New Insights Into the Regulation of HDL Metabolism and Reverse Cholesterol Transport

http://www.100md.com 循环研究杂志 2005年第6期

     The Departments of Medicine and Physiology (G.F.L), University of Toronto, Canada

    The Institute for Translational Medicine and Therapeutics (D.J.R.), The Cardiovascular Institute

    the Institute for Diabetes, Obesity

    Metabolism, University of Pennsylvania School of Medicine, Philadelphia.

    Abstract

    The metabolism of high-density lipoproteins (HDL), which are inversely related to risk of atherosclerotic cardiovascular disease, involves a complex interplay of factors regulating HDL synthesis, intravascular remodeling, and catabolism. The individual lipid and apolipoprotein components of HDL are mostly assembled after secretion, are frequently exchanged with or transferred to other lipoproteins, are actively remodeled within the plasma compartment, and are often cleared separately from one another. HDL is believed to play a key role in the process of reverse cholesterol transport (RCT), in which it promotes the efflux of excess cholesterol from peripheral tissues and returns it to the liver for biliary excretion. This review will emphasize 3 major evolving themes regarding HDL metabolism and RCT. The first theme is that HDL is a universal plasma acceptor lipoprotein for cholesterol efflux from not only peripheral tissues but also hepatocytes, which are a major source of cholesterol efflux to HDL. Furthermore, although efflux of cholesterol from macrophages represents only a tiny fraction of overall cellular cholesterol efflux, it is the most important with regard to atherosclerosis, suggesting that it be specifically termed macrophage RCT. The second theme is the critical role that intravascular remodeling of HDL by lipid transfer factors, lipases, cell surface receptors, and non-HDL lipoproteins play in determining the ultimate metabolic fate of HDL and plasma HDL-c concentrations. The third theme is the growing appreciation that insulin resistance underlies the majority of cases of low HDL-c in humans and the mechanisms by which insulin resistance influences HDL metabolism. Progress in our understanding of HDL metabolism and macrophage reverse cholesterol transport will increase the likelihood of developing novel therapies to raise plasma HDL concentrations and promote macrophage RCT and in proving that these new therapeutic interventions prevent or cause regression of atherosclerosis in humans.

    Key Words: high density lipoprotein insulin resistance lipase lipoprotein reverse cholesterol transport

    Introduction

    Population studies have shown a highly consistent, inverse correlation between plasma concentrations of high-density lipoprotein cholesterol (HDL-c) and its major protein apolipoprotein A-I (apoA-I) and atherosclerotic cardiovascular disease risk in humans.1 HDL-c and apoA-I concentrations could simply be integrative markers of other atherosclerotic cardiovascular risk factors and not themselves causal in the disease process. However, studies in animals strongly suggest that HDL and apoA-I have direct antiatherogenic properties. HDL metabolism is somewhat more complex than that of the other major lipoprotein fractions, in that the individual lipid and apolipoprotein components of HDL are mostly assembled after secretion, are frequently exchanged with or transferred to other lipoproteins, are actively remodeled within the plasma compartment, and are cleared at least in part independent from one another. Although the concept of reverse cholesterol transport (RCT) from macrophages to liver and ultimately biliary excretion is the most popular mechanism to explain the ability of HDL to inhibit atherosclerosis, many other properties of HDL have been demonstrated in vitro that could contribute to its antiatherogenic effects.2 To systematically elucidate the relationship between HDL and atherosclerotic risk, we need to better understand the key regulatory factors that determine the net plasma concentration of HDL particles and the flux of lipids through the HDL and RCT pathways.

    In this review, we will attempt to integrate the various components of HDL metabolism, with an emphasis on 3 major evolving themes. The first theme is the concept that RCT does not necessarily imply a unidirectional flux of cholesterol from extrahepatic tissues to liver. HDL also promote substantial cholesterol egress from the liver, which may be a significant source of lipidation for newly secreted nascent HDL particles. HDL should perhaps be viewed as a universal plasma acceptor lipoprotein for cholesterol efflux from cells, playing an important role in unloading excess cholesterol from cells for the maintenance of cellular cholesterol homeostasis. Although efflux of cholesterol from macrophages represents only a tiny fraction of overall cellular cholesterol efflux, it is the most important with regard to atherosclerosis, suggesting that it be specifically termed macrophage RCT.

    The second major theme is the critical role that intravascular remodeling of HDL by lipid transfer factors, lipases, cell-surface receptors, and non-HDL lipoproteins play in determining the ultimate metabolic fate of HDL. Altered HDL composition as a result of enhanced intravascular remodeling results in more rapid clearance, and HDL clearance, rather than production, is the major determinant of plasma HDL-c concentrations.

    The third major theme is the growing appreciation that insulin resistance appears to be associated with the majority of cases of low HDL-c in humans,3,4 although the exact prevalence of the metabolic syndrome and insulin resistance among those with low HDL-c in the general population has not yet been clearly established. Understanding the mechanisms of HDL lowering in insulin resistant states, which remain incompletely understood, could provide insight into the relationship between low HDL and atherosclerosis. There are numerous atherogenic factors that comprise the metabolic syndrome, and it is difficult in this setting to know whether low HDL is simply an associated risk marker or an important cause per se of atherosclerosis. Overall, low HDL probably represents both a risk marker as well as a causal factor for atherosclerotic disease in the metabolic syndrome.

    Regulation of the Synthesis and Secretion of ApoA-I and Nascent HDL Particles

    ApoA-I is present on the majority of HDL particles and constitutes 70% of the apolipoprotein content of HDL particles; as a result, plasma apoA-I concentrations correlate closely with plasma HDL-c. ApoA-I is secreted predominantly by liver and intestine as lipid-poor apoA-I and nascent phopholipid-rich cholesterol-poor HDL particles (Figure 1). Nascent apoA-I/HDL acquire additional phospholipids and cholesterol via cellular efflux as well as by transfer of surface components of triglyceride (TG)-rich lipoproteins (TRL; chylomicrons and VLDL) during lipoprotein lipase (LPL)-mediated intravascular lipolysis of TRL.

    Human apoA-I transgenic mice have elevated levels of HDL containing human apoA-I and are protected against atherosclerosis,5 proving in principle that apoA-I overexpression can positively influence both plasma HDL concentrations as well as atherosclerosis progression. An important issue is whether the rate of apoA-I production is a major determinant of plasma HDL-c and apoA-I concentrations in humans. Regulation of the apoA-I gene occurs primarily at the transcriptional level, mediated by the cis-acting sequences in the proximal promoter of the apoA-I gene, and partly at the posttranscriptional level by increasing the stability of the partially spliced and unspliced nuclear apoA-I mRNA (reviewed in references 6 and 7). Dietary fat, alcohol, estrogen, androgens, thyroid hormone, retinoids, glucocorticoids, fibrates, niacin, and HMG-CoA reductase inhibitors are some of the many nutritional, hormonal, and pharmacological factors known to influence transcriptional induction of the apoA-I gene (reviewed in references 6 and 7). Promotion of apoA-I gene transcription and biosynthesis is an attractive therapeutic target for drug development. Based on animal studies, upregulation of apoA-I expression in humans would be expected to raise HDL-c concentrations and provide protection against atherosclerosis.

    In vivo studies of HDL metabolism in human populations over a wide range of body weights, plasma TG concentrations, and presumably insulin sensitivity, have shown that clearance of apoA-I, rather than its production rate, is the most important determinant of the variability of plasma HDL-c and apoA-I concentrations in populations.8eC11 Within phenotypically narrowly-defined populations (ie, humans within a narrow range of body weights, insulin sensitivity, and plasma TG concentrations), production rates of apoA-I also are an important determinant of the variability of plasma HDL concentrations. Nutritional interventions such as, a switch from high-carbohydrate to a high-fat diet appear to exert their major effect on production rates of apoA-I rather than on clearance.12

    In summary, apoA-I production is influenced by many factors and apoA-I transcriptional regulation has an impact on plasma HDL concentrations. Variation in plasma HDL and apoA-I concentrations in the general population, however, is primarily a function of variation in clearance rather than production rates.

    HDL Apolipoproteins and Protein Components Other Than ApoA-I

    ApoA-II is the second most abundant apolipoprotein of HDL, found on approximately two-thirds of HDL particles. Its physiologic role has not been fully defined. HDL also contains a variety of other proteins, including apoA-IV, apo C-I, apo C-II, apo C-III, apoD, apoE, apoJ, apo L-I, apoM, serum amyloid A proteins, ceruloplasmin, transferrin, and enzymes such as LCAT, PON1, and PAF-AH/Lp-PLA2. These proteins have qualitative effects on HDL function. HDL are comprised of a number of discrete, quantitatively minor species for which discrete metabolic roles are emerging. For a more detailed discussion of this topic please see the online data supplement available at http://circres.ahajournals.org.

    Acquisition of Unesterified Cellular Cholesterol by ApoA-I and Nascent HDL and Its Esterification in Plasma

    As mentioned previously, nascent HDL is secreted by liver and intestine as lipid-poor apoA-I or small particles containing apoA-I and phospholipids and with pre- mobility on electrophoresis. Pre- HDL generally contain 2 copies of apoA-I per particle and 10% by mass of lipid (free cholesterol and phospholipids).13 Similar particles are regenerated during the catabolism of TRL and mature HDL.14 Pre- HDL are present as minor components in plasma and are believed to play a role as initial acceptors of free cholesterol from cells.15 Distinct from pre- HDL is monomolecular, pre--migrating, lipid-poor or -free apoA-I, which promotes cholesterol and phospholipid efflux from cells via ABCA1 (see below). The presence of lipid-poor or -free apoA-I in vivo has not been definitively established, because it is rapidly either reincorporated into mature HDL, relipidated to form pre- HDL, irreversibly lost, or cleared by the kidneys. It is likely that pre- HDL particles are formed very rapidly when monomeric apoA-I is exposed to cells.

    Lipid efflux from cells to these acceptor lipoprotein particles can occur by a number of mechanisms, including regulated transporter-facilitated processes as well as aqueous diffusion (reviewed in reference 16). ABCA1 is an important cellular protein that facilitates efflux of cellular cholesterol to lipid-poor apoA-I as the preferred acceptor. The critical role that ABCA1 plays in determining plasma HDL-c concentrations has been well established. Humans with Tangier disease, who are homozygous for functional mutations of ABCA1, have virtually undetectable plasma concentrations of HDL-c and apoA-I, because of impaired lipidation and subsequent rapid catabolism of lipid-poor apoA-I. Even heterozygotes for functional ABCA1 mutations generally have HDL-c levels that are less than fifth percentile. Cholesterol efflux from skin fibroblasts is impaired in persons with functional ABCA1 mutations and correlates with plasma HDL-c concentrations.17eC19 An important question remains as to the prevalence of ABCA1 mutations in the general population with low HDL-c levels. Studies in a large cohort of Dutch patients with hypoalphalipoproteinemia revealed a low prevalence (4.5%) of defects in ABCA1-mediated cholesterol efflux from skin fibroblasts.20 Probands of French-Canadians with moderate to severe familial hypoalphalipoproteinemia were shown to have a higher prevalence of ABCA1 mutations (29%)21 but accounted for no cases of low HDL-c in those with the metabolic syndrome.22 Other studies have also failed to find functional ABCA1 mutations in populations with low plasma HDL-cholesterol concentrations.23,24 However, in a recent population-based study, 16% of individuals with HDL-c levels less than fifth percentile had nonsynonymous mutations in ABCA1 compared with only 2% of those with HDL-c levels greater than ninety-fifth percentile.25 Similar findings have been reported by others.26 Thus rare private ABCA1 mutations may contribute substantially to the low HDL-c state. Because isolated familial hypoalphalipoproteinemia is a less prevalent condition than the low HDL-c that occurs in conjunction with insulin resistance, it is likely that primary cellular lipid efflux defects account for the minority of cases of hypoalphalipoproteinemia in the general population.

    Animal studies have helped to clarify the physiologic role of ABCA1. ABCA1 knockout mice have an extremely low HDL-c phenotype similar to that of humans with Tangier disease (reviewed in references 27 and 28). Interestingly, macrophage-specific deficiency of ABCA1 had a minimal effect on reducing plasma HDL-c levels in mice, but it resulted in significantly increased atherosclerosis (presumably, although not proven, attributable to impaired macrophage RCT).29,30 Thus, macrophage ABCA1 appears to contribute little to bulk lipidation of HDL and therefore to plasma HDL-c levels31 but does seem to be important for protection from atherosclerosis. Conversely, liver-specific deficiency of ABCA1 in mice dramatically reduced HDL-c levels by 80%.32 Thus, hepatic ABCA1 appears to be critical for the initial lipidation of newly secreted lipid-poor apoA-I (Figure 1), protecting it from rapid degradation and allowing it to go on to form mature HDL. ABCA1 overexpression in liver increased HDL-c levels33,34 and in macrophages and liver was associated with protection against atherosclerosis.35eC37

    Macrophages have other pathways for effluxing excess cholesterol to HDL. ABCG1 and ABCG4 were reported to mediate net mass efflux of cellular cholesterol to mature HDL but not to lipid-poor apoA-I.38 ABCG1 knockout mice have marked macrophage cholesterol accumulation, and ABCG1 overexpression protects tissues from cholesterol accumulation.39 Thus ABCG1 may be another important pathway for macrophage cholesterol efflux. The contribution of ABCG1 to integrated macrophage reverse cholesterol transport or its effect on atherosclerosis has not been determined. Scavenger receptor class B, type I (SR-BI) may also play a role in mediating cellular cholesterol efflux to mature HDL.40 The influence of macrophage SR-BIeCmediated efflux on HDL metabolism and reverse cholesterol transport has not been definitively established. The SR-BI knockout mouse has increased HDL-c levels,41,42 probably because of the key role of hepatic SR-BI in HDL catabolism (see below). However, these mice have increased atherosclerosis,43 which could be due in part to impaired macrophage cholesterol efflux. Indeed, mice specifically lacking macrophage SR-BI have normal HDL-c levels but increased atherosclerosis,44 consistent with this concept.

    The discovery of ABCA1 as a major regulator of cellular cholesterol efflux and determinant of HDL-c levels has led to intense interest in the molecular regulation of ABCA1 expression45 and as a target for the development of new therapies. The liver X receptors (LXR) and are nuclear receptors that sense cellular cholesterol excess and whose physiological ligands are oxysterols.46,47 Synthetic LXR agonists have been shown to upregulate macrophage ABCA1 expression, increase cholesterol efflux in vitro, and reduce atherosclerosis in mice.48,49 Thus far, enthusiasm over potential upregulation of LXR as a therapeutic target has been tempered by the development of hypertriglyceridemia and fatty liver, in part because of LXR-mediated upregulation of hepatic SREBP-1c. Of note, synthetic agonists of peroxisome-proliferator-activated receptor (PPAR) and PPAR have been shown to upregulate LXR and ABCA1 and promote cholesterol efflux in vitro,50 but the in vivo relevance of this observation has not been established.

    Despite the enthusiasm for RCT as a mechanism for HDL protecting against atherosclerosis, it is difficult to measure integrated RCT from macrophage to liver and feces in vivo. Indeed, studies of whole body RCT have suggested that manipulation of apoA-I levels did not change the rate at which peripheral cholesterol was returned to the liver.51,52 However, a method in which macrophages were loaded with cholesterol and labeled with a cholesterol tracer ex vivo and injected intraperitoneally into mice showed a significantly greater rate of macrophage to feces RCT in apoA-I overexpressing mice, indicating that apoA-I does promote macrophage-specific RCT.53 Future studies are necessary to determine the roles of specific gene products and of pharmacological approaches on macrophage specific RCT.

    Intravascular Maturation and Remodeling of HDL Particles by Cholesterol Esterification, Lipid Exchange, and Lipolytic Modification

    The above discussion has focused on the biosynthesis and initial lipidation of nascent HDL particles. This is followed by dynamic intravascular maturation and remodeling of HDL. A number of lipid transfer factors and lipolytic enzymes play key roles in this process. Many of these factors have diverse functions and in many cases their effects on atherosclerosis may be unrelated to their effects on HDL. The following discussion of these factors will focus exclusively on their roles in HDL metabolism.

    Lecithin-cholesterol acyltransferase (LCAT) plays an important role in the maturation of nascent to mature HDL. ApoA-I and nascent HDL acquire cholesterol from cells in the unesterified (or free) form, but much of plasma HDL cholesterol is in the form of cholesteryl esters (CE). LCAT catalyzes the transfer of 2-acyl groups from lecithin to free cholesterol, generating CE and lysolecithin.54 Hydrophobic CE are retained in the HDL core forming larger mature HDL particles. The activity of LCAT is critical to normal HDL metabolism. In humans, genetic LCAT deficiency syndromes are associated with markedly reduced HDL-c and apoA-I levels55 and rapid catabolism of CE-poor apoA-I.56 The mouse LCAT knockout has a similar phenotype.27,57,58 However, the importance of LCAT to the process of RCT, although postulated, has not been firmly established. Absent functional LCAT activity does not necessarily result in a major defect in RCT, perhaps because much RCT may occur as unesterified cholesterol. Indeed, in humans unesterified cholesterol in HDL can be directly transferred to the liver and secreted in bile.59

    Cholesteryl ester transfer protein (CETP) is a hydrophobic glycoprotein made by liver and adipose that circulates in the plasma bound to lipoproteins.60 It promotes the redistribution and equilibration of hydrophobic lipids packaged within the lipoprotein core (CE and TG) between HDL and the apo BeCcontaining lipoproteins (LDL, IDL, VLDL, chylomicrons, and remnants; Figure 2). The net effect of CETP action on HDL is depletion of CE and enrichment with TG, with an overall net reduction in the size of the HDL particle. Under normal physiological conditions the amount of CETP mass in plasma is not the rate-limiting factor that determines CE distribution between the slowly catabolized LDL and HDL, whereas CETP mass is rate limiting in the transfer of lipids between HDL and the more rapidly turning over TRL. Heterotransfer of CEs and TGs between HDL and TRL is increased in hypertriglyceridemia61 and in the postprandial state.62 The preference of CETP for lipid exchange between HDL and TRL is attributable to suppression of LDL lipid exchange by the naturally-occurring lipid transfer inhibitor protein (LTIP).63 Overall, the magnitude of net flux of CE and TG between the lipoproteins is probably dependent to a greater extent on the relative sizes of the respective lipoprotein pools rather than on the amount of CETP mass per se.

    The importance of CETP in HDL metabolism was conclusively demonstrated by the discovery of CETP-deficient patients in Japan, who have extremely elevated levels of HDL-c64 and reduced turnover of apoA-I.65 Mice naturally lack CETP, and when it is transgenically expressed HDL-c levels are markedly reduced.66 Thus, the activity of CETP in exchanging CE out of HDL for TG has the net effect of reducing HDL-c levels. The impact of CETP deficiency on cardiovascular risk has not yet been resolved. Synthetic CETP inhibitors have been developed and have been shown to decrease atherosclerosis in rabbits67,68 and to effectively raise HDL-c levels in humans,69eC71 spurring substantial interest in this approach. However, there remains some uncertainty, because CETP-mediated transfer of CEs from HDL to apo B-containing lipoproteins may be one pathway of RCT. In humans, radiolabeled HDL CE that eventually was excreted into bile (as free cholesterol or bile acid) was transported to the liver almost entirely after transfer (presumably via CETP) to apoB-containing lipoproteins.59 In addition, there is increasing appreciation that the functionality of HDL particles may be an important determinant of their antiatherosclerotic effects, and it is not yet clear whether the large CE-rich HDL particles that accumulate as a result of CETP inhibition will be effective in inhibiting atherogenesis. Thus, it will be extraordinarily interesting and important to determine whether CETP inhibition will reduce atherosclerosis in humans.

    Phospholipid transfer protein (PLTP) transfers surface phospholipids from TRL to HDL during TG lipolysis72 and appears to account for most of the phospholipid transfer in human plasma. Targeted disruption of PLTP in mice results in an 60% reduction in HDL lipid and apoA-I levels73 because of enhanced clearance of phosphaditylcholine-depleted HDL particles. Human PLTP transgenic mice have increased levels of preeC-1 migrating HDL, apoA-I, and phospholipid.74 PLTP is able to remodel HDL particles into larger HDL particles by particle fusion, with concomitant release of lipid-poor apoA-I.72 In addition to PLTP activity, HDL apolipoprotein composition and core lipid composition play an important role in PLTP-mediated HDL particle conversion.72 Remodeling by PLTP is markedly enhanced in triglyceride-enriched HDL,75 perhaps because of destabilization of apoA-I in these particles.76 Genetic PLTP deficiency in humans has not been conclusively described, and the role of PLTP in human physiology and pathophysiology has yet to be clearly elucidated.

    Lipoprotein lipase (LPL) is secreted by many tissues of the body, particularly metabolically active adipose tissue and muscle (reviewed in reference 77). It is transferred to the luminal surface of endothelial cells, where it is bound as homodimers to heparan sulfate proteoglycans and can be released by administration of heparin. LPL has predominantly TG lipase activity with minor phospholipase activity. It is the principal enzyme responsible for the hydrolysis of triglycerides in TRL and the release of free fatty acids, transforming large TG-rich particles into smaller TG-depleted remnant lipoproteins. In the process of hydrolyzing TRL, redundant surface lipid (free cholesterol and phospholipid) and apolipoproteins are transferred from TRL to HDL particles, contributing significantly to plasma HDL-c and HDL-associated apoA-I concentrations. In addition, an accumulation of TRL secondary to LPL deficiency enhances CETP-mediated lipid exchange between TRL and HDL, thereby enriching HDL particles with triglycerides and depleting them of CE.78 Not only would this have the direct effect of lowering plasma HDL-c concentration but the HDL lipid compositional change itself predisposes HDL particles to PLTP-mediated phospholipid exchange and hepatic lipase-mediated clearance of HDL from the circulation, as will be discussed.

    Plasma HDL-c concentrations correlate positively with postheparin plasma LPL activity.79 Homozygous and heterozygous LPL deficiency syndromes in humans are associated with reduced plasma HDL concentration. Similarly, LPL knockout mice not only have marked hypertriglyceridemia but their HDL levels are also low.80 Transgenic overexpression of LPL in mice is associated with elevations of HDL. Interestingly, significant correlations between LPL activity and HDL levels in LPL transgenic mice were only evident in the presence of the CETP transgene,81 suggesting that lipid transfer between TRL and HDL is the dominant mechanism whereby LPL over- and under-expression influences HDL levels. Pharmacological upregulation of LPL elevates HDL,82 whereas in vivo monoclonal antibodyeCmediated inhibition of LPL in monkeys results in a lowering of HDL-c and apoA-I attributable to a marked increase in HDL apolipoprotein catabolic rate and degradation of apoA-I in the kidneys.83 As will be discussed for the other lipases, LPL has also been shown to mediate selective HDL CE uptake by hepatocytes in culture, independent of its lipolytic activity.84

    Hepatic lipase (HL) is a lipolytic enzyme synthesized by hepatocytes and has both TG lipase as well as phospholipase A1 activity (for more detailed reviews of HL structure/function relationships, synthesis, regulation, and role in atherosclerosis see references 85 through 87). It is bound to the surface of liver sinusoidal capillaries anchored by heparan sulfate proteoglycans. Several lines of evidence indicate that HL plays an important role in mediating HDL metabolism. In contrast to LPL, HL has greater activity against HDL than VLDL or chylomicrons and converts larger HDL particles to smaller HDL remnants, pre- HDL, and lipid-poor or -free apoA-I. The magnitude of the effect of HL on HDL is highly dependent on the composition of HDL. CETP-mediated TG enrichment and CE depletion of HDL, as occurs in hypertriglyceridemic conditions, greatly enhances HDL remodelling by HL (reviewed in reference 88).

    In contrast to the positive relationship between postheparin LPL activity and HDL, postheparin HL activity correlates inversely with low HDL-c levels in humans.89 Individuals with a functional mutation of the hepatic lipase gene have moderately raised HDL-c with enlarged TG-rich HDL particles.90 Mice with targeted disruption of the HL gene have a mild elevation of plasma HDL, which becomes more profound compared with wild-type mice when they are fed a high-fat and cholesterol-rich diet.91 Overexpression of HL in mice and rabbits results in marked reductions in HDL-c and reductions in HDL size (reviewed in reference 87). As is the case with LPL, HL possesses both a lipolytic function and a physiologically relevant nonlipolytic function, both of which play a role in mediating HDL metabolism (reviewed in reference 87).

    Endothelial lipase was discovered in 1999 as a new member of the lipase family that has considerable homology with both LPL and HL.92,93 EL is synthesized by endothelial cells, functions at the vascular endothelial surface, and has primarily phospholipase A1 activity, with relatively little triglyceride lipase activity compared with LPL and HL.94 EL hydrolyzes HDL more efficiently than the other lipoprotein fractions.94 There is convincing in vivo evidence that EL plays an important role in modulating HDL metabolism. Adenoviral vector-mediated overexpression of EL in mice resulted in significant reduction in HDL-c and apoA-I levels.92 This decrease in HDL and apoA-I was shown to be associated with the generation of smaller HDL particles, because of increased fractional catabolism, and to be clearly dose-dependent.95 Transgenic expression of human EL was also reported to be associated with reduced HDL-c levels.96 On the other hand, antibody inhibition of EL activity in mice significantly increased plasma HDL-c, phospholipids, and apoA-I levels and resulted in larger HDL particles.97 Gene knockout of EL in mice also results in increased HDL-c levels.96,98 As with HL and LPL, EL can bridge lipoproteins through binding to heparan sulfate proteoglycan99,100 and therefore may have physiologically relevant ligand-binding functions that influence HDL metabolism in vivo; however, lipolytic activity is required for the profound effects on HDL metabolism with overexpression.101 Of note, overexpression of EL also reduces levels of apoB-containing lipoproteins102 and the knockout mice have modest increases in levels of apoB-containing lipoproteins,103 so the action of EL may not be strictly limited to HDL in vivo. The physiological role of EL in humans and its effects on atherosclerosis remain to be determined. Variation in the EL gene may be associated with variation in HDL-c levels.104,105 In the apoE-deficient murine model of atherosclerosis, EL knockout mice have reduced atherosclerosis, indicating that EL may be a proatherogenic enzyme.103

    The relative or combined effects of HL and EL on HDL metabolism have yet to be established. Perhaps HL is most active in hydrolyzing the triglycerides in TG-rich HDL, whereas EL hydrolyzes predominantly HDL phospholipids. HL and EL may exert differential effects on HDL metabolism depending on the prevailing metabolic milieu and their effects may depend on the relative composition of HDL particles, as determined by other genetic and metabolic factors.

    The secretory phospholipase A2 (sPLA2) family consists of low-molecular-weight secreted phospholipases that exhibit sn-2 phospholipase activity,106 and some have the ability to hydrolyze HDL phospholipids and may be physiologically relevant in regulating HDL metabolism.107 The most-studied member of this family is sPLA2-group IIA, which is upregulated in acute and chronic inflammatory states.106 Transgenic overexpression of sPLA2-IIA in mice results in reduced levels of HDL-c, reduction in size of HDL, and more rapid catabolism of the HDL particles.108 Thus, sPLA2-IIA may play a role in reducing HDL-c levels in the setting of inflammation.

    Receptor-Mediated Selective Uptake of HDL-c and Catabolism of HDL Apolipoproteins by Tissues

    The kidney, liver, and steroidogenic tissues are major sites of HDL catabolism. Clearance of HDL may be either by the selective removal of cholesterol (mainly) and other lipids from the particle, without uptake of the whole particle, a process termed selective cholesterol uptake, or by endocytic uptake and degradation of the whole particle, including apoA-I, a process we will refer to as holoparticle HDL uptake.

    SR-BI, a member of the scavenger receptor superfamily of proteins, binds to a variety of ligands including high-affinity binding to HDL and has been shown to play a major role in HDL selective lipid uptake by tissues.43,109 Catabolism of all major HDL lipids can occur via SR-BI, with the highest uptake constants for CE and free cholesterol and lower uptake constants for phospholipids and triglycerides.110 The importance of SR-BI, which is highly expressed in liver, adrenal gland, and ovary, for HDL metabolism has been readily demonstrated in genetically altered animals (for a recent comprehensive review see Trigatti et al43). Lipid is transferred from the HDL core to tissues by a 2-step process (binding of HDL to the receptor followed by diffusion of lipid into the plasma membrane) without concomitant degradation of the particle. Small, dense HDL particles generated by interaction with SR-BI are rapidly remodeled in an ill-defined fashion in plasma to form HDL2 particles, thereby in large part protecting them from rapid clearance.111 There is, however, some shedding of apoA-I in the process, as well as possibly increased subsequent holoparticle uptake of the lipid-depleted HDL particles. Mice deficient in SR-BI have elevated levels of HDL-c but not of plasma apoA-I, consistent with a defect in selective uptake of HDL cholesterol. Overexpression of SR-BI, on the other hand, results in reduced plasma concentrations not only of HDL-c but also of apoA-I, because of accelerated renal and hepatic clearance of cholesterol-depleted HDL particles after their interaction with SR-BI.112eC114 In contrast to the accelerated catabolism of TG-enriched HDL promoted by HL as discussed above, elevated HDL TG content diminishes rather than enhances the capacity of HDL to deliver CEs via SR-BI.115 ApoA-I conformation and particle size also influence HDL interaction with SR-BI,116,117 as does the remodeling of HDL by CETP and hepatic lipase.118,119

    Holoparticle HDL and apoA-I endocytosis and lysosomal degradation are known to occur in both liver and kidney.120,121 In the kidney, lipid-poor apoA-I is probably filtered at the glomerulus and catabolized by the renal tubular cell via the cubilin/megalin system.122eC124 Receptors that endocytose whole HDL particles or apoA-I protein and lead to degradation in the liver have been somewhat elusive. For further discussion of receptors potentially leading to HDL holoparticle or apoA-I uptake and degradation, including cubilin, megalin, AI-BP, HB1, HB2, HBP, ectopic -chain of ATP synthase, please see the online data supplement.

    Mechanism of HDL Lowering in Hypertriglyceridemic and Insulin Resistant States

    Although low HDL is common, single gene disorders (such as those involving apoA-I, LCAT, and ABCA1 mutations) causing low HDL are rare. There is growing appreciation that insulin resistance appears to underlie the majority of cases of low HDL in humans,3,4 although the exact prevalence of the insulin resistance syndrome among those with low HDL-c in the general population has not yet been clearly established. Approximately one quarter of the North American population has evidence of insulin resistance and the prevalence is rising.125 Hypertriglyceridemia, low plasma concentrations of HDL-c, and qualitative changes in LDL comprise the typical dyslipidemia of insulin resistant states.126 In fact, a high TG:HDL-c ratio may be the single most characteristic feature of the insulin resistant syndrome, even more highly predictive of insulin resistance than the presence of abdominal obesity.127 The hypertriglyceridemia of insulin resistance is primarily attributable to increased hepatic production of VLDL particles, with an important additional component of postprandial hyperlipidemia.128,129 In humans, there are significant negative correlations between fasting and postprandial plasma TG levels and HDL-c and apoA-I concentrations,3 suggesting a close link between TG and HDL metabolism.

    In vivo lipoprotein turnover studies in humans have shown that hypertriglyceridemic individuals with low HDL-c have significantly increased catabolic rates of apoA-I but no major reduction in apoA-I production rates, in comparison with normolipidemic subjects.8,10,11,130,131 Similarly, in individuals with impaired glucose tolerance and type 2 diabetes, hypertriglyceridemia was shown to be associated with increased HDL catabolism.132,133 A number of potential mechanisms, many already discussed above, could explain the inverse relationship between the hypertriglyceridemia of insulin resistant states and increased HDL catabolism leading to low plasma HDL-c and apoA-I concentrations. One is a reduction in LPL activity, which would have the effect of impairing the maturation of HDL particles. The normal insulin-mediated stimulation of LPL activity, such as occurs in the postprandial state, has been shown to be blunted in insulin resistance.134 In type 2 diabetes, particularly when glycemic control is poor and in patients who are relatively insulin deficient, LPL activity is reduced.135

    Another theory accounting for increased HDL catabolism in hypertriglyceridemic and insulin resistant states relates to the enhanced CETP-mediated hetero-exchange of TG and CE between TRL and HDL.136,137 Fasting triglycerides need only be mildly elevated for there to be significant TG enrichment of HDL.138 The combination of increased CETP-mediated TG enrichment of HDL coupled with the elevated HL activity that occurs in insulin resistance139 enhances the remodelling of HDL in the circulation, with shedding of lipid-poor apoA-I, the generation of remnant HDL particles, and increased HDL catabolism.137 In vivo stimulation of intravascular lipolysis by heparin administration in hypertriglyceridemic but not normolipidemic humans results in the production of small, dense, atypical HDL particles,140 and this phenomenon can be attenuated by the effective treatment of these patients’ hypertriglyceridemia with TG-lowering fibrate therapy.141 The clearance of apoA-I associated with HDL that had been TG-enriched in vivo was significantly faster than non-TG enriched HDL isolated from the same individuals in the fasted state.142

    A number of lines of evidence suggest that lipid compositional change of HDL alone is not sufficient to destabilize the particle and that lipolytic modification of TG-rich HDL is necessary to promote rapid catabolism. In isolated perfused rabbit kidneys, the renal clearance of HDL apoA-I was not significantly enhanced unless the TG-enriched HDL was pretreated with partially purified lipases.11 Lipolytically-modified TG-enriched HDL are cleared faster from the circulation than TG-rich HDL that have not undergone lipolytic modification by hepatic lipase.143 In the rabbit, an animal model naturally somewhat deficient in hepatic lipase, TG-enrichment of HDL alone is not sufficient to enhance HDL particle clearance.144 However, both ex vivo145 as well as in vivo146 lipolysis of TG-enriched HDL by HL enhances the clearance of HDL-associated apoA-I from the circulation. Hepatic lipase acting on TG-enriched but not TG-poor HDL2 induces the shedding of lipid-poor apoA-I, which is then more rapidly cleared from the circulation, presumably primarily by the kidneys. HL action also results in the formation of a residual -migrating HDL particle named remnant HDL2, which has one less molecule of apoA-I, 60% less TG, and 15% less phospholipids and is distinctly different from HDL3.147 Remnant HDL have conformational changes of apoA-I, changes in the fluidity of the lipid environment, and a high free fatty acid concentration.143,147 which may account for their more avid binding to receptors and more rapid catabolism.

    HL activity is elevated in insulin-resistant states such as abdominal obesity and type 2 diabetes, conditions that are also commonly associated with high rates of CETP-mediated lipid exchange between HDL and TRL, and HL activity is correlated with the low HDL levels in these conditions.139,148eC151 HL activity, however, unlike LPL, is not upregulated in a clear-cut fashion by insulin: although studies in patients with type 2 diabetes have shown positive correlations between HL activity and hyperinsulinemia,148 others have shown that short-term insulin infusion causes a decline in HL activity.152 It is more likely that insulin resistance at the liver induces the increase in HL activity. Consistent with this idea, studies in normal and diabetic rats have shown that increases in liver HL activity are induced by chronic, but not acute, insulin administration.153 HL mRNA, protein, and plasma postheparin TG lipase activity is increased in fructose-fed Syrian golden hamsters, an animal model of insulin resistance, and reduced with rosiglitazone treatment, an insulin sensitizer with PPAR agonist activity.154

    The interaction between hepatic lipase and HDL that is TG-enriched appears to be one important mechanism (not necessarily the exclusive mechanism) whereby HDL catabolism is enhanced in insulin resistant states. Other factors associated with the insulin resistant state, such as a chronic inflammatory mileau,155 may also contribute to HDL-c lowering. For example, endothelial lipase is upregulated by cytokines, providing a potential mechanistic link between inflammation and reduced HDL-c levels.156 Future studies are required to elucidate more precisely the perturbations and contributions of the various HDL metabolic pathways in the lowering of HDL plasma concentrations in insulin resistance.

    Conclusions and Future Directions

    In summary, the metabolism of HDL involves a complex interplay of factors regulating the synthesis, intravascular remodelling, and catabolism of HDL. In contrast to apoB-lipoprotein metabolism, the different components of HDL are largely assembled extracellularly and are subject to continuous dynamic exchange, transfer, and lipolysis within the plasma compartment. Even the catabolism of HDL occurs as separate components and generally not as a single HDL particle. Although HDL promotes RCT from extrahepatic tissues to liver, the liver itself is a major source of lipidation of nascent HDL. Furthermore, the tiny pool of macrophage cholesterol that is effluxed to HDL and returned to the liver is probably most important for protection from atherosclerosis, hence the new term macrophage RCT. HDL metabolism and macrophage RCT are major targets for the development of new therapies for atherosclerotic cardiovascular disease. In addition to RCT, HDL may play a role in processes such as inhibition of endothelial inflammation, promotion of endothelial NO and prostacyclin production, and the sequestration and transport of amyloidogenic proteins, oxidized lipids, and lipids derived from exogenous pathogens. These emerging functions of HDL may affect processes such as atherogenesis. Progress in our understanding of HDL metabolism, RCT, and other HDL functions will increase the likelihood of finding these therapies and proving that they are effective in humans.

    Acknowledgments

    Dr Lewis is the recipient of a Career Investigator Award from the Heart and Stroke Foundation of Canada and a Canada Research Chair in Diabetes (http://www.chairs.gc.ca/). His research is supported by the Heart and Stroke Foundation of Ontario, the Canadian Institutes for Health Research, and the Canadian Diabetes Association. Dr Rader is a recipient of an American Heart Association Established Investigator Award, a Burroughs Wellcome Fund Clinical Scientist Award in Translational Research, and a Doris Duke Distinguished Clinical Investigator Award and is also funded by National Institutes of Health grants from the National Heart, Lung, and Blood Institute, National Institute of Diabetes and Digestive and Kidney Diseases, and National Center for Research Resources, including HL55323, HL70128, HL22633, and M01 RR00040.

    Dr Gary Lewis has acted as a consultant to the following pharmaceutical companies that are involved in the lipid-lowering and diabetes therapeutics fields: Pfizer, Merck Frosst, Astra Zeneca, Eli Lilly, Fournier Pharma, Bristol Myers Squibb.

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