Exchange of Apolipoprotein A-I between Lipid-associated and Lipid-free States: A POTENTIAL TARGET FOR OXIDATIVE GENERATION OF DYSFUNCTIONAL HIGH DENSITY LIPOPROTEINS* |
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Authors: | Giorgio Cavigiolio Ethan G Geier Baohai Shao Jay W Heinecke Michael N Oda |
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Institution: | From the ‡Children''s Hospital Oakland Research Institute, Oakland, California 94609 and ;the §Department of Medicine, University of Washington, Seattle, Washington 98195 |
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Abstract: | An important event in cholesterol metabolism is the efflux of cellular cholesterol by apolipoprotein A-I (apoA-I), the major protein of high density lipoproteins (HDL). Lipid-free apoA-I is the preferred substrate for ATP-binding cassette A1, which promotes cholesterol efflux from macrophage foam cells in the arterial wall. However, the vast majority of apoA-I in plasma is associated with HDL, and the mechanisms for the generation of lipid-free apoA-I remain poorly understood. In the current study, we used fluorescently labeled apoA-I that exhibits a distinct fluorescence emission spectrum when in different states of lipid association to establish the kinetics of apoA-I transition between the lipid-associated and lipid-free states. This approach characterized the spontaneous and rapid exchange of apoA-I between the lipid-associated and lipid-free states. In contrast, the kinetics of apoA-I exchange were significantly reduced when apoA-I on HDL was cross-linked with a bi-functional reagent or oxidized by myeloperoxidase. Our observations support the hypothesis that oxidative damage to apoA-I by myeloperoxidase limits the ability of apoA-I to be liberated in a lipid-free form from HDL. This impairment of apoA-I exchange reaction may be a trait of dysfunctional HDL contributing to reduced ATP-binding cassette A1-mediated cholesterol efflux and atherosclerosis. |
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Keywords: | Apolipoproteins Cholesterol Cholesterol Metabolism High Density Lipoprotein (HDL) Lipid Transport Apolipoprotein A-I Exchangeable Apolipoproteins Oxidation |
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