP inhibition
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Prof. John Chapman
Chapman slides (PPT 7.8MB)
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