title: Exchange of apolipoprotein A-I between lipid-associated and lipid-free states: a potential target for oxidative generation of dysfunctional high density lipoproteins.
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.
authors.affiliation: Children's Hospital Oakland Research Institute, Oakland, California 94609, USA.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Cavigiolio
authors.forename: Ethan G
authors.initials: EG
authors.lastname: Geier
authors.forename: Baohai
authors.initials: B
authors.lastname: Shao
authors.forename: Jay W
authors.initials: JW
authors.lastname: Heinecke
authors.forename: Michael N
authors.initials: MN
authors.lastname: Oda
mesh_terms: D016632:Apolipoprotein A-I / Q000737:chemistry / Q000378:metabolism; D050197:Atherosclerosis / Q000378:metabolism / Q000473:pathology; D002784:Cholesterol / Q000378:metabolism; D003432:Cross-Linking Reagents / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D008055:Lipids / Q000737:chemistry*; D008075:Lipoproteins, HDL / Q000737:chemistry*; D009154:Mutation; D010100:Oxygen / Q000737:chemistry*; D009195:Peroxidase / Q000737:chemistry; D011994:Recombinant Proteins / Q000737:chemistry; D013050:Spectrometry, Fluorescence / Q000379:methods; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods
chemical_list: D016632:Apolipoprotein A-I; D003432:Cross-Linking Reagents; D008055:Lipids; D008075:Lipoproteins, HDL; D011994:Recombinant Proteins; D002784:Cholesterol; D009195:Peroxidase; D010100:Oxygen
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