Increased Cholesterol Efflux in Apolipoprotein AI (ApoAI)–Producing Macrophages as a Mechanism for Reduced Atherosclerosis in ApoAI
            <sup>(−/−)</sup>
            Mice

Major, Amy S.; Dove, Dwayne E.; Ishiguro, Hiroyuki; Su, Yan; Brown, A. C.; Liu, Lily; Carter, Kathy J.; Linton, MacRae F.; Fazio, Sergio

doi:10.1161/hq1101.097798

Cited by 46 publications

(40 citation statements)

References 47 publications

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“…ApoA-I stimulated apoE recycling to nearly the same degree whether it was added exogenously to the pulse or chase or was produced by the macrophage (Figs. 3, 4), even though the apoA-I-producing macrophages accumulate much less apoA-I in the media (33). Taken together, these data are compatible with a mechanism whereby apoE is delivered as part of the HDL-unloading process, possibly as a signaling event to inform the cell of the change in cholesterol burden.…”

Section: Discussionmentioning

confidence: 52%

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The recycling of apolipoprotein E in macrophages

Hasty

Plummer

Weisgraber

et al. 2005

Journal of Lipid Research

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The ability of apolipoprotein E (apoE) to be spared degradation in lysosomes and to recycle to the cell surface has been demonstrated by our group and others, but its physiologic relevance is unknown. In this study, we characterized apoE recycling in primary murine macrophages and probed the effects of HDL and apoA-I on this process. In cells pulsed with 125 I·apoE bound to VLDL, intact apoE was found in the chase medium for up to 24 h after the pulse. Approximately 27 ؎ 5% of the apoE internalized during the pulse was recycled after 4 h of chase. Addition of apoA-I and HDL increased apoE recycling to 45 ؎ 3% and 46 ؎ 3%, respectively, similar to the amount of apoE recycled after pulsing the cells with 125 I·apoE·HDL. In addition, apoA-I-producing macrophages from transgenic mice showed increased apoE recycling at 4 h (38 ؎ 3%). Increased ABCA1 expression potentiated apoE recycling, suggesting that recycling occurs via ABCA1. Finally, in the presence of apoA-I, recycled apoE exited the cells on HDL-like particles. These results suggest that apoE recycling in macrophages may be part of a larger signaling loop activated by HDL and directed at maximizing cholesterol losses from the cell. Apolipoprotein E (apoE) is a 34 kDa glycoprotein found on all plasma lipoproteins except the smallest LDLs. The primary extracellular function of apoE is to serve as a ligand for receptor-mediated uptake of lipoproteins through the LDL receptor, the LDL receptor-related protein, and heparan sulfate proteoglycans (1, 2). ApoE also plays a key role in intracellular lipid metabolism, influencing processes such as the assembly and secretion of lipoproteins (3-6), intracellular routing of endocytosed remnant lipoproteins (7, 8), and cholesterol efflux to HDL (9, 10). In macrophages, the effect of apoE on cholesterol efflux, as well as its other pleiotropic effects (2, 11, 12), may be critical in protecting the artery wall from atherosclerotic lesion formation (13-16).We and others have established that a portion of the apoE internalized by cells via lipoprotein receptors escapes lysosomal degradation and is recycled. This recycling is not cell specific, as it occurs in hepatocytes (17-20), fibroblasts (21, 22), hepatoma cells (21-25), and macrophages (19,26,27). The physiologic relevance of apoE recycling is unknown. Studies in our laboratory have shown that apoE recycling in hepatocytes is stimulated by apoA-I. Heeren et al. (22) showed that HDL increased the recycling of apoE as well as the efflux of cholesterol in fibroblasts using double-label experiments with 125 I-labeled apoE and 3 H-labeled cholesterol. It is also known that apoA-I stimulates the secretion of endogenous apoE by macrophages (28). Based on these observations, we speculated that apoE recycling is linked to reverse cholesterol transport both by serving as a signaling mechanism for HDL cholesterol entry into the cell and by increasing intracellular cholesterol efflux in response to HDL signaling (19). If apoE recycling is associated with cholesterol efflux ...

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Section: Discussionmentioning

confidence: 52%

“…ApoE recycling was also studied in macrophages from mice harboring a macrophage-specific human apoA-I expression construct (33). These cells secrete ‫ف‬ 63 ng/ml apoA-I in 4 h. Recycling of apoE at 4 h was 38 Ϯ 3%, with degradation at 25 Ϯ 3.2% ( Fig.…”

Section: Effects Of Apoa-i On Apoe Recyclingmentioning

confidence: 99%

The recycling of apolipoprotein E in macrophages

Hasty

Plummer

Weisgraber

et al. 2005

Journal of Lipid Research

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“…29 ApoE may be the primary driver of cholesterol efflux in macrophages through a pathway independent from ABC-A1. However, our recent observations that the transgenic or retrovirus-based expression of apoAI from the macrophage corrects the increased atherosclerosis induced by deletion of apoE from the same cell type 22,23 support the notion that apoE-induced cholesterol efflux is quantitatively in the same range as that obtainable through ABCA1-dependent (apoAI-mediated) events. It has been determined that both apoE and ABCA1 genes are regulated by the PPARg-LXR axis, and the macrophage-specific deletion of PPARg reduces levels of apoE and ABCA1 mRNAs, and drastically decreases basal cholesterol efflux.…”

Section: Macrophage Foam Cell Formation and Cholesterol Homeostasismentioning

confidence: 70%

“…20 Furthermore, the removal of macrophage apoE increases lesion size in C57BL/6 mice on a high-fat diet, 21 as well as in apoAI À/À , apoAI overexpressing, and LDL-R À/À mice. 22,23 Expression of very low levels of murine or human apoE from retrovirus-transduced macrophages in apoE-null mice results in decreased lesion area during the early stages of atherosclerosis. 24 This effect is not observed if the human apoE is defective in LDLR-(apoE2) or proteoglycan-binding ability (apoEcys142), thus suggesting that proximity to the plasma membrane is essential for the biologic action of apoE in the vessel wall.…”

Section: Macrophage Foam Cell Formation and Cholesterol Homeostasismentioning

confidence: 99%

Macrophages, inflammation, and atherosclerosis

2003

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The macrophage plays a diverse array of roles in atherogenesis and lipoprotein metabolism. The macrophage functions as a scavenger cell, an immune mediator cell, and as a source of chemotactic molecules and cytokines. Chemokines have been implicated in promoting migration of monocytes into the arterial intima. Monocyte chemoattractant protein-1 (MCP-1) attracts monocytes bearing the chemokine receptor CCR-2. Macrophage expression of cyclooxygenase-2, a key enzyme in inflammation, promotes atherosclerotic lesion formation in low-density lipoprotein receptor (LDLR)-deficient mice. In the arterial intima, monocytes differentiate into macrophages, which accumulate cholesterol esters to form lipid-laden foam cells. Foam cell formation can be viewed as an imbalance in cholesterol homeostasis. The uptake of atherogenic lipoproteins is mediated by scavenger receptors, including SR-A and CD36. In the macrophage, ACAT-1 is responsible for esterifying free cholesterol with fatty acids to form cholesterol esters. Surprisingly, deficiency of macrophage ACAT-1 promotes atherosclerosis in LDLR-deficient mice. A number of proteins have been implicated in the process of promoting the efflux of free cholesterol from the macrophage, including apoE, ABCA1, and SRB-1. Macrophage-derived foam cells express the adipocyte fatty acidbinding protein (FABP), aP2, a cytoplasmic FABP that plays an important role in regulating systemic insulin resistance in the setting of obesity. ApoE-deficient mice null for macrophage aP2 expression develop significantly less atherosclerosis than controls wild type for macrophage aP2 expression. These results demonstrate a significant role for macrophage aP2 in the formation of atherosclerotic lesions independent of its role in systemic glucose and lipid metabolism. Furthermore, macrophages deficient in aP2 display alterations in inflammatory cytokine production. Through its distinct actions in adipocytes and macrophages, aP2 links features of the metabolic syndrome including insulin resistance, obesity, inflammation, and atherosclerosis.

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“…In addition, apo E interacts with ABCA1 to extract cellular cholesterol out of the cell, and drives the formation of larger HDL-sized particles from macrophage foam cells (143,144 ). Because atheromatous plaques are only partially permeable to plasma solutes, such as apo AI, but rich in locally secreted proteins, such as apo E, arterial macrophages may represent cells in a unique microenvironment in which cholesterol efflux is directed more toward apo E-containing particles rather than toward classical apo AI-containing particles (145,146 ).…”

Section: Apo Ementioning

confidence: 99%

HDL Measures, Particle Heterogeneity, Proposed Nomenclature, and Relation to Atherosclerotic Cardiovascular Events

et al. 2011

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BACKGROUND A growing body of evidence from epidemiological data, animal studies, and clinical trials supports HDL as the next target to reduce residual cardiovascular risk in statin-treated, high-risk patients. For more than 3 decades, HDL cholesterol has been employed as the principal clinical measure of HDL and cardiovascular risk associated with low HDL-cholesterol concentrations. The physicochemical and functional heterogeneity of HDL present important challenges to investigators in the cardiovascular field who are seeking to identify more effective laboratory and clinical methods to develop a measurement method to quantify HDL that has predictive value in assessing cardiovascular risk. CONTENT In this report, we critically evaluate the diverse physical and chemical methods that have been employed to characterize plasma HDL. To facilitate future characterization of HDL subfractions, we propose the development of a new nomenclature based on physical properties for the subfractions of HDL that includes very large HDL particles (VL-HDL), large HDL particles (L-HDL), medium HDL particles (M-HDL), small HDL particles (S-HDL), and very-small HDL particles (VS-HDL). This nomenclature also includes an entry for the pre-β-1 HDL subclass that participates in macrophage cholesterol efflux. SUMMARY We anticipate that adoption of a uniform nomenclature system for HDL subfractions that integrates terminology from several methods will enhance our ability not only to compare findings with different approaches for HDL fractionation, but also to assess the clinical effects of different agents that modulate HDL particle structure, metabolism, and function, and in turn, cardiovascular risk prediction within these HDL subfractions.

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Increased Cholesterol Efflux in Apolipoprotein AI (ApoAI)–Producing Macrophages as a Mechanism for Reduced Atherosclerosis in ApoAI ^(−/−) Mice

Cited by 46 publications

References 47 publications

The recycling of apolipoprotein E in macrophages

The recycling of apolipoprotein E in macrophages

Macrophages, inflammation, and atherosclerosis

HDL Measures, Particle Heterogeneity, Proposed Nomenclature, and Relation to Atherosclerotic Cardiovascular Events

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Increased Cholesterol Efflux in Apolipoprotein AI (ApoAI)–Producing Macrophages as a Mechanism for Reduced Atherosclerosis in ApoAI (−/−) Mice

Cited by 46 publications

References 47 publications

The recycling of apolipoprotein E in macrophages

The recycling of apolipoprotein E in macrophages

Macrophages, inflammation, and atherosclerosis

HDL Measures, Particle Heterogeneity, Proposed Nomenclature, and Relation to Atherosclerotic Cardiovascular Events

Contact Info

Product

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Increased Cholesterol Efflux in Apolipoprotein AI (ApoAI)–Producing Macrophages as a Mechanism for Reduced Atherosclerosis in ApoAI ^(−/−) Mice