Methionine oxidation impairs reverse cholesterol transport by apolipoprotein A-I

Shao, Baohai; Cavigiolio, Giorgio; Brot, Nathan; Oda, Michael N.; Heinecke, Jay W.

doi:10.1073/pnas.0802025105

Cited by 166 publications

(178 citation statements)

References 56 publications

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“…Oxidation of apoA-I by MPO impairs its ability to activate ABCA1 and LCAT, key steps in reverse cholesterol transport and HDL maturation (64,65,87). We found that MPO-mediated oxidation also severely limited the ability of apoA-I to exchange between the HDL-associated and lipid-free/lipidpoor states.…”

Section: Discussionmentioning

confidence: 73%

Exchange of Apolipoprotein A-I between Lipid-associated and Lipid-free States

Cavigiolio¹,

Geier²,

Shao

et al. 2010

Journal of Biological Chemistry

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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.Apolipoprotein A-I (apoA-I), 4 the primary protein constituent of HDL, inhibits atherosclerosis in hypercholesterolemic mice (1-3). Moreover, increasing evidence indicates that HDL is cardioprotective in humans (4). The ability of HDL to promote cholesterol efflux from cholesteryl ester-laden macrophage foam cells is of central importance to the initiation and progression of atherosclerosis (5-7).In plasma, the vast majority of apoA-I associates with spherical HDL, a complex of apolipoproteins, phospholipids, triglycerides, free cholesterol, and cholesterol esters (8). However, the primary acceptor of cholesterol and phospholipids from macrophages is lipid-free or lipid-poor apoA-I (containing up to four phospholipid molecules (9)), which is the preferred substrate of the plasma membrane transporter ATP-binding cassette A1 (ABCA1) (10 -15). Circulating HDL is remodeled by the action of proteins and enzymes (16) such as cholesteryl ester transfer protein (17), lechitin:cholesterol acyltransferase (LCAT) (18, 19), phospholipid transfer protein (20, 21), and hepatic lipase (22). Plasma HDL remodeling can result in the destabilization of HDL and the release of lipid-free/lipid-poor apoA-I. Furthermore, the selective uptake of lipids from HDL through scavenger receptor B, type 1 can yield lipid-poor apoA-I (23).We hypothesized that the production of lipid-free/lipid-poor apoA-I from mature HDL and relipidation by ABCA1 is a dynamic process in the arterial wall, which is critical in protecting macrophages from cholesteryl ester accumulation. Previously, we showed that lipid-free/lipid-poor apoA-I is released from reconstituted HDL (rHDL) by long term (3-7 days) incu...

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Section: Discussionmentioning

confidence: 73%

Exchange of Apolipoprotein A-I between Lipid-associated and Lipid-free States

Cavigiolio¹,

Geier²,

Shao

et al. 2010

Journal of Biological Chemistry

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“…Zheng et al (15,16) first discovered that MPO, a leukocytederived heme protein implicated in atherosclerosis, binds to HDL via a specific binding domain on apoA1, promoting selective targeting of the lipoprotein in human plasma and atherosclerotic plaque for oxidative modification and a resultant loss of cholesterol efflux function. Independent studies have confirmed these observations (17,18) as well as shown that sitespecific oxidative modification of apoA1 within nascent HDL may inhibit the ability of the particle to activate LCAT, a critical process in HDL particle maturation and presumably the overall RCT pathway (19,20).…”

Section: High Density Lipoprotein (Hdl)mentioning

confidence: 81%

Modification of High Density Lipoprotein by Myeloperoxidase Generates a Pro-inflammatory Particle

Undurti

Huang

Lupica

et al. 2009

Journal of Biological Chemistry

238

178

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High density lipoprotein (HDL) is the major atheroprotective particle in plasma. Recent studies demonstrate that myeloperoxidase (MPO) binds to HDL in vivo, selectively targeting apolipoprotein A1 (apoA1) of HDL for oxidative modification and concurrent loss in cholesterol efflux and lecithin cholesterol acyl transferase activating activities, generating a "dysfunctional HDL" particle. We now show that (patho)physiologically relevant levels of MPO-catalyzed oxidation result in loss of noncholesterol efflux activities of HDL including anti-apoptotic and anti-inflammatory functions. One mechanism responsible is shown to involve the loss of modified HDL binding to the HDL receptor, scavenger receptor B1, and concurrent acquisition of saturable and specific binding to a novel unknown receptor independent of scavenger receptors CD36 and SR-A1. HDL modification by MPO is further shown to confer pro-inflammatory gain of function activities as monitored by NF-B activation and surface vascular cell adhesion molecule levels on aortic endothelial cells exposed to MPO-oxidized HDL. The loss of non-cholesterol efflux activities and the gain of pro-inflammatory functions requires modification of the entire particle and can be recapitulated by oxidation of reconstituted HDL particles comprised of apoA1 and nonoxidizable phosphatidylcholine species. Multiple site-directed mutagenesis studies of apoA1 suggest that the pro-inflammatory activity of MPO-modified HDL does not involve methionine, tyrosine, or tryptophan, oxidant-sensitive residues previously mapped as sites of apoA1 oxidation within human atheroma. Thus, MPO-catalyzed oxidation of HDL results not only in the loss of classic atheroprotective reverse cholesterol transport activities of the lipoprotein but also both the loss of non-cholesterol efflux related activities and the gain of pro-inflammatory functions. High density lipoprotein (HDL)3 is a complex mixture of cholesterol carrying lipoprotein particles built upon a predominantly apolipoprotein A1 (apoA1) backbone. HDL is currently thought to function primarily in mediating reverse cholesterol transport (RCT), the net transport of cholesterol from peripheral tissues to the liver for ultimate elimination into the intestinal lumen as biliary cholesterol for excretion in feces (1). RCT involves multiple biochemical processes, including both lipid poor apoA1 and HDL serving as acceptors of cholesterol efflux from peripheral cholesterol loaded cells, maturation of HDL from a nascent relatively cholesterol poor particle into a cholesterol-laden spherical form through interaction with lecithin cholesterol acyl transferase (LCAT), and delivery of cholesterol to liver and steroidogenic tissues through the HDL receptor, scavenger receptor B1 (SR-B1) (2).Although the RCT related functions of apoA1 and HDL are thought to primarily account for both the atheroprotective activity and the strong inverse association of HDL cholesterol and apoA1 levels and cardiovascular risks, other non-cholesterol efflux-related activities have a...

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“…Oxidative modification of Met-148 or nitration of Tyr-166 by MPO in apoA-I was also associated with a loss of apoA-I-mediated activation of lecithin:cholesterol acyltransferase (LCAT), 130,133,136 which is crucial to help maintain a concentration gradient for cholesterol efflux from the cell to the HDL particle surface. The injection of purified MPO into mice reduced the net movement of labeled-cholesterol from macrophages to plasma and feces.…”

Section: Myeloperoxidase-mediated Protein Modificationsmentioning

confidence: 99%

Dysfunctional high-density lipoproteins in coronary heart disease: implications for diagnostics and therapy

Annema

Eckardstein

2016

Translational Research

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Low plasma levels of high-density lipoprotein (HDL) cholesterol are associated with increased risks of coronary heart disease. HDL mediates cholesterol efflux from macrophages for reverse transport to the liver and elicits many anti-inflammatory and anti-oxidative activities which are potentially antiatherogenic. Nevertheless, HDL has not been successfully targeted by drugs for prevention or treatment of cardiovascular diseases. One potential reason is the targeting of HDL cholesterol which does not capture the structural and functional complexity of HDL particles. Hundreds of lipid species and dozens of proteins as well as several microRNAs have been identified in HDL. This physiological heterogeneity is further increased in pathologic conditions due to additional quantitative and qualitative molecular changes of HDL components which have been associated with both loss of physiological function and gain of pathologic dysfunction. This structural and functional complexity of HDL has prevented clear assignments of molecules to the functions of normal HDL and dysfunctions of pathologic HDL. Systematic analyses of structure-function relationships of HDL-associated molecules and their modifications are needed to test the different components and functions of HDL for their relative contribution in the pathogenesis of atherosclerosis. The derived biomarkers and targets may eventually help to exploit HDL for treatment and diagnostics of cardiovascular diseases.

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Methionine oxidation impairs reverse cholesterol transport by apolipoprotein A-I

Abstract: atherosclerosis ͉ dysfunctional HDL ͉ hypochlorous acid ͉ inflammation ͉ methionine sulfoxide reductase

Cited by 166 publications

References 56 publications

Exchange of Apolipoprotein A-I between Lipid-associated and Lipid-free States

Exchange of Apolipoprotein A-I between Lipid-associated and Lipid-free States

Modification of High Density Lipoprotein by Myeloperoxidase Generates a Pro-inflammatory Particle

Dysfunctional high-density lipoproteins in coronary heart disease: implications for diagnostics and therapy

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