The complexity of HDL

Biochimica et Biophysica Acta 1801 (2010) 1286–1293

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Biochimica et Biophysica Acta j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / b b a l i p

Review

The complexity of HDL Gordon A. Francis ⁎ Department of Medicine and UBC James Hogg Research Centre, Providence Heart and Lung Institute, 1081 Burrard St., Vancouver, British Columbia, Canada V6Z 1Y6

a r t i c l e

i n f o

Article history: Received 25 June 2010 Received in revised form 16 August 2010 Accepted 17 August 2010 Available online 21 August 2010 Keywords: High-density lipoprotein Apolipoprotein A-I ABCA1 Coronary artery disease Reverse cholesterol transport Inflammation

a b s t r a c t Plasma high-density lipoprotein cholesterol (HDL-C) levels are inversely associated with coronary artery disease risk in large epidemiologic studies. This rule, however, has many exceptions in individual patients, and evidence suggests that other facets of high-density lipoprotein particle biology not captured by measuring HDL-C levels are responsible for HDL's effects in vivo. This article reviews the evidence for the protective nature of HDL, current evidence from animal and human studies regarding HDL-based therapies, the major steps in HDL particle formation and metabolism, alterations leading to dysfunctional HDL in diabetes and inflammatory states, and potential alternatives to HDL-C to measure HDL function and predict its protective value clinically. © 2010 Elsevier B.V. All rights reserved.

1. Introduction Low levels of the alpha-migrating or high-density fraction of human plasma lipoproteins were first shown to be associated with increased risk of coronary artery disease (CAD) by Barr et al. in 1951 [1]. Despite numerous subsequent prospective population studies from multiple countries confirming the strength and independence of reduced highdensity lipoprotein cholesterol (HDL-C) as a risk factor for CAD, and in stark contrast to the conclusive evidence that reducing low-density lipoprotein cholesterol (LDL-C) levels protects against coronary events, studies clearly demonstrating benefits of raising HDL-C levels in humans still do not exist in 2010. In addition, it has become evident that simply measuring HDL's cholesterol content frequently fails to provide a reliable prediction of HDL's value in protecting against CAD. Multiple other characteristics of HDL, including apolipoprotein content, other protein or lipid content, HDL particle size, and oxidation status have a large impact on the functional capacity of HDL particles to confer protection or risk. The assessment of benefit of existing and novel therapies affecting HDL to treat or prevent atherosclerosis, based on the assumption of the protective nature of HDL particles, therefore, must take into account other HDL parameters and functionality besides the simple measurement of changes in plasma HDL-C. The purpose of this paper is to review the protective nature of HDL, the factors involved in HDL particle formation and metabolism, alterations of HDL content and function with impaired glucose metabolism and inflammation, and potential ways forward including pending clinical trials of HDL-related therapies and the development ⁎ Tel.: + 1 604 806 9269; fax: + 1 604 806 8351. E-mail address: [email protected]. 1388-1981/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.bbalip.2010.08.009

of novel methods to measure HDL's function and protective capacity. In so doing, it is hoped the complexity of HDL can be reduced. 2. Low HDL-C and risk for coronary heart disease Following the initial demonstration of the correlation between low levels of plasma alpha lipoproteins and increased risk for CAD [1], large population studies including the Framingham Heart Study [2], the Lipid Research Clinics Prevalence Study [3], the Trømso Heart Study [4], the Prospective Cardiovascular Münster Trial [5], the Physician's Health Study [6], and others [7] confirmed this relationship, with several of these studies indicating a low level of HDL-C to be the single strongest predictor of CAD events [8]. This relationship is independent of other major coronary risk factors, as well as plasma triglyceride levels [9], and is present in both men and women, the elderly, and those with and without CAD at baseline [8]. Confounding this general population trend, however, are genetic HDL deficiency states that are frequently but not always associated with increased risk for atherosclerosis. Examples of genetically low HDL-C with absence of premature atherosclerosis include apoA-IMilano [10] and lecithin: cholesterol acyltransferase (LCAT) deficiency (reviewed in Rousset et al. [11]). Even complete apolipoprotein A-I (apoA-I) deficiency is frequently, but not always, associated with premature atherosclerosis [12–19]. It should be noted, however, that familial hypercholesterolemia is also not always associated with premature CAD [20]. 3. The protective effects of HDL Research to understand the protective effects of HDL against CAD has yielded a large number of likely beneficial actions of HDL particles

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and their components [21]. While further adding to the intrigue and complexity of HDL, these numerous potentially protective functions suggest increasing HDL particle formation therapeutically, possibly independent of changes in HDL-C, would protect against atherosclerosis and other disease states for multiple reasons. The bestcharacterized protective action of HDL is its ability, and that of free HDL apolipoproteins, to stimulate the removal of cholesterol from cultured cells and tissues—the so-called reverse cholesterol transport pathway [22]. The “reverse” in this definition refers to the ability of HDL to carry excess cholesterol, which cannot be catabolized in most cells, from nonhepatic tissues back to the liver for excretion in bile. HDL and apoA-I also exert potent anti-inflammatory effects, by inhibiting the production of leucocyte adhesion molecules by endothelial cells [21,23], blocking almost entirely the influx of leucocytes in an in vivo model of acute arterial injury [24], and by reducing production of inflammatory cytokines by macrophages [25]. Some of these effects may be independent of HDL- or apoA-I-induced cholesterol efflux. In addition, HDL increases the production of nitric oxide by endothelial cells [26], promotes endothelial repair [27], and reduces platelet aggregability by inhibiting production of platelet activating factor [28] and stimulating prostacyclin production by endothelial cells [29]. HDL also binds lipopolysaccharide [30] and inhibits the oxidation of LDL [31]. HDL provides the scaffold for proteins that mediate innate immunity against trypanosome infection [32,33]. HDL have been implicated in the protection of pancreatic islet cells against lipotoxicity and the stimulation of insulin secretion by these cells [34–36]. HDLs are the sole lipoprotein made in the brain and critical for normal neurologic function [37]. Overall, HDL appears to be important for disease prevention generally, providing extremely strong impetus to understand these mechanisms of protection and to enhance the beneficial actions of HDL therapeutically.

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support of the “HDL hypothesis” to date comes from several animal models made transgenic for human apolipoprotein A-I. Rubin and colleagues initially showed that overexpression of human apoA-I in C57BL/6 mice fed atherogenic diets led to a greater than 2-fold increase in plasma HDL-C and marked protection against arterial fatty streak development [38]. Apolipoprotein E-deficient mice expressing human apoA-I similarly showed a 2-fold increase in plasma HDL-C and a marked reduction in atherosclerotic lesion development [39,40], an effect shown to depend on changes in HDL-C rather than on non-HDL cholesterol fractions. Cholesterol-fed rabbits expressing human apoA-I showed an approximate 50% reduction in atherosclerosis development when compared to control animals, with the result again dependent on the changes in HDL-C and independent of apolipoprotein B-containing lipoproteins [41]. Atherosclerotic lesion regression has also been demonstrated in cholesterol-fed LDL receptor-deficient mice injected with adenovirus to express human apoA-I in the liver, resulting in an approximate 50% increase in circulating HDL-C and no change in non-HDL cholesterol [42]. In addition to these apoA-I transgenic studies, Hoeg et al. [43] demonstrated a 7-fold increase in plasma HDL-C and marked resistance to diet-induced atherosclerosis in rabbits made transgenic for human LCAT. The concept that raising HDL-C, or at least increasing HDL particle formation, will reduce atherosclerosis is still, to a very large extent, dependent on the results of these animal studies. Suggestive studies in humans include reductions of CAD events in subjects treated with fibric acid derivatives [44,45], and with niacin [46], which work in part by raising HDL-C. While niacin has a multitude of beneficial effects on lipoproteins, its effectiveness is believed to be in large part through it being the best HDL-C-raising agent currently available. 5. HDL formation and metabolism

4. Evidence that raising HDL-C is protective Proof of the hypothesis that specifically raising HDL-C results in reduced rates of CAD and other ischemic vascular events in humans, however, remains lacking. This is due in large part to the absence of therapeutic maneuvers and drugs that specifically raise HDL-C without affecting other lipoprotein fractions. The best evidence in

Conclusions about potential HDL-related therapies based on levels of plasma HDL-C require an understanding of the mechanisms of initial HDL formation and the metabolism of HDL throughout its life span. The major metabolic points in an HDL particles' life are summarized in Fig. 1. Numbered sections below refer to the major steps shown in the figure.

Plasma Tissues e.g. artery wall

Cholesterol

pre-βHDL, α-HDL

1. ApoA-I 2. ABCA1 5. SR-BI 6. HL

3. LCAT C

Hepatocytes

Cholesterol

4. CETP CE/TG

Bile

CE VLDL, LDL

2. ABCA1 Passive Diffusion ABCG1?

Intestine

LDLR LRP

Chylo/VLDL hydrolysis

Fig. 1. Major steps in HDL metabolism. Apolipoprotein A-I (apoA-I) made in the liver and intestine (1) and partially lipidated there (pre-β HDL) is lipidated further with phospholipids and cholesterol by the ATP-binding cassette transporter A1 (ABCA1) (2) in the liver and other tissues, into discoidal α-HDL particles, thereby removing tissue cholesterol. Additional steps including passive diffusion of cholesterol from cells onto the HDL surface and possibly the actions of ABCG1 remove more cholesterol from tissues. In plasma, lecithin:cholesterol acyltransferase (LCAT) converts cholesterol (C) on HDL into cholesteryl esters (CE), which move into the core of the particle converting discoidal to spherical HDL particles (3). Cholesteryl ester transfer protein (CETP) associated with HDL mediates the exchange of CE off HDL onto VLDL and LDL in exchange for triglycerides (TG) (4). Additional surface lipid and protein components are transferred to HDL during hydrolysis of chylomicrons and VLDL in the circulation. HDL interact at the hepatocyte with scavenger receptor BI (SR-BI), which selectively takes up CE and other HDL lipids into the liver (5). Cholesterol taken up from HDL is preferentially shunted into bile. HDL is also digested at the hepatocyte surface by hepatic lipase (HL), which hydrolyzes HDL phospholipids and triglycerides, releasing smaller HDL and lipid-poor apoA-I that can then recirculate in the pathway (6). The pathway of return of tissue cholesterol to the liver by HDL for excretion in bile is referred to as reverse cholesterol transport.

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5.1. Apolipoprotein synthesis and initial lipidation The major apolipoproteins of HDL, apoA-I and apoA-II, are synthesized in the liver and intestine. Transcriptional regulation of apoA-I has been quite well studied and is affected by factors including thyroid hormone, glucocorticoids, estrogen, and PPAR-alpha agonists [47,48]. ApoA-I secreted by hepatocytes is partially lipidated by ATPbinding cassette transporter A1 (ABCA1)-independent mechanisms, to produce pre-beta HDL, as defined by 2-dimensional (2D) gel electrophoresis of plasma lipoproteins [49], and as seen in ABCA1deficient mouse hepatocytes [50] and human plasma of patients lacking ABCA1 activity [51]. Currently, there are no therapeutic agents available having a major effect on plasma HDL-C levels, other than the fibrate medications, through manipulation of transcriptional regulation of apoA-I. The novel compound RVX-208 increases apoA-I mRNA and protein levels in cultured hepatoma cells and increases plasma apoA-I and HDL-C in an animal model by mechanisms that are not yet clear [52]. This compound is currently under investigation in human CAD patients. Synthetic apoA-IMilano and shorter peptides mimicking the structure and activity of apoA-I and other amphipathic helical apoproteins are also currently under investigation for their antiatherogenic and anti-inflammatory properties [53,54]. These proteins may exert their benefit without having any or only little impact on circulating plasma HDL-C levels. 5.2. Initial HDL particle formation and the critical role of ABCA1 The critical step of more complete lipidation of apoA-I and other HDL apolipoproteins to generate the first viable alpha-HDL particles, as also defined by 2D gel electrophoresis, is mediated by the membrane lipid transporter ABCA1 [55,56]. Identification of this transporter was facilitated by early studies in the severe hypoalphalipoproteinemia condition Tangier disease, including that synthesis of apoA-I was normal in this disease [57], but that lipidation of apoA-I with cellular phospholipids [58,59] and cholesterol [58–60] by skin fibroblasts from patients with Tangier disease was defective. These studies indicated that the active lipidation of apoA-I by cellular lipids is a critical determinant of circulating plasma HDL-C levels. In 1999, several groups internationally reported that the mutation in Tangier disease leading to impaired HDL formation is in ABCA1 [61–65]. ABCA1 expression is tightly regulated by cell cholesterol content, with elevations in cell cholesterol and therefore oxysterol levels activating the nuclear receptor liver X receptor, causing the release of ABCA1 to an active form [66] and a rapid up-regulation of ABCA1 transcription and protein level [55]. ABCA1 serves to offload excess cellular cholesterol along with phospholipids to apoAI and other HDL apolipoproteins, and in so doing, creating viable nascent HDL particles [67]. Additional removal of cell cholesterol to these preformed HDL particles can then occur by passive diffusion down a concentration gradient from the cell surface to the HDL surface [68] and through the actions of an additional ABC lipid transporter, ABCG1 [69,70]. The absence of changes in plasma HDL-C levels in ABCG1-deficient mice, however, raises questions about the overall importance of ABCG1 in transporting tissue cholesterol to HDL [71]. Efforts to increase ABCA1 expression or activity are being actively pursued as a way of increasing new HDL particle formation, which may or may not lead to a lasting change in plasma HDL-C concentration. Of particular interest is the fact that deficiency in ABCA1 activity, as seen in both heterozygous Tangier disease and the lysosomal cholesterol storage disease Niemann–Pick disease type C, leads to a specific defect in the formation of larger alpha (alpha-1) HDL particles [72,73]. This particular species of HDL is most highly correlated with risk for atherosclerosis, with low alpha-1 particle concentration predicting increased risk [74] and elevated alpha-1 HDL predicting protection against CAD events and progression [75]. The low alpha-1 particle number in ABCA1 deficiency states raises two

very interesting points. One is that nothing post-ABCA1 in the HDL metabolism pathway makes up for an initial defect in ABCA1 activity to correct alpha-1 HDL particle formation. This suggests that alpha-1 HDL are a key initial product among the variety of HDL particles generated during the ABCA1–apoA-I–cell interaction [76]. The second point is that increased levels of alpha-1 HDL appear to be a very good indicator of ABCA1 activity, which would make assessment of these particles an excellent biomarker of efficient HDL particle formation when testing novel HDL therapeutics, as well as a marker for atherosclerosis protection. 5.3. Esterification of HDL cholesterol by LCAT Cholesterol removed from tissues onto nascent HDL by ABCA1 and other mechanisms is then esterified by the HDL-associated enzyme lecithin:cholesterol acyltransferase (LCAT) [77]. The cholesteryl esters thus formed move into the core of the particle between the discoidal HDL lipid bilayer, converting HDL into a spherical particle with a monolayer of phospholipids and proteins on its surface [78]. Whether or not esterification of cholesterol by LCAT actually drives the efflux of cholesterol out of cells, by maintaining a cholesterol gradient that allows HDL to receive more cholesterol onto its surface, remains controversial. Some evidence suggests this to be the case [79,80]. LCAT overexpression in human apolipoprotein A-I transgenic mice, while it did increase plasma HDL-C levels, did not increase the release of cholesterol from macrophages [81]. LCAT-transgenic or deficient mice have shown changes in susceptibility to atherosclerosis opposite to those expected based on effects on their plasma HDL-C levels (reviewed in Rousset et al. [11]). Some studies of LCAT-deficient humans suggest they have increased atherosclerosis based on carotid intima–media thickness [82], while others find a protective effect on this parameter in these patients [83]. A recent study found that low plasma levels of LCAT did not correlate with plasma HDL-C and were not associated with increased atherosclerosis in the general population [84]. A role for therapeutically increasing LCAT activity as a way of increasing HDL-C in non-LCAT-deficient patients, therefore, remains uncertain but still potentially promising. 5.4. Transfer of neutral lipids between HDL and apoB-containing lipoproteins Some of the cholesteryl esters produced in HDL by LCAT are then transferred from HDL to the apoB-containing lipoprotein fraction, in exchange for other neutral lipids including triacylglycerols (triglycerides, TG) by the lipid transporter cholesteryl ester transfer protein (CETP) [85]. Cholesterol removed from tissues via HDL formation and onto preformed HDL and transferred by CETP therefore serves as a major source of the cholesterol content of apoB-containing lipoproteins. Much of the reduction in HDL-C seen in diabetes and impaired glucose tolerance is due to transfer of excess triglycerides from TGrich lipoproteins that are elevated under these conditions onto HDL by CETP. Whether inhibiting CETP, to maintain more cholesterol in the HDL fraction and reduce its delivery to VLDL or LDL, is likely to be beneficial therapeutically remains controversial. Individuals with CETP mutations resulting in elevations in plasma HDL-C have shown variable degrees of protection against ischemic vascular events [85]. The prevailing evidence, however, suggests that reduced CETP activity leading to increased HDL-C may be beneficial in reducing atherosclerosis. The first major CETP inhibitor tested clinically, torcetrapib, despite raising HDL-C very effectively as well as lowering LDL-C, resulted in increased deaths from cardiovascular events as well as allcause mortality [86]. The reasons for this remain unclear but are felt to be potentially related to off-target effects of torcetrapib unrelated to the changes in HDL-C or HDL particles [87]. The possibility exists, however, that the HDL particles created in the presence of torcetrapib lose their ability to promote the final steps of reverse cholesterol

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transport effectively or that they lose other protective activities. Newer agents, including dalcetrapib and anacetrapib, with variable degrees of potency as CETP inhibitors, and which are not known to increase blood pressure as torcetrapib does, are currently under clinical investigation to assess their ability to reduce vascular events [88,89]. 5.5. Uptake of HDL cholesterol by SR-BI Completion of delivery of cholesterol derived from tissues on HDL back to the liver is mediated by its selective uptake, along with other HDL lipids, by scavenger receptor type B, class 1 (SR-BI) [67]. Cholesterol delivered back to the liver on HDL, as opposed to from apoB-containing lipoproteins via the LDL receptor and LDL receptorrelated protein, appears to be preferentially trafficked for excretion into bile [90]. The ability of HDL to interact with SR-BI and the actions of SR-BI are therefore critical to the final steps of RCT and to the generation of smaller HDL and lipid-free or lipid-poor apoA-I that can then recirculate in the RCT pathway. Deficiency of SR-BI in mice leads to a massive accumulation of cholesterol-rich HDL but a marked decrease in biliary cholesterol excretion and increased susceptibility to atherosclerosis [91]. Conversely, overexpression of SR-BI in mice leads to a reduction in plasma HDL-C but with an increase in fecal sterol excretion and a reduction in atherosclerosis, presumably due to enhancing reverse cholesterol transport [92,93]. LDL receptordeficient mice overexpressing SR-BI, while showing reduced HDL-C, did not exhibit reduced apoA-I levels, indicating the apoA-I remained available for recirculation in the RCT pathway [92]. Stimulation of RCT by enhancing the SR-BI pathway, which would likely result in a reduction in circulating plasma HDL-C but in a beneficial way, remains a therapeutic option to be explored. 5.6. Catabolism of HDL by hepatic lipase Additional catabolism of HDL at the hepatocyte surface occurs by the action of hepatic lipase, which hydrolyzes HDL triglycerides and phospholipids, generating smaller HDL particles and lipid-free or lipid-poor apoA-I that can then recirculate in the RCT pathway [94]. Overexpression of hepatic lipase in rabbits leads to a marked reduction in circulating HDL-C levels [95]. Deficiency of hepatic lipase in humans leads to enrichment of triglycerides in HDL and increased risk for premature atherosclerosis [96], again presumably due to generating abnormal and large HDL particles and a failure to regenerate smaller HDL and apoA-I for continued cycling in the RCT pathway. Whether enhancing hepatic lipase activity, which would also lead to a reduction in HDL-C, is a viable therapeutic target remains unknown at present. 5.7. Endothelial lipase, phospholipid transfer protein, and effects of triglyceride-rich lipoprotein hydrolysis on HDL In addition to the major players in HDL metabolism and RCT indicated above, HDLs are also modified by additional processes including the delivery of triglyceride-rich lipoprotein surface components to HDL during the hydrolysis of these lipoproteins by lipoprotein lipase [97] and the actions of endothelial lipase [98] and phospholipid transfer protein (PLTP) [99]. Increases in lipoprotein lipase activity as are seen with treatment of diabetes, aerobic exercise, and fibric acid therapy [100] result in a decrease in triglycerides and an increase in circulating plasma HDL-C, the latter through delivery of TG-rich lipoprotein components to the HDL pool and a reduction in the replacement of HDL cholesterol by TG via CETP. Endothelial lipase binds to the endothelial surface and primarily hydrolyzes phospholipids on circulating HDL particles, resulting in accelerated apoA-I catabolism [98,101]. Endothelial lipase levels have been shown to correlate directly with presence of the metabolic

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syndrome and coronary calcification [102], and human gene studies have indicated variations in or near the EL gene are an important determinant of plasma HDL-C levels [103–105]. These results, plus the increase in HDL-C and reduction in atherosclerosis seen in ELdeficient mice [106], suggest that inhibitors of EL could be useful as novel agents to increase HDL-C therapeutically. PLTP acts by promoting transfer of phospholipids from VLDL and chylomicrons onto HDL [99] and contributes to the remodeling of HDL by creating larger and smaller HDL particles [107]. Loss-of-function mutations in PLTP have not yet been described in humans, and the overall importance of this protein as a target for manipulation of HDL therapeutically is not yet known. 6. Conversion of protective HDL into dysfunctional HDL Multiple studies have now documented that the protective nature of HDL can be altered in the presence of glucose intolerance or diabetes and under conditions of inflammation where HDL can be modified by oxidative processes and replacement or modification of its protein and lipid components. The protective effect of HDL against coronary disease seen in large population studies was shown to be lost in individuals with impaired fasting glucose or diabetes in the Prospective Cardiovascular Münster Trial, even when plasma HDL-C is not decreased (http://www.chd-taskforce.com/pdf/sk_procam_06.pdf ). Glycation of apoA-I has been shown to impair its ability to promote ABCA1 stabilization and ABCA1-dependent cholesterol efflux, inhibition of adhesion molecule expression [108], and activation of LCAT [109]. HDL from diabetic patient plasma has a reduced ability to stimulate endothelial nitric oxide production and endothelial-dependent vasodilation and to promote endothelial progenitor cell-mediated endothelial repair [110]. Interestingly, these activities are restored in HDL from diabetic patients treated with extended-release niacin [110]. Several studies have shown that HDL can be oxidized in vitro and in vivo by mechanisms including myeloperoxidase-generated hypochlorous acid and peroxynitrite [111–114], or malondialdehyde [115], and that these modifications reduce the ability of apoA-I to promote cholesterol efflux via ABCA1 [111–113,115]. The proteome of HDL has also been shown to be altered markedly in individuals with CAD when compared to healthy controls [116]. In addition to previously known proteins, a host of other proteins including complement regulatory factors and serine protease inhibitors can associate with HDL under conditions of inflammation [116]. How this affects the functionality of HDL is an area of great interest and importance, as the protective nature of specific HDL particles may be partially or completely lost under these conditions. It is likely a safe assumption, however, that protecting HDL against these harmful modifications comes back to the same advice given to all patients to reduce risk for coronary heart disease: eat a healthy diet, exercise regularly, stop smoking, maintain a healthy weight, and prevent the development of diabetes, or if present, maintain optimal blood sugar control and triglyceride levels. 7. Potential assays to measure HDL functionality As indicated above, multiple situations exist, including in the large population of individuals with impaired glucose tolerance or diabetes, where plasma HDL-C measurements alone fail to provide an accurate assessment of the protective or dysfunctional nature of an individual's HDL particles. Additional assays that measure or correlate with the protective activities of HDL, which are predictive of vascular outcomes, and that are technically viable for use on a large scale by clinical laboratories, are sorely needed. Possible candidates for such assays, including measurement of the cholesterol efflux capacity of an individual's serum using cultured cells [117], measurement of HDL particle species—in particular, alpha-1 HDL—by 2-dimensional gel electrophoresis [72,75] or a more convenient method, HDL particle

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size and number using nuclear magnetic resonance (NMR) spectroscopy [118,119], an improved method for measuring fecal sterol excretion, or measurement of the levels or alterations in HDL proteins [116], need to be explored in large studies to test their predictive value and feasibility. Of these, only NMR is currently available for diagnostic testing. It is possible that a panel of gene single nucleotide polymorphisms, mRNA expression patterns, and/or novel plasma protein biomarkers might be developed that would in total provide a highly predictive survey of a variety of HDL-associated parameters. The ability of any such new clinical test or panel to reliably predict risk for development of atherosclerosis or beneficial responses to therapy, and to be feasible and cost-effective on a large clinical scale, will determine the likelihood of such a test being adopted widely. 8. Upcoming clinical trials Given the multiple complexities of HDL metabolism and the continuing uncertainty about the value of pursuing HDL-based therapies, support for the continued development and approval of such therapies will depend in large part on the outcome of trials of HDLraising agents due to be completed in the next 3–4 years. The Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides and Impact on Global Health Outcomes (AIM HIGH) trial of simvastatin plus niacin on cardiovascular outcomes will be completed in 2011 (http://clinicaltrials.gov/ct2/show/ NCT00120289). The Heart Protection Study 2 Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) trial will assess the effect of simvastatin ± ezetimibe plus extended-release niacin and laropiprant on cardiovascular outcomes, and this is due for completion in 2013 (http://clinicaltrials.gov/ct2/show/NCT00461630). If positive, the ability of these trials to ascribe the benefits to changes in HDL-C will need to be determined in consideration of all the other beneficial effects of niacin on lipoproteins, including reduction of LDL-C and apolipoprotein B, triglycerides, lipoprotein (a), and the beneficial anti-inflammatory effects of niacin that are now being reported [120]. The dalOUTCOMES trial will assess the ability of the CETP inhibitor dalcetrapib to affect cardiovascular outcomes in CAD patients after acute coronary syndrome [121] (http://clinicaltrials.gov/ct2/show/NCT00658515). This study is due for completion in 2013. This and further trials using anacetrapib will be critical to know whether CETP inhibition is an important and viable therapeutic target. 9. Conclusions The complexity of HDL is based on the strong but not always consistent trend that low HDL-C is a risk factor for, and that high HDLC is protective against, coronary artery disease. HDL is also complex due to the multiple steps in HDL formation and metabolism that could serve as potential therapeutic intervention points, the alterations and loss of protective function that occur in HDL in the presence of glucose dysmetabolism and inflammation, and a lack of clear understanding how to feasibly measure HDL function clinically. Some things are apparent: (1) the lack of a consistent increase in CAD risk with any single inherited cause of low HDL-C makes the “HDL hypothesis” more difficult to prove than the “LDL hypothesis”; (2) increasing HDL production pharmacologically may nonetheless have very profound beneficial effects, based on the large number of reported protective actions of HDL; (3) HDL-cholesterol is frequently a poor indicator of protection or risk at the individual patient level and may not be an informative read-out of benefit when assessing novel therapies affecting HDL or in identifying novel genes affecting HDL by genome-wide association studies; and (4) other parameters including specific protective HDL particles, e.g., alpha-1 HDL, and the flux of cholesterol through the reverse cholesterol transport pathway and excretion from the body are likely more important to measure than HDL-C. The outcomes of several major clinical trials in the next 3–

4 years will be critical in determining whether HDL-based interventions become front-line therapy in the treatment and prevention of atherosclerosis and other diseases. Acknowledgments This review is dedicated to the memory of John F. Oram, a superb HDL scientist, colleague, and friend. It was funded by CIHR operating grant MOP-12660. References [1] D.P. Barr, E.M. Russ, H.A. Eder, Protein–lipid relationship in human plasma: II. In atherosclerosis and related conditions, Am. J. Med. 11 (1951) 480–493. [2] T. Gordon, W.P. Castelli, M.C. Hjortland, W.B. Kannel, T.R. Dawber, High density lipoprotein as a protective factor against coronary heart disease, Am. J. Med. 62 (1977) 965–968. [3] D.R. Jacobs Jr., I.L. Mebane, S.I. Bangdiwala, M.H. Criqui, H.A. Tyroler, High density lipoprotein cholesterol as a predictor of cardiovascular disease mortality in men and women: the follow-up study of the Lipid Research Clinics Prevalence Study, Am. J. Epidemiol. 131 (1990) 32–47. [4] N.E. Miller, D.S. 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