BBAMCB-57655; No. of pages: 6; 4C: Biochimica et Biophysica Acta xxx (2014) xxx–xxx

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Review

HDL and atherosclerosis: Insights from inherited HDL disorders☆ Laura Calabresi a,⁎, Monica Gomaraschi a, Sara Simonelli a, Franco Bernini b, Guido Franceschini a a b

Centro Grossi Paoletti, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, Italy Department of Pharmacy, University of Parma, Parma, Italy

a r t i c l e

i n f o

Article history: Received 23 May 2014 Received in revised form 14 July 2014 Accepted 20 July 2014 Available online xxxx Keywords: High density lipoprotein HDL subclasses Inherited HDL disorder Cholesterol efflux Endothelium Carotid intima media thickness

a b s t r a c t Plasma high density lipoproteins (HDL) comprise a highly heterogeneous family of lipoprotein particles, differing in density, size, surface charge, and lipid and protein composition. Epidemiological studies have shown that plasma HDL level inversely correlates with atherosclerotic cardiovascular disease. The most relevant atheroprotective function of HDL is to promote the removal of cholesterol from macrophages within the arterial wall and deliver it to the liver for excretion in a process called reverse cholesterol transport. In addition, HDLs can contribute to the maintenance of endothelial cell homeostasis and have potent antioxidant properties. It has been long suggested that individual HDL subclasses may differ in terms of their functional properties, but which one is the good particle remains to be defined. Inherited HDL disorders are rare monogenic diseases due to mutations in genes encoding proteins involved in HDL metabolism. These disorders are not only characterized by extremely low or high plasma HDL levels but also by an abnormal HDL subclass distribution, and thus represent a unique tool to understand the relationship between plasma HDL concentration, HDL function, and HDL-mediated atheroprotection. This article is part of a Special Issue entitled Linking transcription to physiology in lipodomics. © 2014 Elsevier B.V. All rights reserved.

1. Introduction A strong inverse correlation between plasma HDL cholesterol (HDL-C) concentrations and the incidence of coronary heart disease (CHD) has been firmly established in general populations [1,2], but the significance of such association for CHD development has been recently questioned by Mendelian randomization studies [3–5]. Moreover, intervention trials carried out with agents effective in raising HDL-C, including niacin and cholesteryl ester transfer protein (CETP) inhibitors, have failed in showing a reduction in cardiovascular events [6–8]. One possible explanation for this discrepancy is that the plasma HDL-C concentration is a relatively simple measure of a more complex picture involving HDL particles with different structure, metabolism, and function. Moreover, cholesterol is not the active component of HDL and there is convincing evidence that at least some of the potentially atheroprotective functions of HDL relate to specific HDL components or subclasses, which concentration in plasma may be totally unrelated to the HDL-C level, and that may represent a crucial determinant of individual CHD risk [9,10]. This review discusses the available data on the structural and functional properties of HDL from carriers of inherited HDL disorders, and their relationship to cardiovascular disease, in the attempt of answering

☆ This article is part of a Special Issue entitled Linking transcription to physiology in lipodomics. ⁎ Corresponding author at: Department of Pharmacological and Biomolecular Sciences, University of Milano, Via Balzaretti 9, 20133 Milano, Italy. Tel.: + 39 02 50319906; fax: + 39 02 50319900. E-mail address: [email protected] (L. Calabresi).

the question on whether certain subclasses of HDL may be better predictors of cardiovascular risk than HDL-C. 2. HDL quality HDLs are the most dense and smallest lipoproteins, with density of 1.063–1.21 g/mL and a mean diameter of 8–12 nm. HDL particles are quasi-spherical or discoidal complexes composed predominantly of polar lipids solubilized by apolipoproteins, mainly apolipoprotein A-I (apoA-I) and apoA-II. HDL particles also contain a number of nonstructural proteins, including enzymes and acute-phase proteins [11]. HDL particles are highly heterogeneous in their structural properties [12]. Two HDL subclasses can be separated by ultracentrifugation; the HDL2, less dense (1.063–1.125 g/mL) and relatively lipid-rich, and the HDL3, more dense (1.125–1.21 g/mL) and relatively protein-rich. These two major HDL subclasses can be further fractionated in distinct subclasses by nondenaturing polyacrylamide gradient gel electrophoresis (GGE) [13], which separates HDL subclasses on the basis of particle size. Two HDL2 and three HDL3 subclasses have been identified and characterized by this method: HDL3c, 7.2–7.8 nm diameter; HDL3b, 7.8–8.2 nm; HDL3a, 8.2–8.8 nm; HDL2a, 8.8.–9.7 nm and HDL2b, 9.7–12.0 nm. By agarose gel electrophoresis, which separates according to surface charge and shape, HDL can be separated into α-migrating particles, which represent the majority of circulating HDL, and preβ-migrating particles, consisting of nascent discoidal and poorly-lipidated HDL. The agarose gel and the GGE can be combined into a 2-dimensional (2D) electrophoretic method, which separates HDL according to charge in the first run, and according to size in the second run. This is by far the method with the highest

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Please cite this article as: L. Calabresi, et al., HDL and atherosclerosis: Insights from inherited HDL disorders, Biochim. Biophys. Acta (2014), http:// dx.doi.org/10.1016/j.bbalip.2014.07.015

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resolving power; up to 12 distinct apoA-I-containing HDL subclasses can be identified according to their mobility and size [14]. HDL heterogeneity is a consequence of continual remodeling and interconversion by the action of various factors, including structural proteins, membrane transporters, enzymes, transfer proteins and receptors [15]. There is conflicting epidemiological evidence on the relative atheroprotective potential of the different HDL subclasses; the prevailing view is that large HDL particles are associated with lower CHD risk [16–18], but which is the good HDL particle in CHD prevention remains to be determined. 3. HDL functions 3.1. Reverse cholesterol transport The best known and most relevant atheroprotective function of HDL is to promote the removal of cholesterol from macrophages within the arterial wall and deliver it to the liver for excretion in a process called reverse cholesterol transport (RCT) [19]. The removal of unesterified cholesterol from cells is the first, ratelimiting step in RCT and occurs via multiple mechanisms [20]. The release of cholesterol via passive diffusion occurs in all cell types and is accelerated when the scavenger receptor class-B type I (SR-BI) is present on the cell membrane. Both passive diffusion and SR-BI-mediated efflux occur to mature HDL and lipidated apolipoproteins [20,21]. ATP-binding cassette A1 (ABCA1) belongs to the ATP-binding cassette transporter family and promotes unidirectional efflux of phospholipids and cholesterol to lipid-free apolipoproteins and small discoidal preβ-HDL [20,21]. Macrophages may also release cholesterol via the ABCG1 transporter, which effluxes cell cholesterol to mature α-migrating HDL particles, as well as to discoidal preβ-HDL, but not to lipid-free apoA-I [20,21]. Therefore, all HDL particles are able to promote cell cholesterol efflux, by interacting with specific cell membrane proteins, but the plasma content of small preβ-HDL, which mainly promotes cholesterol efflux through ABCA1, appears to account for most of the individual variability in macrophage cholesterol removal [22]. Once accumulated into HDL, cholesterol is esterified in plasma by the enzyme lecithin: cholesterol acyltransferase (LCAT), with the formation of cholesteryl esters [23]. The majority of the cholesteryl esters are then transferred by CETP, in exchange for triglycerides, to the apoB-containing lipoproteins (VLDL and LDL), which will then be catabolized by the liver through their receptors [24]. A minor fraction of cholesteryl esters is directly delivered to the liver by HDL through interaction with SR-BI [25], which can also uptake HDL unesterified cholesterol [26]. 3.2. HDL and endothelial protection Several in vitro and in vivo evidences have shown that HDL can contribute to preserve endothelial cell homeostasis by promoting vasorelaxation, inhibiting the production of cell adhesion and pro-inflammatory molecules, and favoring the integrity and repair of the endothelial layer [27]. HDL can modulate vascular tone by inducing the release of vasoactive molecules, particularly nitric oxide (NO). In fact, HDLs are able to induce the expression and the activation of endothelial nitric oxide synthase (eNOS) [28,29]; HDL2 and HDL3 are equally effective [30]. This effect is mediated by the interaction of apoA-I with the scavenger receptor SR-BI [31], with the subsequent activation of the PI3K/Akt signaling pathway leading to eNOS phosphorylation; in addition, the sphingolipid sphingosine-1-phosphate (S1P) carried by HDL can also mediate eNOS activation by binding with its receptor S1P3 [32]. HDLs are also able to inhibit the expression of cell adhesion molecules induced by different stimuli in endothelial cells [33,34], thus preventing blood cell adhesion and their consequent extravasation. The mechanism(s) responsible for this effect are not completely understood and may involve an HDL-mediated inhibition of sphingosine

kinase activity and NF-kB nuclear translocation, and an increased expression of heme-oxygenase 1 mediated by SR-BI [35,36]. HDL3 has been shown to be more efficient than HDL2 in inhibiting cell adhesion molecule expression in cultured endothelial cells [37]. 3.3. HDL antioxidant activity HDLs exert potent antioxidant properties through a variety of mechanisms [38]. The removal of oxidized lipids from LDL represents the first step of HDL-mediated protection from oxidative damage [39]. Once incorporated into HDL, the oxidized lipids can be degraded by antioxidant enzymes carried by HDL (PON-1, PAF-AH, and LCAT), or reduced by apoA-I and apoA-II with the concomitant oxidation of their methionine residues [40]. HDL3 is more effective than HDL2 in accumulating and inactivating these reactive lipid species, because of sphingomyelin depletion, apoA-I enrichment, or distinct apoA-I conformation as compared to HDL2 [39]. Indeed, small, dense HDL3 particles are also more resistant to oxidative modification compared with large, light HDL2 [41]. 4. Inherited HDL disorders as a tool to understand the relationship between HDL quantity, quality, and function 4.1. Inherited HDL disorders Inherited HDL disorders are rare monogenic diseases due to mutations in genes encoding proteins involved in HDL metabolism. Mutations in the ABCA1, APOA1, and LCAT genes cause hypoalphalipoproteinemia, while mutations in the CETP gene cause hyperalphalipoproteinemia. The ABCA1 gene, located on chromosome 9 (9q31), encodes a 2261amino acid membrane protein belonging to the ABC family. To date, more than 170 mutations in the ABCA1 gene have been reported, which differently affect the function of the ABCA1 protein. Mutations in both ABCA1 alleles cause Tangier disease (TD), a rare recessive disease characterized by an almost complete absence of HDL [42]. Heterozygous loss of ABCA1 function causes familial HDL deficiency, a more common and relatively milder disorder, with a wide range of biochemical and clinical phenotypes in carriers, depending on the mutation [43]. One of the key biochemical features of TD is a defective efflux of cholesterol from the cell plasma membrane to extracellular acceptors [44]. The defective ABCA1 activity prevents the lipidation of lipid-free and lipid-poor apoA-I and thus the formation of mature HDL. Indeed, TD subjects have only small preβ-HDL, while heterozygotes have HDL particles that are small in size, poor in cholesterol, and relatively enriched in apoA-I [45]. The APOA1 gene is located on chromosome 11 (11q23–q24) and encodes a 243 amino acid polypeptide. More than 60 mutations in the APOA1 gene have been reported to date; more than half of them are associated with low plasma HDL-C levels [46], mostly located in the central region of apoA-I [47]. The apoA-IMilano (A-IM), characterized by a cysteine for arginine substitution at position 173, has been the first apoA-I mutant described in humans [48,49], and it is the best characterized apoA-I variant. All identified carriers are heterozygous for the variant, and have low plasma HDL-C levels, a partial LCAT deficiency, and variable degree of hypertriglyceridemia [50,51]. Carrier HDLs are small and dense [52], and are enriched in discoidal particles containing the A-IM–A-IM dimer and migrating in preβ-position on agarose gel [53]. The LCAT gene is located on chromosome 16 (16q 22), and encodes a glycoprotein of 416 residues. Mutations in the LCAT gene cause a partial or complete defect of enzyme activity and hypoalphalipoproteinemia [54]. Carriers of two mutant LCAT alleles have remarkably low plasma HDL-C levels associated with multiple alterations in HDL structure and particle distribution, with a selective depletion of large apoA-II containing particles and predominance of small preβ-HDL [55,56]. Heterozygous carriers of LCAT mutations have on average low plasma HDL-C levels and an enrichment in small preβ-HDL particles [55,56].

Please cite this article as: L. Calabresi, et al., HDL and atherosclerosis: Insights from inherited HDL disorders, Biochim. Biophys. Acta (2014), http:// dx.doi.org/10.1016/j.bbalip.2014.07.015

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The CETP gene is located on chromosome 16 (16q21) and encodes a 476 residue hydrophobic glycoprotein. To date, 39 CETP mutations have been described, mostly in Japanese subjects. Carriers of two mutant CETP alleles have up to five times normal HDL-C levels [57,58]. In complete absence of CETP activity, the failure to transfer cholesteryl esters from HDL to other lipoproteins leads to the accumulation of cholesteryl esters in HDL, which become very large [58,59]. Heterozygous carriers of CETP deficiency show increased plasma HDL-C and apoA-I levels and increased HDL size [58,60]. 4.2. Cell cholesterol efflux in inherited HDL disorders The ability of HDL from carriers of genetic HDL disorders to promote cell cholesterol efflux has been evaluated in a number of laboratories. Results of the different studies are not always comparable, due to the use of different cell models, variably expressing the various cell cholesterol efflux pathways. During the last decade we investigated, by using validated and reproducible assays, the sera from subjects with genetically proven inherited HDL disorders for their ability to promote cell cholesterol efflux through the different pathways. These studies allow a direct comparison of the impact of distinct HDL disorders on cell cholesterol efflux, and provide important information on the relationship between HDL particle distribution and pathway-specific cell cholesterol efflux. Serum from A-IM carriers is more efficient than control serum in promoting cell cholesterol efflux via ABCA1 (Fig. 1) [53], likely due to the accumulation of a small preβ-migrating HDL particle, containing a single molecule of the A-IM–A-IM dimer [53]. The ABCG1- and SRBImediated cholesterol effluxes are instead reduced compared to control, reflecting the overall reduction in the serum content of large HDL particles [53,61]. Something similar is observed with serum from carriers of LCAT deficiency. Cell cholesterol efflux through the ABCA1 transporter is

Fig. 1. ABCA1-mediated cholesterol efflux from J774 macrophages to sera from carriers of inherited HDL disorders (A-IM carriers, n = 14; LCAT deficiency, n = 40; CETP deficiency, n = 3) and control subjects (n = 30). Macrophages were labeled with 4 μCi/ml [3H]cholesterol for 24 h in RPMI medium with 1% FCS and 2 μg/ml of an ACAT inhibitor. Cells were then incubated for 18 h with 0.2% BSA in the absence or presence of 0.3 mM CPT-cAMP, washed, and incubated for 4 h with 5% serum. Each sample was run in triplicate. ABCA1-mediated cholesterol efflux was calculated as the percentage efflux from CPT-cAMP-stimulated cells minus the percentage efflux from unstimulated cells. The box plot displays median values with the 25th and 75th percentiles; capped bars indicate the 10th and 90th percentiles. P b 0.001 by ANOVA.

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significantly higher than in controls (Fig. 1) [62], and correlates with the serum content of preβ-HDL [62]. Notably, in a large series of homozygous and heterozygous carriers, a significant gene-dose dependent effect was observed in both serum preβ-HDL content and ABCA1mediated efflux [54]. On the contrary, the ability of serum from carriers to promote ABCG1- and SR-BI-mediated efflux was significantly reduced, and correlated with the total amount of circulating HDL [62]. LCAT-deficient serum was as effective as control serum in decreasing cell cholesterol content in cholesterol-loaded mouse peritoneal macrophages [62], a cell model that releases cholesterol through all known pathways [63], suggesting that the enhanced preβ-HDL-mediated cholesterol efflux via ABCA1 to LCAT deficient serum compensates for reduced HDL-mediated efflux via ABCG1 and SR-BI. Serum from subjects carrying CETP gene mutations behaves differently from what was described above. ABCA1-mediated efflux is significantly reduced compared to control serum (Fig. 1), whereas efflux through ABCG1 and SR-BI is normal or even enhanced [58]. These results are not surprising in view of the accumulation in carrier plasma of large mature HDL2 particles, known to be the best acceptors of cholesterol through these latter pathways. When we tested the ability of sera to remove cholesterol from cholesterol-loaded macrophages, sera from carriers showed a significantly reduced capacity than control sera [58], again favoring the concept that ABCA1-mediated efflux to preβ-HDL is the most relevant pathway in cell cholesterol removal.

4.3. Endothelial protection in inherited HDL disorders The impact of mutations causing hypo- or hyperalphalipoproteinemia on HDL ability to preserve endothelial function has been scarcely addressed to date. Two approaches could be used to this purpose: (i) the evaluation of in vivo or ex vivo parameters of endothelial function in carriers, such as the measurement of flow-mediated vasodilation (FMD) of the brachial artery [64] or the assay of plasma levels of inflammatory molecules [65] and (ii) the isolation of HDL from carriers' plasma and their in vitro testing using cell-based functional assays. The in vitro testing of isolated HDL allows defining if changes of in vivo/ex vivo markers of endothelial function are merely the consequence of the variable number of circulating HDL or are due to alterations in HDL particle distribution and function. Carriers of ABCA1 mutations have very compromised FMD, likely due to the lack of circulating HDL, since the infusion of synthetic HDL completely restores endothelial function [66]. No in vitro studies testing HDL isolated from carriers of ABCA1 mutations have been performed yet. The vascular function of A-IM carriers, evaluated as vasodilation in response to reactive hyperemia, was comparable to that of control subjects [67], despite the low HDL-C levels, which are normally associated with compromised vasodilation [67,68]. In addition, plasma levels of the soluble forms of cell adhesion molecules were comparable between A-IM carriers and controls [67]. In vitro studies explained the preserved vascular function observed in A-IM carriers despite the severe hypoalphalipoproteinemia; indeed, carriers' HDL showed a superior capacity to induce eNOS activation and to exert anti-inflammatory activity in cultured endothelial cells when compared to HDL isolated from control subjects [67]. The ability of HDL and HDL subclasses from a limited number of carriers of different CETP mutations to modulate endothelial cell homeostasis has been recently reported [30]. HDL from CETP-deficient subjects displayed a fully preserved ability to inhibit VCAM-1 expression in cultured endothelial cells; consistently, carriers of CETP deficiency had lower plasma levels of cell adhesion molecules than controls, in association with the higher plasma HDL-C levels [30]. On the contrary, CETPdeficient HDL showed an impaired ability to activate eNOS and promote NO production in endothelial cells, when compared to control HDL, likely due to their lower content of S1P [30].

Please cite this article as: L. Calabresi, et al., HDL and atherosclerosis: Insights from inherited HDL disorders, Biochim. Biophys. Acta (2014), http:// dx.doi.org/10.1016/j.bbalip.2014.07.015

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4.4. HDL antioxidant activity in inherited HDL disorders Very few studies have evaluated the antioxidant capacity of HDL isolated from carriers of inherited HDL disorders. In a single study on a limited number of carriers of apoA-I, ABCA1, and LCAT mutations, all HDL particles from carriers were at some degree defective in inactivating oxidized LDL [69], at in least in part because of a reduced PON1 activity and PAF-AH activity [69]. Lipid oxidation was evaluated in a large cohort of Dutch carriers of LCAT deficiency; the results show a mild increase of oxidized phospholipids in heterozygotes but not in carriers of two mutant LCAT alleles [70]. These results are quite surprising in view of the expected antioxidant role of LCAT [71], and may suggest that carrier HDL efficiently clear oxidized phospholipids. Finally, a recent study evaluated the antioxidant activity of HDL and HDL subclasses from carriers of CETP mutations, showing that carriers' HDL maintain the ability to prevent LDL oxidation, due to a preserved antioxidant capacity of small HDL3b and HDL3c [72].

5. Inherited HDL disorders and preclinical atherosclerosis Fig. 2. Average carotid IMT in investigated carriers of inherited HDL disorders (A-IM carriers, n = 21; LCAT deficiency, n = 40; CETP deficiency, n = 4) and control subjects (n = 122). Data are expressed as mean ± SD.

Carotid intima-media thickness (IMT) has been established as a surrogate marker for human atherosclerosis, and applied in the assessment of preclinical atherosclerosis in carriers of inherited HDL disorders. Carotid IMT was measured in 21 carriers of the A-IM mutation and 42 age-gender matched unaffected relatives (Table 1); the average IMT values were remarkably similar in A-IM carriers and controls, despite the very low HDL-C levels [9] (Fig. 2). Notably, the carriers of the A-IM mutation behave clearly distinct from carriers of the apoA-I (L202P) mutation, who instead present with enhanced carotid IMT, associated with a severe cardiovascular risk [73]. The striking difference in preclinical atherosclerosis between carriers of two missense mutations in the APOA1 gene, both leading to similar plasma HDL-C and apoA-I reductions [9,73], is likely due to the different effects of the two mutations on the protein and HDL structure. The A-IM variant contains a cysteine, which allows the formation of dimers with a prolonged half-life [74], and circulates in plasma in small HDL particles with enhanced cellular cholesterol efflux capacity [53], while the apoA-I(L202P) is associated with reduced in vivo tissue cholesterol efflux [75]. Three IMT studies have been carried out in carriers of LCAT gene mutations [76–78]; altogether, the results suggest that LCAT deficiency does not remarkably increases preclinical atherosclerosis, and according to the Italian study could even be protective for human arteries [78]. The Italian study evaluated 40 carriers of LCAT deficiency (12 homozygotes or compound heterozygotes, and 28 heterozygotes, Table 1) in comparison with 80 matched control subjects [78]; average carotid IMT was 0.07 mm smaller in the carriers than controls (Fig. 2), and the inheritance of a

mutated LCAT genotype had a remarkable gene-dose dependent effect in reducing carotid IMT [78]. Carotid IMT data are available for a limited number of Caucasian carriers of CETP mutations; 25 heterozygotes for the IVS7 + 1 defect showed carotid IMT comparable to non-affected family members [79], and 4 carriers of the R37X mutation (Table 1) showed carotid IMT values similar to age-gender matched controls [58] (Fig. 2). 6. Conclusion and perspectives Carotid IMT studies clearly show that genetically determined low HDL-C levels due to mutations in ABCA1, apoA-I and LCAT are not necessarily associated with increased atherosclerosis, and high HDL-C levels due to CETP mutations are not associated with decreased atherosclerosis. These results contradict those from large epidemiological studies, which repeatedly showed an inverse correlation between plasma HDL-C levels, IMT, and cardiovascular events, but are consistent with those of recent Mendelian randomization studies indicating that in well defined genetic populations the plasma HDL-C level per se does not necessarily reflect the atheroprotective potential of HDL. Indeed, carriers of inherited HDL disorders not only have extremely low or high HDL-C levels but also have abnormal HDL subclass distributions. Carriers of the

Table 1 Demographic and biochemical characteristics of investigated carriers of inherited HDL disorders.

n Homozygotes or Compound heterozygotes Heterozygotes Age (y) Gender (M/F) Hypertension (n, %) Smokers (n, %) Total cholesterol (mg/dl) LDL-cholesterol (mg/dl) HDL-cholesterol (mg/dl) Triglycerides (mg/dl) Apolipoprotein A-I (mg/dl) Apolipoprotein A-II (mg/dl)

A-IM carriers

LCAT deficiency

CETP deficiency

Controls

21 0

40 12

4 1

122 –

21 42.2 ± 17.5 11/10 5 (23.8%) 7 (33.3%) 189.2 ± 49.6 131.7 ± 35.0 19.8 ± 9.8 186.0 ± 107.2 78.5 ± 28.1 17.3 ± 4.8

28 41.7 ± 17.0 25/15 9 (22.5%) 5 (12.5%) 164.2 ± 56.5 102.7 ± 51.5 30.1 ± 17.4 156.5 ± 111.3 83.3 ± 34.2 23.9 ± 11.8

3 55.5 ± 29.5 3/1 0 0 222.0 ± 90.7 102.8 ± 21.0 102.3 ± 72.3 83.8 ± 41.0 169.0 ± 72.0 46.3 ± 12.6

– 41.9 ± 16.3 72/50 4 (3.3%) 31 (25.4%) 199.6 ± 33.2 125.0 ± 31.0 53.6 ± 14.0 107.7 ± 63.1 136.2 ± 22.8 37.1 ± 5.7

Data are expressed as means ± SD.

Please cite this article as: L. Calabresi, et al., HDL and atherosclerosis: Insights from inherited HDL disorders, Biochim. Biophys. Acta (2014), http:// dx.doi.org/10.1016/j.bbalip.2014.07.015

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A-IM variant and carriers of LCAT mutations accumulate in plasma small preβ migrating HDL particles, which are very efficient in the removal of cell cholesterol via ABCA1 and in inducing NO production; on the contrary, carriers of CETP mutations accumulate large HDL particles with reduced capacity to promote ABCA1 efflux in macrophages and to stimulate NO release in endothelial cells. These current insights from inherited HDL disorders thus support the notion that small, dense HDL particles play atheroprotective functions towards macrophages and endothelium; interestingly, the same particles have been also shown to provide potent protection of LDL from oxidation. Acknowledgement The work of the authors was supported in part by grants from Fondazione Cariplo (2009-2576 to M.G. and 2011-0628 to L.C.) and Telethon-Italy (GGP07132 to L.C. and GGP08052 to M.G.). References [1] T. Gordon, W.P. Castelli, M.C. Hjortland, W.B. Kannel, T.R. 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Please cite this article as: L. Calabresi, et al., HDL and atherosclerosis: Insights from inherited HDL disorders, Biochim. Biophys. Acta (2014), http:// dx.doi.org/10.1016/j.bbalip.2014.07.015