Predictive value of different HDL particles for the protection against or risk of coronary heart disease

Biochimica et Biophysica Acta 1821 (2012) 473–480

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Review

Predictive value of different HDL particles for the protection against or risk of coronary heart disease☆ Kerry-Anne Rye a, b, c,⁎, Philip J. Barter a, b a b c

Lipid Research Group, The Heart Research Institute, Sydney, NSW, Australia Faculty of Medicine, University of Sydney, NSW, Australia Department of Medicine, University of Melbourne, Victoria, Australia

a r t i c l e

i n f o

Article history: Received 21 July 2011 Received in revised form 10 October 2011 Accepted 13 October 2011 Available online 19 October 2011 Keywords: High density lipoproteins HDL function HDL subpopulations

a b s t r a c t The inverse relationship between plasma HDL levels and the risk of developing coronary heart disease is well established. The underlying mechanisms of this relationship are poorly understood, largely because HDL consist of several functionally distinct subpopulations of particles that are continuously being interconverted from one to another. This review commences with an outline of what is known about the origins of individual HDL subpopulations, how their distribution is regulated, and describes strategies that are currently available for isolating them. We then summarise what is known about the functionality of specific HDL subpopulations, and how these findings might impact on cardiovascular risk. The final section highlights major gaps in existing knowledge of HDL functionality, and suggests how these deficiencies might be addressed. This article is part of a Special Issue entitled Advances in High Density Lipoprotein Formation and Metabolism: A Tribute to John F. Oram (1945–2010). © 2011 Elsevier B.V. All rights reserved.

1. Introduction Numerous population studies have established that the concentration of high density lipoprotein (HDL) cholesterol in human plasma is inversely correlated with cardiovascular risk. The underlying mechanisms of this cardioprotective effect are not well understood, mainly because HDL consist of numerous subpopulations of particles that are highly diverse in terms of size and composition and cannot be isolated individually using existing technology. Evidence is now emerging that HDL subpopulations are also functionally heterogeneous, and that they vary in terms of their ability to protect against cardiovascular disease. The most extensively studied cardioprotective function of HDL relates to their participation in the first step of the reverse cholesterol transport pathway, the process whereby excess cholesterol is exported to HDL from peripheral cells, such as macrophages in the artery wall, and transported to the liver for excretion or recycling. HDL also have antioxidant, anti-inflammatory, anti-thrombotic and anti-apoptotic properties. They promote the repair of damaged endothelium, have recently been shown to improve beta cell function in isolated pancreatic islets and improve glycemic control in humans. There are likely to be several other beneficial functions of HDL that are, as yet, unreported. A key unanswered

☆ This article is part of a Special Issue entitled Advances in High Density Lipoprotein Formation and Metabolism: A Tribute to John F. Oram (1945–2010). ⁎ Corresponding author at: Lipid Research Group, The Heart Research Institute, 7 Eliza St, Newtown, Sydney, New South Wales, Australia, 2042. Tel.: + 61 2 8208 8900; fax: + 61 2 9565 5584. E-mail addresses: [email protected], [email protected] (K.-A. Rye). 1388-1981/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.bbalip.2011.10.012

question is whether HDL subpopulations mediate all of these functions equally well, or whether there is specificity in their ability to do so. This review describes what is currently known about the origins and functional specificity of HDL subpopulations, how this relates to their cardioprotective properties and highlights areas where further research is required. 2. Origins of HDL and regulation of HDL subpopulation distribution HDL originate as discoidal particles that consist of a phospholipid bilayer with a small amount of unesterified cholesterol that is surrounded by an annulus of two or more apolipoproteins. Discoidal HDL biogenesis involves the association of lipid-free or lipid-poor apolipoproteins with phospholipids and unesterified cholesterol that are exported from cell membranes via the ATP-binding cassette transporter, ABCA1 (Fig. 1) [1–3]. The lipid-free or lipid-poor apolipoproteins that are involved in HDL biogenesis either originate from the liver or intestine, have dissociated from triglyceride-rich lipoproteins that are undergoing lipolysis by lipoprotein lipase or, in the case of apolipoprotein (apo) A-I, the main HDL apolipoprotein, have dissociated from mature spherical HDL that are being remodelled by various plasma factors (Fig. 1, Table 1). Lipid-free apoA-I migrates to a pre-β-1 position when subjected to agarose gel electrophoresis, which separates lipoproteins on the basis of surface charge. As the lipid-free apoA-I progressively acquires phospholipids and unesterified cholesterol from cells expressing ABCA1, discoidal HDL that are significantly larger than lipid-free apoA-I are generated. Because of their larger size, these particles migrate to a pre-β-2 position during agarose gel

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Fig. 1. Origins of HDL. Discoidal HDL are assembled in the plasma when lipid-free or lipid-poor apolipoproteins acquire phospholipids and unesterified cholesterol from cell membranes and triglyceride-rich lipoproteins that are undergoing lipolysis by lipoprotein lipase. The discoidal HDL are converted into spherical HDL by LCAT.

electrophoresis (Fig. 2) [4]. ApoA-I-containing, pre-β-2-migrating discoidal HDL are rapidly converted by lecithin:cholesterol acyltransferase (LCAT) into the α-migrating spherical particles that predominate in normal human plasma (Figs. 1 and 2) [4,5]. Spherical HDL consist of a central core of neutral lipids (cholesteryl esters and a minor amount Table 1 Plasma factors contributing to HDL heterogeneity. CETP PLTP LCAT HL

EL SR-B1

Remodels spherical HDL into large and small particles Generates lipid-free/lipid-poor apoA-I Remodels spherical HDL into large and small particles Generates lipid-free/lipid-poor apoA-I Remodels discoidal HDL into spherical HDL Generates lipid-free/I ipid-poor apoA-I Remodels large triglyceride-rich spherical HDL into small spherical HDL Generates lipid-free/lipid-poor apoA-I Remodels spherical HDL into smaller particles. Does not generate lipid-free/lipid-poor apoA-I Remodels spherical HDL into smaller particles. Does not generate lipid-free/lipid-poor apoA-I

of triglyceride) surrounded by a monolayer of phospholipids, unesterified cholesterol and apolipoproteins. The heterogeneity of spherical HDL is a consequence of continuous remodelling by plasma factors. Remodelling is defined as processes that change the size, surface charge and composition of HDL, and cause lipid-free/lipid-poor apoA-I to dissociate from the particles. It has been suggested that remodelling has the capacity to alter HDL functionality, although this possibility has not been explored systematically. The key plasma factors involved in HDL remodelling are LCAT, cholesteryl ester transfer protein (CETP), phospholipid transfer protein (PLTP), hepatic lipase (HL) and, to a lesser extent, endothelial lipase (EL) and scavenger receptor-B1 (SR-B1) (Table 1). LCAT esterifies the cholesterol in discoidal HDL, generating waterinsoluble cholesteryl esters that partition into the particle core and mediate the conversion of discoidal HDL into small spherical HDL with two apoA-I molecules/particle, and ultimately into large spherical HDL particles that contain three apoA-I molecules/particle [5,6]. Lipid-free/lipid-poor apoA-I can dissociate from HDL during the conversion of small spherical HDL into large spherical HDL. This occurs, paradoxically, when the availability of lipid-free/lipid-poor apoA-I is

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Fig. 2. Classification of HDL on the basis of density, size, apolipoprotein composition and surface charge.

restricted. Under these circumstances LCAT mediates the fusion of two small spherical HDL particles that each have two molecules of apoA-I to generate a large, unstable particle with four apoA-I molecules. The fusion product then undergoes a structural rearrangement into a large spherical HDL particle with three molecules of apoA-I, in a process that is accompanied by the dissociation of a molecule of lipid-free/lipid-poor apoA-I [6] CETP is a member of the LPS-binding lipid transfer protein family. It transfers cholesteryl esters from HDL to other plasma lipoprotein fractions, and triglycerides from triglyceride-rich lipoproteins into HDL and low density lipoproteins (LDL) [7,8]. In states of hypertriglyceridemia and insulin resistance, transfers of cholesteryl esters out of HDL and triglycerides into HDL generate cholesteryl ester-poor, triglyceride-rich particles that are excellent substrates for HL, which is a member of the triglyceride lipase gene family with both phospholipase and triglyceride lipase activities [9]. Hydrolysis of the triglycerides in triglyceride-rich HDL by HL depletes the particles of core lipids, generating a redundancy of surface constituents. This imbalance is rectified by the dissociation of lipid-free/lipid-poor apoA-I and a reduction in HDL size [10–12]. Studies with reconstituted HDL have established that CETP can also remodel HDL into small particles without mediating the dissociation of lipid-free/lipid-poor apoA-I by a process that involves particle fusion and a structural rearrangement of fusion product [13]. PLTP, a member of the same lipid transfer protein family as CETP, transfers phospholipids between different HDL particles, as well as between HDL and triglyceride-rich lipoproteins. PLTP remodels HDL

into large and small particles via a process that is accompanied by the dissociation of lipid-free/lipid-poor apoA-I [14]. Studies of reconstituted HDL have established that the PLTP-mediated remodelling of HDL into large and small particles, and the dissociation of lipid-free/ lipid-poor apoA-I, proceeds by way of particle fusion, and a structural reorganisation of the fusion product [15]. EL is a member of the same gene family as HL. It has high phospholipase activity [16,17] and low triglyceride lipase activity [18,19]. As HDL phospholipids are the predominant substrate of this enzyme, it has a limited capacity to deplete HDL of core lipids, can only mediate a modest reduction in HDL size, and does not promote the dissociation of lipid-free/lipid-poor apoA-I [20]. The scavenger receptor SR-B1 plays a key role in the selective hepatic uptake of cholesteryl esters from HDL in the final step of the reverse cholesterol transport pathway. These cholesteryl esters are either targeted for secretion in the bile, or used for de novo lipoprotein assembly in the liver [21]. The removal of cholesteryl esters from HDL by SR-B1 is accompanied by a reduction in particle size [22], without the dissociation of lipid-free lipid-poor apoA-I [23]. The resulting core lipid-depleted particles are subsequently remodelled into larger HDL by a process that presumably involves LCAT [24]. It has also been reported that the selective uptake of HDL cholesteryl esters by SR-B1 is regulated by the apolipoprotein composition of the particles. For example, cholesteryl esters are selectively removed from reconstituted HDL that contain apoA-I as well as apoAII (the second most abundant HDL apolipoprotein) more effectively

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than from reconstituted HDL that only contain apoA-I [25]. SR-B1 has also been reported to remove cholesteryl esters from HDL2 more effectively than from HDL3 [26]. 3. Assessment of HDL subpopulation distribution in human plasma Over the years the subpopulation distribution of HDL in human plasma has been characterised on the basis of particle size, density, surface charge, as well as apolipoprotein composition and nuclear magnetic resonance (NMR) spectroscopy. 3.1. Particle size The separation of HDL subpopulations on the basis of particle size was initially undertaken by size exclusion chromatography [27]. While the resolution of this approach is not sufficient to isolate individual subpopulations of particles, and the resulting samples are quite dilute, it does provide HDL in amounts that are sufficient for proteomic [28,29] and lipidomic studies [30]. Size exclusion chromatography also has the advantage of not involving the high shear forces and salt concentrations that are associated with the ultracentrifugal isolation of HDL, and therefore causes minimal structural disruption to the particles. At present non-denaturing gradient gel electrophoresis is the most sensitive approach for quantifying the size distribution of HDL subpopulations [31]. This technique has been used to classify HDL into five distinct subpopulations on the basis of average diameter: HDL2b (10.6 nm), HDL2a (9.2 nm), HDL3a (8.4 nm), HDL3b (8.0 nm) and HDL3c (7.6 nm) (Fig. 2) [31]. Although non-denaturing gradient gel electrophoresis is not preparative, it has proved to be extremely useful for understanding the remodelling processes outlined above. Its use in combination with agarose gel electrophoresis, which separates lipoproteins on the basis of surface charge (2-D gel electrophoresis), has provided a great deal of information about the impact of cardiovascular disease, and the effects of lipid-lowering interventions, on the subpopulation distribution of HDL [4,32,33] 3.2. Apolipoprotein composition The most abundant HDL apolipoproteins are apoA-I (Mr 28.3 kDa), which comprises approximately 70% of the total protein content of HDL, and apoA-II (Mr 17.4 kDa), which contributes another 20% to the total HDL apolipoprotein content. Immunoaffinity chromatography has been used to classify HDL on the basis of their apoA-I and apoA-II content into those that contain apoA-I, but not apoA-II, (A-I)HDL, and those that contain apoA-I as well as apoA-II, (A-I/A-II)HDL [34]. Approximately 50% of the total apoA-I is associated with (A-I)HDL, although this can vary markedly from person to person. The remaining apoA-I is incorporated into (A-I/A-II)HDL. There is mounting evidence to suggest that (A-I)HDL are functionally and metabolically distinct from (A-I/A-II)HDL (see below). The third and fourth most abundant HDL apolipoproteins are apoA-IV (Mr 46 kDa) and apoE (Mr 34.2 kDa), respectively. HDL that contain apoA-IV or apoE are significantly larger than (A-I)HDL or (A-I/A-II)HDL (Fig. 2). The isolation of apoA-IV-containing HDL is problematic because this apolipoprotein has a low affinity for lipid, and tends to dissociate from HDL. This means that isolation protocols involving high shear forces, such as ultracentrifugation, may cause the amount of lipid-free apoA-IV relative to lipid-associated apoA-IV to be significantly overestimated. To this end, lipid-associated apoAIV has been reported to vary from as little as 2% of the total apoA-IV for HDL isolated by sequential ultracentrifugation [35], to 15–96% when HDL are isolated by immunoprecipitation or size exclusion chromatography [36–38]. Evidence that apoA-I is also present in apoA-IV-containing HDL is conflicting. When samples of normal plasma

are subjected to 2-D gel electrophoresis, minimal co-migration of apoA-I and apoA-IV is observed [39]. However, the small size of the apoA-IV-containing HDL reported in that study raises the possibility that the structural integrity of the particles may have been compromised by storage conditions or other factors. Despite these challenges, apoA-IV-containing HDL have been isolated in amounts sufficient for structural and functional studies [40,41]. Since HDL that contain apoE tend to be significantly larger than most other HDL particles, they can be isolated relatively easily, either by size exclusion chromatography [42,43] or by immunoaffinity chromatography [44] in amounts sufficient for limited functional studies. ApoE-containing HDL isolated by immunoaffinity chromatography have also been reported to contain apoA-I and apoA-II [44]. However, when plasma samples from normolipidemic humans are subjected to 2-D gel electrophoresis, most of the apoE-containing HDL do not comigrate with HDL that contain apoA-I or apoA-II [39,44]. This discrepancy suggests that apoE-containing HDL that are earmarked for use in functional studies should be characterised very carefully prior to use. 3.3. Surface charge The HDL in human plasma can be subfractionated analytically on the basis of surface charge by capillary isotachophoresis [45,46], as well as by free solution isotachophoresis, which is semi-preparative [46]. Although the latter approach is potentially very informative, it requires specialised equipment, which limits its utility. HDL are more commonly separated on the basis of surface charge by agarose gel electrophoresis [47]. As mentioned above, the use of agarose gel electrophoresis in combination with non-denaturing gradient gel electrophoresis has generated a great deal of information about the regulation of HDL subpopulation distribution by plasma factors under numerous pathophysiological conditions. When subjected to agarose gel electrophoresis, spherical (A-I)HDL and (A-I/A-II)HDL migrate to an α-position (Fig. 2) [39,48]. Discoidal HDL and lipid-free/ lipid-poor apoA-I, by contrast, migrate to a pre-β-position (Fig. 2) [4]. Spherical HDL containing apoE as the only apolipoprotein migrate to a γ-position (Fig. 2) [49]. There is very little information about the electrophoretic mobility of apoA-IV-containing HDL during agarose gel electrophoresis, other than that they migrate to an α-position, irrespective of whether or not they contain apoA-I [39,48] 3.4. NMR spectroscopy Proton NMR spectroscopy is used widely to quantify HDL subpopulation size and concentration in clinical settings [50,51]. NMR is currently the approach of choice for analysing large numbers of samples. In addition to offering high throughput, NMR spectroscopy has the advantage of generating information from whole plasma without prior sample manipulation. One of the drawbacks of this technique is that all lipoprotein classes are not measured with the same degree of accuracy. For example HDL3 levels are determined with an accuracy that is approximately three times greater than that for HDL2 levels [52]. This approach also uses several mathematical assumptions that do not take into account variations in the protein and lipid cargoes of the particles. The importance of this issue has only been recognised recently, with the publication of detailed proteomic and lipidomic analyses highlighting the extensive compositional heterogeneity of HDL [28,53–56]. Thus, any conclusions drawn from the proton NMR approach should be viewed with a degree of caution and with the limitation that readouts for small HDL are likely to be more reliable than those for large HDL. 3.5. Particle density The HDL in human plasma consist of two main subfractions, HDL2 and HDL3, HDL2 are considerably larger and less dense than HDL3

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(Fig. 2). This difference in hydrated density can be exploited to isolate HDL2 and HDL3 by sequential ultracentrifugation in the 1.063 b d b 1.125 and 1.125 b d b 1.21 g/ml density range, respectively. The HDL2 subfraction contains mainly (A-I)HDL, whereas (A-I/A-II)HDL are largely, but not exclusively, confined to the HDL3 subfraction [34]. Comparative studies with these preparations have given numerous insights into HDL functionality (see below). The downside of this approach is that ultracentrifugally isolated HDL2 and HDL3 contain multiple subpopulations of particles, which precludes the assignment of specific functions to discrete subpopulations of particles. An interesting variation on sequential ultracentrifugation involves the isolation of HDL2b, HDL2a, HDL3a, HDL3b and HDL3c from whole plasma by single step density gradient ultracentrifugation using predefined, narrow density ranges [57]. These preparations have provided a number of insights into the structure and functionality of HDL [57,58], and have also been useful in studies of the HDL proteome [59]. However, it should be emphasised once again that individual subpopulations of HDL particles cannot be isolated using this approach. 4. Cardioprotective properties of HDL subpopulations 4.1. HDL2 and HDL3 Numerous population studies have suggested that HDL2 may be more cardioprotective than HDL3 [60,61]. However, there are also inconsistencies, with reports suggesting that HDL2 and HDL3 are equally cardioprotective on the one hand [62,63] while HDL3 confers enhanced cardioprotection relative to HDL2 on the other [64]. These discrepancies may relate to the fact that the relative concentrations of HDL2 and HDL3 vary widely, are dependent on the coronary heart disease and smoking status of the subjects, and whether or not pathophysiologies such as diabetes, obesity, hypertension and dyslipidemia are present [65]. As reasonably large amounts of HDL2 and HDL3 can be isolated from human plasma, insights into their relative cardioprotective properties have been investigated extensively in ex vivo functional studies. The results of these studies are inconsistent and have not clearly demonstrated an enhanced cardioprotective benefit of HDL2 relative to HDL3, or vice versa. For example, HDL3 have been reported to inhibit expression of vascular cell adhesion molecule-1 in cytokineactivated human umbilical vein endothelial cells more effectively than HDL2 [66]. On the other hand, HDL2 and HDL3 appear to be equally effective at exporting cholesterol from cells that express ABCG1 [67]. Similarly, Chantepie et al. have reported that HDL2 and HDL3 are equally susceptible to oxidation by physiologically relevant oxidants such as hypochlorous acid [68], and there is evidence that this is also the case for the oxidation of HDL2 and HDL3 by other reagents such as copper [69]. HDL2 and HDL3 are also indistinguishable in terms of their ability to reduce cholesteryl ester hydroperoxides to the corresponding, less deleterious, cholesteryl ester hydroxides [70]. On the other hand, smaller and more dense HDL, especially HDL3b and HDL3c, have been reported to inhibit the oxidation of LDL more effectively than HDL2 [57]. Clearly there is an urgent need for additional research in this area. 4.2. (A-I)HDL and (A-I/A-II)HDL Significant metabolic differences have been reported between (A-I)HDL and (A-I/A-II)HDL. For example, Rader et al. have shown that the apoA-I in (A-I)HDL is cleared from normal human plasma more rapidly than the apoA-I in (A-I/A-II)HDL [71]. This is most likely due to apoA-II increasing the stability of the (A-I/A-II)HDL, which inhibits apoA-I from dissociating from the particles and delays the clearance of (A-I/A-II)HDL from the circulation [72]. This result could be interpreted in terms of the shorter plasma residence time of (A-I)HDL causing an apparent enhancement of the cardioprotective

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properties of (A-I/A-II)HDL. On the other hand, it is also consistent with reports of subjects with coronary heart disease having lower (A-I)HDL levels and higher (A-I/A-II)HDL levels than normal subjects [73], and plasma (A-I/A-II)HDL levels being predictors of the inflammatory response in subjects with ST-elevation myocardial infarction [74] These findings are not, however, in agreement with other observational studies showing that (A-I)HDL and (A-I/A-II)HDL are equally cardioprotective [75], or with a more recent report showing that variations in the proportions of (A-I)HDL and (A-I/A-II)HDL are not associated with differences in coronary heart disease prevalence in the Framingham Offspring Study, or with recurrent cardiovascular events in the Veterans Affairs HDL Intervention Trial (VA-HIT) [76]. The results of studies that have directly investigated functional differences between (A-I)HDL and (A-I/A-II)HDL are also inconsistent. This is most likely because such studies are carried out in vitro under conditions that are not standardised. For example, Rinninger et al. have reported that cholesteryl esters are selectively taken up from (A-I)HDL by HepG2 cells and fibroblasts more rapidly than from (A-I/ A-II)HDL [77]. However, this observation was not confirmed in studies of the Wistar rat, which reported comparable selective uptake of cholesteryl esters from (A-I)HDL and (A-I/A-II)HDL by the liver [78]. The ability of (A-I)HDL and (A-I/A-II)HDL to efflux cholesterol from a range of cell types has also been investigated with varying results. For example, while (A-I)HDL, but not (A-I/A-II)HDL, have been reported to efflux cholesterol from adipocytes [79], they display comparable efficacy when accepting the cholesterol that is exported from fibroblasts [80]. (A-I)HDL, by contrast, are more effective at accepting cholesterol from the 5FuAH rat hepatoma cell line and normal skin fibroblasts than (A-I/A-II)HDL [81,82]. Again, much more research is needed in this area, ideally using standardised techniques.

4.3. Pre-β migrating lipid-free/lipid-poor apoA-I The pre-β migrating lipid-free/lipid-poor apoA-I that dissociates from spherical HDL that are being remodelled by plasma factors has been regarded as atheroprotective by virtue of its ability to accept cholesterol that is exported from macrophages in the artery wall in the first step of the reverse cholesterol transport pathway. This relationship has been reported consistently in studies of apoE-deficient mice [83–85]. It has also been tested in a small single-blind placebo controlled study of acute coronary syndrome (ACS) subjects in which cholesterol was selectively removed from HDL to generate pre-β migrating HDL-enriched plasma [86]. Seven weekly infusions of this product caused a mean 12 mm3 reduction in total atheroma volume by intravascular ultrasound [86]. This outcome is similar to what has been reported previously for ACS subjects who received five weekly infusions of a dimeric form of apoA-I (apoA-IMilano) complexed with phospholipid [87]. However, these results are not consistent with an analysis of the HDL subpopulation distribution as a predictor of cardiovascular events in VA-HIT [88]. This study revealed, as expected, that subjects with new cardiovascular disease events had significantly lower levels of HDL-C and apoA-I than subjects who had not experienced such events. The people with events also had lower levels of larger HDL, and significantly higher levels of small, poorly lipidated HDL particles relative to the controls as judged by 2-D gel electrophoresis [88] and NMR spectroscopy [89]. A similar conclusion was also reached in a study of male subjects from the Framingham Offspring Study [90]. Of all HDL subpopulations, the largest α-migrating HDL were the best negative predictors of recurrent cardiovascular events, while the smaller, α-migrating HDL emerged as a positive, rather than negative, predictor. This is consistent with high concentrations of small, poorly lipidated, pre β-migrating HDL being associated with increased cardiovascular risk in conditions such as type 2 diabetes, hypertriglyceridemia and the metabolic syndrome.

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4.4. ApoE-containing HDL While a plethora of evidence from studies of apoE-deficient mice has demonstrated that apoE is cardioprotective [91], these reports do not provide an insight as to whether the cardioprotection is related in any way to the apoE that associates with HDL. The results from a prospective, nested case–control study in the Cholesterol and Recurrent Events (CARE) trial identified apoE-containing HDL as an independent risk factor for recurrent coronary events [92], suggesting that apoEcontaining HDL may not have cardioprotective properties. However, this conclusion is not consistent with in vitro studies which show that apoE-containing HDL accept the cholesterol that is exported from macrophages and hepatocytes, and therefore presumably protect against atherosclerosis [44], or that the apoE-enriched HDL from subjects who are deficient in CETP accept the cholesterol that is exported from macrophages via ABCG1 [93]. While there are recent reports of lipid-free apoE promoting an anti-inflammatory phenotype in macrophages [94], we do not know if this is also the case for the apoE that associates with HDL. This possibility is worthy of further consideration as treatment with agents such as CETP inhibitors and niacin, both of which raise HDL levels and increase plasma levels of apoE-containing HDL, are either currently being used extensively in some countries, or are being investigated in large-scale clinical trials. The three main isoforms of human apoE also have anti-oxidant properties [95], but there are no reports that this is also the case for the apoE that associates with HDL. ApoE-enriched HDL do, however, inhibit extracellular matrix retention of oxidised LDL in vitro [96]. 4.5. ApoA-IV-containing HDL Studies of mice transgenic for hepatic [97] and intestinal [98] human apoA-IV have indicated that this apolipoprotein has antiatherogenic properties. ApoA-IV also has the capacity to export cholesterol from adipocytes [40] and macrophages [99], and has profound anti-inflammatory effects in an animal model of colitis [100]. It also inhibits lipopolysaccharide-induced systemic inflammation [101] and has anti-oxidant properties [98,102]. Two case control studies have reported that low apoA-IV levels are associated with coronary artery disease independent of HDL levels [103], suggesting that lipid-free apoA-IV, rather than HDL-associated apoA-IV may be cardioprotective. This is consistent with what has been reported for studies of atherosclerotic lesion development in apoE-deficient and wild-type control mice transgenic for human apoA-IV, which display a significant reduction in lesion size independent of changes in plasma HDL levels [97]. Clearly there is a need for considerable additional research into this interesting apolipoprotein. 5. Effect of increasing HDL levels on HDL subpopulation distribution and function There is a major effort currently being directed towards the use of agents that raise the concentration of HDL. Given the potential differences in properties and atheroprotection conferred by different HDL subpopulations, it is most important that the effects of these HDL raising agents on the subpopulation distribution and the anti-atherogenic properties of the resulting HDL are understood. Disturbingly, there is a remarkable lack of information in this area. It is, however known that statins [104–106] and niacin [105,107] both increase larger, apoA-I containing HDL subpopulations to a greater extent than other subpopulations. Conversely, fibrates tend to selectively increase smaller (A-I/A-II)HDL subpopulations [33]. The clinical implications of these differences are completely unknown. Nor is it known whether the selective increase in larger (A-I)HDL species (that may also be enriched in apoE) in people and animals treated with CETP inhibitors has any clinical implications [45,108].

Even less is known about the effects of HDL-raising agents on the many potentially cardioprotective properties of HDL. While YvanCharvet et al. have reported that HDL isolated from people treated with niacin and the CETP inhibitor, anacetrapib, increase cholesterol efflux from macrophages by 30% and 100%, respectively [109], there is at present no information about the effects of these interventions on the other cardioprotective functions of HDL. Given the currently high level of clinical research activity directed towards investigating novel HDL-raising agents, it is extremely worrying that we do not have this information. We propose that this area of research should receive the highest priority in studies conducted in parallel with the ongoing clinical trials.

6. Conclusion HDL as a therapeutic target is the new frontier with huge potential for positive public health implications. The fact that many of the current clinical studies are being conducted on faith, with a disturbing absence of the basic science that should be informing their design, and ultimately their clinical use is of significant concern. Well-designed studies that will move towards redressing this deficit should be a top priority.

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