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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:12.)
© 2006 American Heart Association, Inc.

Brief Reviews

What Is So Special About Apolipoprotein AI in Reverse Cholesterol Transport?

Linda K. Curtiss; David T. Valenta; Neil J. Hime; Kerry-Anne Rye

From the Department of Immunology (L.K.C., D.T.V., N.J.H.), The Scripps Research Institute, La Jolla, Calif; The Heart Research Institute, Ltd (K.-A.R.), Camperdown, Sydney, New South Wales, Australia; the Department of Medicine (K.-A.R.), University of Sydney, New South Wales, Australia; and the Department of Medicine (K.-A.R.), University of Melbourne, Victoria, Australia.

Correspondence to Linda K. Curtiss, The Scripps Research Institute, 10550 North Torrey Pines Rd, Department of Immunology, La Jolla, CA 92037. E-mail lcurtiss{at}scripps.edu

	Abstract

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An initial step in reverse cholesterol transport is the movement of unesterified cholesterol from peripheral cells to high-density lipoproteins (HDLs). This transfer usually occurs in extracellular spaces, such as the subendothelial space of a vessel wall, and is promoted by the interaction of lipid-free or lipid-poor apolipoprotein (apo)AI with ATP binding cassette A1 cellular transporters on macrophages (M). Because HDL does not interact with M ATP binding cassette A1 and apoAI is not synthesized by macrophages, this apoAI must be generated from spherical HDL. In this brief review, we propose that spherical apoAI is derived from HDL by remodeling events that are accomplished by proteins secreted by cholesteryl ester–loaded foam cells, including the lipid transfer proteins, phospholipid transfer protein, and cholesteryl ester transfer protein, and the triglyceride hydrolases hepatic lipase and lipoprotein lipase.

In this brief review, we propose that spherical apoAI is derived from HDL by remodeling events that are accomplished by proteins secreted by cholesteryl ester–loaded foam cells, including the lipid transfer proteins, phospholipid transfer protein, and cholesteryl ester transfer protein, and the triglyceride hydrolases hepatic lipase and lipoprotein lipase.

Key Words: apoprotein AI • PLTP • CETP • HL • macrophage

	Introduction

Top Abstract Introduction References

 
To remove cholesterol from the body, it must be dissolved into or converted to bile acids in the liver. This biliary excretion pathway is fed by the transport of cholesterol from peripheral tissues and is referred to as reverse cholesterol transport (RCT). An early step in RCT is the transfer of peripheral-cell unesterified cholesterol to plasma high-density lipoproteins (HDLs). The HDLs serve as transport vehicles for excess cellular cholesterol through the plasma compartment to the liver. Importantly, the transfer of cellular cholesterol to HDL does not occur in plasma. It occurs in extracellular spaces, like the subendothelial space or intima of a vessel within an atherosclerotic lesion. We do not yet fully understand how apolipoprotein AI (apoAI) promotes the efficient transfer of excess cholesterol from peripheral cells [ie, intimal macrophage (M) foam cells] to HDL. Convincing data have been published that in vivo apoAI participates in efficient free-cholesterol efflux from peripheral tissues, including atherosclerotic lesions.^1,2 There is no documented unique specificity for apoAI in mediating cellular cholesterol efflux in vitro, because many other exchangeable amphipathic alpha helical apoproteins can substitute for apoAI. Why is there specificity for apoAI in vivo in mediating efficient M cholesterol efflux from lesions? In this review, we wish to speculate that the in vivo efficiency of apoAI is a direct function of its ability to dissociate from spherical HDL and to form stable, lipid-poor apoAI, which can be rapidly lipidated with cellular M ATP binding cassette A1 (ABCA1)–transported free cholesterol and phospholipids. Multiple locally produced M liver X receptor (LXR)–regulated proteins probably participate in this interstitial remodeling of HDL to produce lipid-poor apoAI. Phospholipid transfer protein (PLTP) and cholesteryl ester (CE) transfer protein (CETP) are expressed by M, can generate lipid-poor apoAI from spherical HDL, are present in lesions, and are induced by ligation of LXR. Thus, M-expressed PLTP and CETP could promote M cholesterol efflux by generating lipid-poor apoAI. The lipoprotein triglyceride (TG) hydrolase hepatic lipase (HL) and perhaps even lipoprotein lipase (LpL) participate in the generation of lipid-poor apoAI in vitro. Both of these lipases are expressed by M, present in lesions, and upregulated by CE loading. Thus, lipid transfer mediated by M-derived PLTP and/or CETP together with TG hydrolase activity by HL could promote the formation of lipid-poor apoAI from mature HDL. We predict that both lipid transfer proteins and neutral TG lipases participate in HDL remodeling and in M cholesterol efflux from atherosclerotic lesions.

In Vivo Specificity for ApoAI to Reduce Cholesterol Accumulation in Peripheral Tissues
ApoE and apoAI promote cholesterol efflux from foam cells, and this facilitates the transport of cholesterol out of lesions to the liver. The unique role of apoAI for this function in vivo was documented by lethally irradiating apoE-deficient (apoE–/–) mice and double-deficient apoE–/–apoAI–/– mice and reconstituting them with bone marrow cells isolated from wild-type mice.¹ The transplanted bone marrow–derived cells synthesized apoE but not apoAI. Therefore, this study design generated chimeric apoE–/– mice with atherosclerotic lesions that contained both apoE and apoAI and chimeric apoE–/– mice with lesions that contained macrophage synthesized apoE but no systemic apoAI. As expected, in both groups the transplanted wild-type M-derived apoE dramatically lowered the plasma hypercholesterolemia. With consumption of a high-fat diet after transplantation, plasma cholesterol levels were increased in both groups of chimeric mice, but the levels in the apoE–/–apoAI recipients were 2-fold to 3-fold higher than in the apoE–/–apoAI–/– recipients. However, despite a 2-fold to 3-fold lower total plasma cholesterol in the apoE–/–apoAI–/– recipient mice, the CEs recovered from isolated aortas were &60% higher, and the mean lesion area in serial sections of the aortic valves was 45% larger. Therefore, in vivo, only apoAI efficiently reduces the accumulation of cholesterol in lesions beyond that accomplished by apoE. These observations are consistent with those reported by Zabalawi et al² in their studies of low-density lipoprotein (LDL) receptor (LDLr) and apoAI double-knockout mice. In these studies, double-deficient LDLr–/–apoAI–/– mice compared with LDLr–/– mice had lower levels of plasma cholesterol after consuming a high-fat diet yet had statistically significant higher aortic esterified cholesterol and a major accumulation of skin cholesterol.² It is key to point out that in both of these studies the mice had detectable and comparable amounts of other exchangeable apoproteins including apoAIV, apoAII, and the C apoproteins. But, these proteins did not substitute for apoAI and did not facilitate efficient cholesterol efflux from lesions or skin.^1,2

HDL and RCT
The predictive power of plasma HDL cholesterol levels for the development of atherosclerosis is well established.^3–5 There is little doubt that the increased susceptibility to cardiovascular disease experienced by subjects with low-HDL cholesterol levels reflects a causal effect of 1 components of HDL metabolism. Raising HDL pharmacologically remains a key target to reduce the incidence of disease in hypercholesterolemic subjects, particularly beyond that which is obtainable by a reduction of LDL alone. In mice, variations at multiple gene loci affecting plasma HDL concentrations⁶ have major effects on diet-induced atherosclerosis.

Cellular cholesterol is exquisitely controlled and numerous metabolic pathways exist to maintain a critical cellular sterol balance. A vast array of sterol response elements and transcriptional regulators, such as LXR, participate in the coordinate regulation of gene transcription to maintain cellular sterol balance. In this way, multiple pathways are regulated for acquiring cholesterol when it is needed and esterifying or effluxing it when it is in excess. ApoAI-containing HDLs are key participants in this homeostatic process. Jolley et al⁷ astutely pointed out that RCT (or centripetal cholesterol flux) to the liver is not dictated by plasma HDL or apoAI concentrations but instead is dictated by events that occur in peripheral organs. Two events dictate the rate of movement of cholesterol out of peripheral cells: an energy-dependent transport of cholesterol out of the cell and the availability of a lipid-poor acceptor of this transported cholesterol⁸ (Figure 1). After transfer of excess cellular-free cholesterol to lipid-poor apoAI, cholesterol is converted to CEs by lecithin cholesteryl acyltransferase (LCAT) to form larger, spherical HDL particles that transport the cholesterol to the liver. In the presence of plasma CETP, a portion of the CE is exchanged into apoB containing lipoprotein particles for clearance by the liver via LDLrs. Moreover, any HDL that accumulates apoE from the periphery can be taken up in the liver via the apoE and/or the LDLr. There is also selective uptake by the liver of CE from circulating HDL via the scavenger receptor-type BI receptor.⁹ In hypercholesterolemic mice, this cholesterol balance is disrupted.

View larger version (34K): [in this window] [in a new window]   Figure 1. Schematic diagram of the possible forms of interstitial HDL present in the intima of an atherosclerotic lesion in close proximity to a CE-loaded M foam cell. Whereas the most abundant form is most likely spherical -migrating HDL, because it is the major HDL species in plasma, this species has a low affinity for the ABCA1 membrane transporter. We propose that the ideal substrate for ABCA1, lipid-free or lipid-poor apoAI, is generated in the intima from spherical HDL on remodeling by M foam cell–secreted lipases and lipid transfer proteins HL, LpL, PLTP, and CETP. On the interaction of lipid-free apoAI with cellular ABCA1, it acquires free cholesterol (FC) and phospholipids to form pre-ß HDL. This pre-ß can either enter the plasma compartment or be converted to spherical HDL by LCAT and return to the plasma.

Importantly, the key acceptors of unesterified cholesterol from peripheral cells represent only a minor component of plasma lipoproteins. Rapid equilibration of plasma HDL with HDL in the extravascular compartment occurs.¹⁰ As illustrated in Figure 1, cholesterol efflux in most cells occurs via movement of unesterified cholesterol and phospholipids from the plasma membrane to an acceptor particle in the interstitial compartment.⁵ Whereas this process can occur by deabsorption, active transport of cholesterol and phospholipid from cells is a function of the cellular plasma membrane sterol transporter, ABCA1.¹¹ The major acceptors of unesterified cholesterol in the extracellular space are thought to be apoAI-containing HDLs that are characterized by their pre-ß mobility on agarose electrophoresis.⁸ This electrophoretic property is in contrast to the major plasma spherical HDLs, which have an mobility. A recent review by Rye and Barter¹² provides a clear and important distinction between pre-ß migrating discoidal HDLs and pre-ß migrating monomolecular, lipid–poor apoAI. Both lipid-free/lipid-poor apoAI and discoidal apoAI-containing HDLs have a pre-ß mobility when electrophoresed in agarose. But these are different entities. Lipid-poor apoAI contains a single molecule of apoAI with or without a small amount of phospholipid and has a molecular mass of 29 to 30 kDa. In contrast, discoidal apoAI–containing HDL contains 2 or 3 molecules of apoAI plus phospholipid with or without free cholesterol. It has a molecular mass of >60 kDa and a diameter of <7 nm.¹² These 2 pre-ß migrating entities are distinguished in Figure 1. The lipid-free or lipid-poor apoAI is illustrated on the left side as a product of the remodeling of spherical migrating HDLs. Discoidal pre-ß HDL is illustrated on the right side as a product of M ABCA1–mediated lipid efflux to lipid-free or lipid-poor apoAI.

Many molecules with amphipathic helices can accept cellular cholesterol in vitro including apoAIV, apoE, and the apoCs.¹³ Whereas apoAI facilitates active efflux in vivo, these other apoproteins do not. Perhaps this in vivo preference for apoAI is a function of its capacity to readily dissociate from a fully lipidated HDL particle and to form stable lipid–poor apoAI. We hypothesize that apoAI readily dissociates from spherical HDL to form lipid-poor apoAI and that it is this property of apoAI that is responsible for the in vivo specificity we and others observe.^1,2 This expectation has been supported by the identification of lipid-poor apoAI in dog peripheral lymph lipoproteins and of lipid-poor lipoproteins extracted from human aortas that are not found in ultracentrifuged plasma HDLs.^14,15

Interstitial ApoAI and HDL
The crystal structure of apoAI (with the N-terminal 43 residues deleted) has been elucidated at 4Å resolution.¹⁶ In association with lipids, it is predicted that antiparallel dimers of apoAI form an extended "belt" around the periphery of both spherical lipoproteins and bilayer disc complexes with hydrophobic regions of protein in contact with a lipid surface.^17,18 A unique feature of all amphipathic exchangeable apoproteins is their ability to exist relatively stably in lipid-poor, as well as lipid-associated, states. This property explains their ability to transfer among lipoproteins. ApoAI is considered a good progenitor of nascent lipoproteins. ApoAI is not synthesized within lesions.¹ Thus, it must enter the intima either in the form of lipid-free or lipid-poor apoAI, discoidal pre-ß HDL, or as spherical HDL (Figure 1). Because spherical HDL is the dominant species in plasma, probably most, if not all, of the apoAI enters the intima in this form.

ABC Transporters
The discovery of the genetic defect in ABCA1 in patients with Tangier disease¹⁹ has identified an important participant in intimal M cholesterol efflux. These studies confirmed that ridding the cell of excess cholesterol is facilitated by active transport of free cholesterol by ABCA1.²⁰ The identification of ABCA1 as a sterol-regulated transporter in M has substantial implications. ABCA1 plays an obligatory role in HDL metabolism. It participates in the conversion of lipid-poor apoAI into discoidal pre-ß HDL by the addition of free cholesterol and phospholipids (Figure 1). These particles then mature into spherical HDL like those found in plasma. In the absence of functional ABCA1, lipid-poor apolipoproteins do not acquire cellular lipids and are rapidly cleared from the plasma compartment (supposedly by the kidney). This is dramatically demonstrated by differences in plasma residence times in normal and Tangier disease subjects. Mature spherical ¹²⁵I-HDL and lipid-free ¹²⁵I-apoAI have plasma residence times of 4.1 to 6.6 days and 3 to 4.5 days, respectively, in normal subjects. Plasma residence times of 0.53 days and 0.22 days for HDL and apoAI, respectively, are observed in Tangier patients.³ ABCA1-mediated efflux in M is a process that is ATP-dependent, is induced by CE loading, and effluxes both free cholesterol and phospholipid. ABCA1 does not interact with spherical HDL. However, Wang et al²¹ recently reported the existence of another M transporter of unknown function that can interact with HDL. Nevertheless, the cellular location and the role that this half transporter plays in vivo in lesions is unknown.

LXRs
The LXRs, LXR and LXRß, are important regulators of cholesterol metabolism and transport.^22,23 These receptors control transcription of multiple genes, some of which participate in the regulation of cholesterol metabolism (Figure 2). In response to lipid loading, M activate a compensatory pathway for cholesterol efflux mediated by ABCA1. When systemic hyperlipidemia or hypercholesterolemia exists, this homeostatic function is overwhelmed, and M within a fatty streak lesion take on the appearance of foam cells. M LXR signaling is critical for initiating this homeostatic response to cellular cholesterol lipid loading. M uptake of oxidized LDL (oxLDL) leads to increased cellular concentrations of oxysterols, which are physiological ligands for LXRs.²⁴ Subsequent activation of LXR in M results in the expression of multiple genes, including ABCA1, CETP, PLTP, and endothelial lipase (EL) lipoprotein lipase (LpL), as well as the apoprotein gene cluster, apoCII, CI, CIV, and apoE^25–31 (Figure 2). Both LXR and LXRß are expressed in M and are particularly sensitive to changes in cholesterol homeostasis.

View larger version (43K): [in this window] [in a new window]   Figure 2. The expression of the lipases, lipid transfer proteins, and the ABCA1 transporters are upregulated by interaction of oxysterols with nuclear LXR regulatory receptors. The oxysterols are derived from the uptake of oxidatively modified LDL by M scavenger receptors. This regulation provides for a coordinate increase in the expression and secretion of those M proteins that provide efficient removal of excess cellular cholesterol within cells of the fatty streak lesion.

An important role of LXR receptors was shown in studies of LXRß-deficient M using bone marrow transplantation to selectively eliminate M LXR expression in apoE–/– mice.³² These authors demonstrated that LXRs play a key role in atherogenesis, as well as altering lipid accumulation, CE efflux, and HDL levels. We reported that peroxisome proliferator-activated receptor (PPAR) is associated with decreased atherosclerotic lesions.³³ The activation of PPAR leads to a direct increase in expression of LXR via a PPAR binding site in the LXR promoter consistent with the reported results demonstrating the antiatherogenic effects of LXR and indicates that LXR is a downstream target of PPAR with regard to the antiatherogenic effects of PPAR ligands. Our hypothesis for the uniqueness of apoAI in RCT focuses on products secreted by M foam cells in response to CE loading, specifically those factors that are regulated by LXRs and have the capacity to modify 2 important steps in reverse cholesterol efflux. First, the remodeling of spherical HDL and, second, ABCA1-mediated efflux of cholesterol and phospholipid from CE-loaded M. The end result of the LXR-mediated transcriptional cascade is the successful transfer of excess cellular cholesterol to the key extracellular acceptor, apoAI. The pathophysiologic significance of this LXR-dependent cholesterol efflux pathway is best illustrated by the observations that synthetic LXR ligands reduce atherosclerosis in mice, and the loss of LXR expression accelerates the disease.^32,34

It is important to reiterate that apoAI is not made by M, and there is no evidence that its gene expression is sensitive to LXR agonists. Thus, the successful maintenance of cholesterol homeostasis within a lesion must take into account the roles played by genes expressed by M, such as the lipid transfer proteins and lipases, to generate lipid-poor apoAI. Our initial characterization of the in vivo role of apoAI in mediating cholesterol efflux was performed in apoE–/– mice reconstituted with apoE-expressing M.¹ ApoE is an important LXR-inducible gene product. In mice, apoE is a major protein carried on HDL, and lipoproteins containing apoE as the only protein component have been identified as a minor component of human plasma.³⁵ Like apoAI, apoE is a surface-active, exchangeable, and water-soluble apoprotein with a multiple, amphipathic helical structure. Moreover, when apoE is examined for its ability to accept cellular-free cholesterol, it is recovered in an extracellular compartment in association with free cholesterol and sphingomyelin-rich phospholipids, which indicates that these complexes were generated with cellular lipids.⁸ Furthermore, it was shown that in apoAI-deficient plasma, apoE could substitute for apoAI as a backup system to generate pre-ß HDL.³⁵ ApoE is an important player; its involvement needs to be understood. However, its presence does not identify the basis for the efficient in vivo specificity for apoAI in RCT.

Remodeling of HDL by PLTP
Systemic PLTP deficiency in mice is associated with a decrease in atherosclerosis susceptibility despite a decrease in plasma HDL levels, whereas overexpression of PLTP is accompanied by increased atherosclerosis susceptibility.^36–38 Nevertheless, the role of PLTP in the development of atherosclerosis may be complex, and a differing influence of PLTP may exist depending on its site of expression. A balance between lesion activity, which we propose is antiatherogenic, and plasma activity, which is proatherogenic, probably determines the overall contribution of PLTP to atherosclerosis.

We demonstrated that, in humans, both CETP and PLTP cause conversion of HDL in vitro into larger- and smaller-sized particles (including pre-ß HDL).³⁹ When the lipid composition of a lipoprotein is altered sufficiently by lipid transfer activity, its apoproteins are destabilized. For PLTP, this results in the loss of apoAI from HDL.⁴⁰ In humans, PLTP is responsible for the majority of phospholipid transfer activity in plasma.⁴¹ Overexpression of PLTP and apoAI in mice leads to enhanced shedding of nascent, lipid-poor apoAI from mature HDL. This results in increased plasma pre-ß HDL, apoAI, and phospholipid.⁴² The importance of PLTP for remodeling is revealed by the fact that it acts on particles that contain apoAI.⁴³ Oram et al⁴⁴ reported that PLTP can also interact directly with and stabilize ABCA1 and thereby enhance cholesterol efflux. We reported that PLTP is secreted by M and is highly expressed in atherosclerotic lesions.⁴⁵ The addition of LXR or retinoid X receptor ligands increases PLTP activity, and this induction of PLTP expression occurs in both human and mouse M. Therefore, although increased risk for atherosclerosis is observed by elevated plasma levels of PLTP,⁴⁶ M-generated PLTP may have a very different effect on disease. We defined the mechanism of the remodeling of HDL by PLTP and determined that it is enhanced in TG-enriched HDL.⁴⁷ In studies even more germane to understanding the role of macrophage-expressed PLTP in vivo, we recently performed bone marrow transplantations of LDLr–/– mice, which expressed either normal levels of mouse apoAI or very high levels of human apoAI, with bone marrow from either PLTP-expressing or PLTP-deficient mice. In the presence of normal levels of plasma HDL and PLTP, a deficiency of macrophage PLTP led to an increase in atherosclerosis, suggesting an atheroprotective role for macrophage-derived PLTP. In contrast, in the presence of a large excess of lipid-poor apoAI that was present in the human apoAI transgenic LDLr–/– mice, the macrophage-derived PLTP was not atheroprotective (submitted for publication). Current studies to verify that macrophage-derived PLTP can remodel TG-rich HDLs in vitro to generate lipid-poor apoAI and to promote cellular cholesterol efflux are under way.

Remodeling of HDL by CETP
CETP is a hydrophobic plasma lipoprotein, mainly synthesized in the liver, that possesses the unique ability to facilitate the transfer of CE among lipoproteins. Whether CETP is a proatherogenic or antiatherogenic protein has been debated for years.^48–50 Most of this work was motivated by the need to understand the physiological and pathophysiologic role of CETP in lipoprotein metabolism. Initial observations indicated that animals naturally lacking CETP are resistant to the development of atherosclerosis, whereas those expressing CETP are sensitive to diet-induced atherosclerosis. Mice naturally lack CETP. However, Kawano et al⁵¹ bred the CETP transgene into PLTP–/– mice and found no redundancy in function of PLTP and CETP in vivo. The combination of the CETP transgene with PLTP deficiency results in an additive lowering of HDL levels in mice, suggesting that the phenotype of a human PLTP deficiency state would include reduced HDL levels. Biochemical experiments indicate that only CETP can transfer neutral lipids, but there could be overlap in the ability of PLTP and CETP to transfer or exchange phospholipids.

Expression of the CETP gene in mice has resulted both in promotion and prevention of aortic atherosclerosis.⁵⁰ In C57/BL6, apoE knockout, apobec-1 knockout, and LDLr–/– mice, transgenic expression of CETP results in a redistribution of CE from HDL into apoB-containing lipoproteins and increased atherosclerosis. However, in other mouse models, such as apoE–/– human AITg, human apoC-III Tg, and human LCAT Tg, expression of the CETP gene protects against atherosclerosis. These studies confirm the lesson learned from animal studies that the role of CETP in lipoprotein metabolism and in the development of atherosclerosis is complex and may reflect the interaction of this protein with several factors.⁵² Like PLTP, CETP is present in lesions,⁵⁰ it is expressed by M,⁵³ its expression in M is regulated by LXR,⁵⁴ it remodels spherical HDL,³⁹ the remodeling is accompanied by a reduction in the size of HDL and by the dissociation of lipid-poor apoAI,¹² it has nonoverlapping functions with PLTP in mice,⁵¹ and, most importantly, it is present in humans. Clinical population–based studies have established a correlation with CETP deficiency, high-HDL cholesterol levels, and a lower prevalence of coronary heart disease.⁵⁰

Processes that reduce the size of HDL or promote HDL particle fusion have the capacity to promote the dissociation of lipid-poor apoAI. But, lipid-poor apoAI does not dissociate from HDL unless the remodeling is accompanied by a reduction in core lipids.⁵⁵ CETP promotes the transfer of CE from HDL to other lipoproteins and TG from TG-rich lipoproteins to HDL. These processes deplete the HDL core of CE and enrich it with TG. When HDLs are incubated in vitro with TG-rich lipoproteins in the presence of CETP, the magnitude of the transfer of CE out of HDL may be greater than that of the transfer of TG into HDL. Under these circumstances, there is a net reduction in HDL core lipid content and a reduction in particle size.¹² This results in an excess of surface constituents that is alleviated by the dissociation of pre-ß-migrating, lipid-poor apoAI. These processes probably also operate in vivo, but this has not yet been demonstrated. This is most likely because, in vivo, the dissociated apoAI is lipidated as rapidly as it is generated. We predict that this relipidation of apoAI in vivo can involve accepting lipids from M foam cells in lesions. The initial plasma acceptor of unesterified cholesterol and phospholipids from M peripheral cells is pre-ß migrating, lipid-free, or lipid-poor apoAI. This pre-ß apoAI is formed when CETP is incubated with spherical HDL. The in vivo and in vitro proof-of-concept studies described above for PLTP now need to be performed in CETP transgenic mice. Can macrophage-derived CETP remodel spherical HDL in vitro to generate lipid-poor apoAI, and is macrophage-derived CETP atherprotective in vivo?

Role of Lipases in Remodeling of HDL
It is thought that fusion of spherical HDL with discoidal surface remnants released from TG-containing lipoproteins by lipases produces lipid-poor apoAI. Lipoprotein lipase deficiency is associated with low HDL levels, and this is caused in part by a decrease in the availability of the surface components necessary for formation of HDL.^56,57 Sparks et al.⁵⁸ show that a reduction in core contents, which results in a loss of TG or increase in CE/TG ratio of HDL, reduces the thermodynamic stability of the particle and promotes the dissociation of partially lipidated monomeric molecules of apoAI. This explains why apoAI dissociates from HDL after lipolysis by HL or LpL.¹²

LpL hydrolizes lipoprotein TGs and is synthesized by M and M-derived foam cells in atherosclerotic lesions.⁵⁹ Local LpL activity in the artery wall has been proposed to promote atherosclerosis.⁶⁰ M LpL facilitates the uptake of CE, presumably by remodeling TG-rich lipoproteins.⁶¹

HL hydrolyzes TGs and phospholipids in all of the lipoproteins, including HDL.⁶² Its role in modulating atherogenic risk remains controversial. HL activity is inversely correlated with the development of atherosclerosis, although other studies suggest a proatherogenic role for HL.^26,63 Of particular interest is the observation that HL deficiency in apoE–/– mice and in LCAT-Tg mice markedly reduces aortic lesion formation despite significant increases in plasma total and apoB-containing lipoprotein cholesterol.²⁶ This suggests that HL modulates atherogenic risk through a pathway that does not involve changes in plasma lipoprotein metabolism. This pathway could involve remodeling of HDL. HL is expressed in mouse M.⁶⁴ Coadministration of LXR agonists and a PPAR agonist in vivo regulates HDL and TG metabolism.⁶⁵

An attractive idea is that LXR up regulates HL and LpL to help the body clear cholesterol-rich lipoproteins via M uptake, so that cholesterol can be transported via HDL back to the liver. Thus, TG lipolysis participates in the efficient remodeling of HDL in the interstitial space by CETP and PLTP. HL readily hydrolyzes the core TG of spherical HDL and the expression of this lipase in M is controlled by CE loading.⁶⁴ Therefore, each factor that we predict to be a participant in the generation of lipid-poor apoAI from spherical-mature HDL within atherosclerotic lesions is present at the same place and at the same time (illustrated in Figure 2). Studies are urgently needed to examine the role that M TG lipases play in HDL remodeling mediated by M-expressed PLTP and CETP.

EL is a recently described member of the TG lipase gene family that hydrolyzes HDL phospholipids. Importantly, it has low TG lipase activity.⁶⁶ We reported recently that EL-mediated remodeling of recombinant HDL occurs by a process that does not involve the dissociation of apoAI from spherical HDL.⁶⁷ For this reason, EL is not at this time a potential candidate for the generation of lipid-poor apoAI, although EL is made by M and is present in lesions.

Conclusions
If M synthesized apoAI, our hypothesis would be irrelevant. But M do not express apoAI. They do, however, express and secrete PLTP, CETP, LpL, and HL, and they upregulate the expression of these proteins in a coordinated fashion in response to cholesterol loading. We do not yet fully appreciate why M do this. However, it is worth considering the possibility that each of these proteins participates in remodeling of spherical HDL within the intima to generate substrate for the M ABCA1 transporter, which can efflux excess cellular cholesterol. The transfer of cellular cholesterol to HDL does not occur in plasma. It occurs in extracellular spaces, like the subendothelial space or intima of a vessel within an atherosclerotic lesion (Figure 3). Thus, we speculate that the in vivo specificity we observe for apoAI to remove CE from atherosclerotic lesions¹ resides in its capacity to fall off spherical HDL within lesions. Moreover PLTP, CETP, LpL, and HL may work in concert to efficiently remodel spherical HDL and to generate lipid-poor apoAI.

View larger version (104K): [in this window] [in a new window]   Figure 3. Cholesterol efflux from M foam cells does not occur in plasma but in interstitial spaces. This illustration depicts the lumen of an artery (bottom left) containing plasma, red blood cells, and circulating blood monocytes. At lesion-prone sites, these monocytes enter the intima where thy take up oxidatively modified LDL, accumulate CEs, and differentiate into resident M foam cells (bottom right). Detail of the intima of an atherosclerotic lesion (circular inset) illustrates the proposed initial stages of removal of cholesterol from the intima via reverse cholesterol transport. The lipid-poor apoAI is derived from spherical HDL in the intima and is a crucial rate-limiting step. PLTP, CETP, and HL are secreted in large amounts by the M and remodel HDL to generate the lipid-poor (or pre-ß) apoAI. Image created by D.T.V.

	Acknowledgments

 
This work was supported by National Institutes of Health grant HL043815 (to L.K.C.), American Heart Association fellowship 0525201y (to D.T.V.) and National Health Medical Research Council program grant 222722 (to K.-A.R.). We thank Anna Meyers for her assistance.

Received August 25, 2005; accepted October 19, 2005.

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