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Keywords:

  • apolipoprotein A-I;
  • atherosclerosis;
  • high-density lipoproteins;
  • inflammation

Abstract.

  1. Top of page
  2. Abstract.
  3. Introduction
  4. Composition and structure of HDLs
  5. Metabolism of A-I HDLs
  6. Functions of A-I HDLs
  7. Conclusions
  8. Conflict of interest
  9. References

An inverse relationship between the concentration of high-density lipoprotein (HDL) cholesterol and the risk of developing cardiovascular is well established. There are several documented functions of HDLs that may contribute to a protective role of these lipoproteins. These include the ability of HDLs to promote the efflux of cholesterol from macrophages and foam cells in the artery wall and to anti-inflammatory/antioxidant properties of these lipoproteins. The fact that the main apolipoprotein of HDLs, apoA-I, plays a prominent role in each of these functions adds support to the view that apoA-I should be measured as a component of the assessment of cardiovascular risk in humans.


Introduction

  1. Top of page
  2. Abstract.
  3. Introduction
  4. Composition and structure of HDLs
  5. Metabolism of A-I HDLs
  6. Functions of A-I HDLs
  7. Conclusions
  8. Conflict of interest
  9. References

The concentration of cholesterol in high-density lipoproteins (HDLs) has long been known to correlate inversely with the risk of developing premature coronary heart disease [1–5]. It has been shown in animal studies that increasing the concentration of HDLs reduces atherosclerosis [6–12], although the evidence of a direct protective effect in humans is still circumstantial rather than direct. In one ‘proof of concept’ study; however, it was found that infusing reconstituted HDLs into humans reduced the atheroma burden in coronary arteries [13].

Several known functions of HDL have antiatherogenic potential but which of these is of clinical importance is uncertain. These functions include the ability of HDLs to act as extracellular acceptors of cholesterol released from macrophages and foam cells in the artery wall, as well as anti-inflammatory, antioxidant and antithrombotic properties of these lipoproteins.

This study focuses on the role played by the main apolipoprotein of HDLs, apolipoprotein A-I (apoA-I) in these functions. In order to put the role of apoA-I in perspective, it is necessary first to understand what HDLs are, how they are metabolized and to know something of their functions and the mechanisms by which they protect against cardiovascular disease.

Composition and structure of HDLs

  1. Top of page
  2. Abstract.
  3. Introduction
  4. Composition and structure of HDLs
  5. Metabolism of A-I HDLs
  6. Functions of A-I HDLs
  7. Conclusions
  8. Conflict of interest
  9. References

High-density lipoproteins are the smallest and densest of the plasma lipoproteins. As with other plasma lipoproteins, they contain a hydrophobic core (mainly cholesteryl esters plus a small amount of triglyceride) surrounded by a surface molecular monolayer consisting of phospholipids, unesterified cholesterol and apolipoproteins. There are two main HDL apolipoproteins, apoA-I and apoA-II, which collectively account for 80–90% of the total protein in human HDL. Human HDLs also contain several other minor apolipoproteins, including apoA-IV, apoA-V, the C apolipoproteins, apoD, apoE, apoJ and apoL. In addition, HDLs act as transport vehicles for other proteins that are involved in plasma lipid metabolism. These include cholesteryl ester transfer protein (CETP), lecithin : cholesterol acyltransferase (LCAT) and phospholipid transfer protein (PLTP).

The HDL fraction in human plasma is heterogeneous, consisting of several distinct subpopulations of particles that differ in shape, size, density, composition and surface charge. Most human HDLs are spherical particles that may be separated by ultracentrifugation into two major subfractions, HDL2 (1.063 < d < 1.125 g mL−1) and HDL3 (1.125 < d < 1.21 g mL−1). Nondenaturing polyacrylamide gradient gel electrophoresis separates HDLs on the basis of particle size into at least five distinct subpopulations of particles with diameters ranging from 7.6 to 10.6 nm [14].

High-density lipoproteins may also be divided into two main subpopulations on the basis of their apolipoprotein composition. One subpopulation comprises HDLs containing apoA-I but no apoA-II (A-I HDLs), whilst the other consists of particles containing both apoA-I and apoA-II (A-I/A-II HDLs) [15, 16]. ApoA-I is distributed approximately equally between A-I HDLs and A-I/A-II HDLs in most people, whilst almost all of the apoA-II is in A-I/A-II HDLs [15, 16]. Most of the A-I/A-II HDLs are found in the HDL3 density range, whilst A-I HDLs are prominent components of both HDL2 and HDL3 [15, 16].

Human HDLs are also heterogeneous in terms of their electrophoretic mobility. Agarose gel electrophoresis identifies subpopulations with α, pre-α, pre-β and γ-migration. Most HDLs in human plasma are spherical particles with an α-mobility. Minor subpopulations of pre-β-migrating HDLs consists of discoidal apoA-I-containing particles or even lipid-free/lipid-poor apoA-I.

The various HDL subpopulations are closely interrelated and many are interconvertible by factors acting in the vascular compartment [17].

The functional implications of HDL heterogeneity are still uncertain. There is evidence that the preferred extracellular acceptor of cell cholesterol in the process mediated by ATP-binding cassette A1 (ABCA1) is a minor subfraction of lipid-poor (or even lipid-free) apoA-I [18–20]. There is also evidence that discoidal A-I HDLs are the preferred substrates for LCAT [21], whilst larger, spherical A-I HDLs are the preferred acceptors of cell cholesterol in the efflux process mediated by the scavenger receptor type B1 (SR-B1) [18] and the ABCG1 transporter [22, 23]. The remainder of this study focuses on the A-I HDL subpopulation.

Metabolism of A-I HDLs

  1. Top of page
  2. Abstract.
  3. Introduction
  4. Composition and structure of HDLs
  5. Metabolism of A-I HDLs
  6. Functions of A-I HDLs
  7. Conclusions
  8. Conflict of interest
  9. References

Formation of A-I HDLs

ApoA-I originates in the liver and intestine [24, 25]. Once in plasma the lipid-free apoA-I interacts with ABCA1 in cell membranes [26], in a process that generates discoidal A-I HDLs containing apoA-I, phospholipids and a small amount of unesterified cholesterol. Discoidal A-I HDLs are also generated from the interaction of lipid-poor apoA-I with redundant surface components that are shed from triglyceride-rich lipoproteins following hydrolysis of their triglyceride by lipoprotein lipase [27, 28].

Once formed, discoidal A-I HDLs acquire additional unesterified cholesterol that is passively transferred either from other plasma lipoproteins or from cell membranes. The unesterified cholesterol in A-I HDL discs is then rapidly esterified by LCAT in a reaction that provides the particle with a core of cholesteryl esters and, as a consequence, converts the disc into a small A-I HDL sphere. This LCAT-mediated esterification of cholesterol in discoidal A-I HDLs is very rapid, explaining why most of the A-I HDLs in plasma are spherical rather than discoidal.

Like A-I HDLs, A-I/A-II HDLs are formed only after the individual components have been secreted into the plasma. ApoA-I and apoA-II enter the plasma separately and are assembled into spherical A-I/A-II HDL particles within the plasma in a fusion reaction that appears also to be dependent on activity of LCAT [29].

Catabolism of A-I HDLs

High-density lipoprotein catabolism is complex. Most HDL constituents are metabolized as discrete entities rather than being removed from the circulation as an uptake of the whole HDL particle [17]. For example, the cholesteryl esters in A-I HDLs are either transferred to very low-density lipoproteins (VLDLs) and low-density lipoproteins (LDLs) by CETP or are selectively taken up by the liver following binding of HDLs to SR-B1. HDL triglyceride and phospholipids are removed from the particle by hydrolysis in reactions catalysed by lipases, including hepatic lipase (HL), endothelial lipase (EL) and secretory phospholipase A2 (sPLA2). The apoA-I in HDLs may also be independently metabolized following its dissociation from the particle during HDL remodelling [30]. Once dissociated from HDLs, lipid-poor/lipid-free apoA-I may be excreted in urine [31] or relipidated and thus recycled into the HDL fraction as part of the continual remodelling of HDLs in plasma.

Remodelling of A-I HDLs

High-density lipoproteins are subject to continuous remodelling during their circulation in plasma. Small, spherical A-I HDLs retain a degree of reactivity with LCAT and continue to acquire cholesteryl esters in an expanding particle core. Additional surface constituents (including apolipoproteins) are then required to accommodate the expanded lipoprotein core. Extra apoA-I is provided either in the form of lipid-free apolipoprotein [32] or in a process involving the fusion of the particle with an apoA-I-containing HDL disc [33]. Additional apolipoproteins may also be provided in the form of apoA-II by fusion of the expanding particle with an apoA-II-containing HDL disc [29]. Additional phospholipids and unesterified cholesterol are acquired as transfers from other plasma lipoproteins or as diffusion from cell membranes. The size of spherical, A-I HDLs may also be increased by PLTP in a process of particle fusion that is accompanied by dissociation of lipid-poor apoA-I from the fusion product [34–36].

Remodelling of HDLs may also result in a reduction in particle size. The combined activities of CETP and HL in the presence of triglyceride-rich lipoproteins are especially effective in reducing HDL size [37]. CETP promotes the transfer of cholesteryl esters from HDLs to triglyceride-rich lipoproteins in exchange for triglyceride that is transferred into HDLs. This exchange results in formation of HDLs that are depleted of cholesteryl esters and enriched in triglyceride. This triglyceride enrichment provides particles with the preferred substrate for HL. When HL hydrolyses the newly acquired HDL triglyceride, the consequent reduction in HDL core volume is accompanied by a decrease in HDL particle size and dissociation of lipid-free/lipid-poor apoA-I from the particle.

Metabolism of lipid-free/lipid-poor apoA-I in plasma

Remodelling of A-I HDLs by PLTP, CETP and HL generates a pool of lipid-poor (or lipid-free) apoA-I [38]. A small proportion of this newly generated apoA-I may be excreted in urine [31], although most appears to be recycled into the HDL fraction. There are at least two mechanisms by which lipid-poor apoA-I returns to the HDL fraction (Fig. 1). The simplest involves incorporation directly into pre-existing spherical HDLs that are expanding as a consequence of an interaction with LCAT [38]. ApoA-I may also be relipidated by acquiring phospholipids and unesterified cholesterol from cells in the ABCA1-mediated process [26] to form new discoidal HDL particles. Of the potential metabolic fates of lipid-poor apoA-I, the most important physiologically appears to be the interaction with ABCA1 in a process that promotes efflux of cholesterol from cells.

image

Figure 1.  Cycling of apolipoprotein (apo)A-I between lipid-associated and lipid-poor pools. Remodelling of A-I high-density lipoproteins (HDLs) by cholesteryl ester transfer protein (CETP) and hepatic lipase (HL) reduces the size of spherical A-I HDL particles in a process that is accompanied by the dissociation of a proportion of the apoA-I from the particle. This generates a pool of lipid-poor (or lipid-free) apoA-I that has several potential fates. It may be excreted in urine or recycled into the HDL fraction. Lipid-poor apoA-I may be incorporated directly into pre-existing small spherical A-I HDLs that are expanding as a consequence of an interaction with lecithin : cholesterol acyltransferase (LCAT). Or it may be relipidated by acquiring phospholipids and unesterified cholesterol from cells in the ATP-binding cassette transporter A1 (ABCA1)-mediated process to form new discoidal A-I HDL particles that are, in turn, reconverted back into spherical A-I HDLs by the action of LCAT.

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Functions of A-I HDLs

  1. Top of page
  2. Abstract.
  3. Introduction
  4. Composition and structure of HDLs
  5. Metabolism of A-I HDLs
  6. Functions of A-I HDLs
  7. Conclusions
  8. Conflict of interest
  9. References

Efflux of cellular cholesterol to extracellular acceptors

There are at least four distinct processes that promote the efflux of cholesterol from cell membranes to acceptors in the extracellular space. One involves ABCA1, another SR-B1, a third involves passive diffusion and the fourth involves ABCG1 (Fig. 2).

image

Figure 2.  Role of A-I high-density lipoproteins (HDLs) in promoting the efflux of cholesterol from cells. HDL particles may accept cholesterol (Chol) from cells via several mechanisms. The ATP-binding cassette transporter A1 (ABCA1) promotes the efflux of cholesterol to lipid-free/lipid-poor apolipoprotein (apo)A-I resulting in the formation of discoidal A-I HDLs. Esterification of the cholesterol in discoidal A-I HDLs by lecithin : cholesterol acyltransferase (LCAT) generates spherical A-I HDL particles. Cholesterol may also efflux to mature HDL particles by passive diffusion or by a receptor-mediated pathway, including the scavenger receptor B-1 (SR-B1) or the newly identified ATP-binding cassette transporter G1 (ABCG1).

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ATP-binding cassette A1 translocates phospholipids and cholesterol from the inner to the outer leaflets of cell membranes where they are picked up by apoA-I in the extracellular space [39]. This interaction is limited to apoA-I that contains no or very little lipid. Once formed, the discoidal complexes of apoA-I, phospholipids and unesterified cholesterol are subsequently transported, via lymphatics, to the plasma compartment where they are further metabolized as outlined above.

Mature, spherical A-I HDLs in plasma accept unesterified cholesterol efflux from cells in a process of passive aqueous diffusion that does not require ABCA1 [18]. Unesterified cholesterol in cell membranes is spontaneously released into the aqueous, extracellular space where it collides with and incorporates into any preformed HDL particles that are present. This is a bidirectional process in which unesterified cholesterol exchanges between HDLs and cell membranes. However, a net transfer of cholesterol into HDLs may be achieved by the formation of a concentration gradient generated by LCAT-mediated esterification of cholesterol on the A-I HDL surface.

A third process involved in cholesterol efflux is SR-B1 [18] that mediates a facilitated bidirectional transfer of unesterified cholesterol between cells and HDLs. This process results in a net efflux to HDLs only if there is a concentration gradient of unesterified cholesterol from the donor cell to the acceptor HDL. Larger, spherical HDLs are preferred as acceptors in the efflux promoted by SR-B1.

A forth process is promoted by ABCG1, another cell membrane transporter that differs from ABCA1 in that it promotes the transfer of cholesterol from cells, including macrophages, to large, spherical HDLs in the extracellular space [22, 23].

Once cell cholesterol has been transferred to extracellular acceptors and ultimately incorporated into HDLs, it may be transported to the liver for elimination from the body by several pathways.

Delivery of HDL cholesterol to the liver

The unesterified cholesterol that is incorporated into HDLs may be taken up directly by the liver in a process involving binding of HDLs to hepatic SR-B1. Alternatively, the unesterified cholesterol may be converted by LCAT into cholesteryl esters that are then delivered to the liver by either a direct or indirect pathway. The direct pathway involves binding of HDL to hepatic SR-B1 followed by a selective hepatic uptake of the HDL cholesteryl esters, leaving core lipid-depleted particles to return to the circulation. In the indirect pathway, HDL cholesteryl esters are transferred by CETP to the VLDL/LDL fraction and then delivered to the liver as a consequence of the receptor-mediated uptake of LDLs.

Until recently, most research into HDL function has focussed on the role of these lipoproteins in reverse cholesterol transport. There is growing evidence, however, that anti-inflammatory and antioxidant properties of HDL may contribute as much as their cholesterol transport functions to their ability to protect against vascular disease.

Anti-inflammatory properties of HDL

In studies conducted both in vitro and in vivo, HDLs have been shown to have profound anti-inflammatory properties. Both native HDLs and reconstituted A-I HDLs (A-I rHDLs; containing apoA-I as their only protein and phospholipids as their only lipid) have been shown in vitro to inhibit the expression of the cell adhesion molecules, vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1) and E-selectin in activated endothelial cells growing in tissue culture [40, 41]. Anti-inflammatory properties of A-I rHDLs have also been observed in vivo in several animal models. For example, intravenous infusions of A-I rHDLs reduces the in vivo expression of endothelial adhesion molecules induced by insertion of carotid periarterial cuffs in cholesterol-fed, apoE knockout mice [42]. In another study of apoE knockout mice, the increase in HDL concentration accompanying an overexpression of the human apoA-I gene reduced macrophage accumulation in the aortic root by more than threefold [43]. This was associated with a reduced in vivo oxidation of β-VLDL, lower ICAM-1 and VCAM-1 expression and diminished ex vivo leucocyte adhesion. Anti-inflammatory effects of infusing either native HDLs or A-I rHDLs have also been observed in the setting of the experimental atherosclerosis induced by aortic balloon injury in cholesterol-fed rabbits [44].

Anti-inflammatory properties of HDLs have also been observed in studies conducted in normocholesterolaemic animals. Intravenous infusions of A-I rHDLs inhibit the development of a local inflammatory infiltrate following the subcutaneous administration of interleukin-1 in a porcine model [45]. And in studies of experimental stroke in rats, pretreatment with A-I rHDLs significantly and substantially reduces the brain necrotic area [46]. Furthermore, in a study of haemorrhagic shock in rats, the resulting multiple organ dysfunction syndrome was largely abolished by a single injection of human HDL given 90 min after the haemorrhage [47]. And in a more recent study of normocholesterolaemic rabbits implanted with a nonocclusive carotid periarterial collars, it was found that the acute inflammation induced by the collars was almost completely abolished by intravenous infusions of relatively small amounts of either A-I rHDLs or lipid-free apoA-I [48] (Fig. 3).

image

Figure 3.  Effects of A-I reconstituted high-density lipoproteins (rHDLs) and lipid-free apolipoprotein (apo)A-I on arterial inflammation. Normocholesterolaemic rabbits had a nonocclusive, silastic collar implanted around a carotid artery. When the animals were killed 48 h after collar insertion, carotid arteries were removed and the infiltration of neutrophils quantitated by immunohistochemistry. A noncollared control is also shown. The collared animals each received three intravenous infusions, one 24 h before, one at the time of and one 24 h after collar insertion. The infusions contained either saline, A-I rHDLs at a dose of 8 mg apoA-I per kg or lipid-free apoA-I at a dose of 8 mg kg−1 (adapted from Ref. [44]).

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There is mounting evidence that HDLs may also have acute anti-inflammatory effects in vivo in humans. In one study, a single intravenous infusion of A-I rHDLs into hypercholesterolaemic humans normalized endothelium-dependent vasodilation [49]. In a second human study a single injection of A-I rHDLs corrected the endothelial dysfunction associated with low levels of HDLs in ABCA1 heterozygotes [50].

Further protective effects of HDLs may be achieved by their antioxidant potential [51] although, as with the anti-inflammatory properties, the clinical importance of this remains to be defined.

Antioxidant properties of HDLs

High-density lipoprotein inhibit the oxidative modification of LDLs, in part as a consequence of the activity of antioxidants, such as paraoxonase that are transported by HDLs [51]. However, HDL apolipoproteins, including apoA-I, have intrinsic antioxidant properties [52] that may contribute to the cardioprotective potential of these lipoproteins. The importance of antioxidant properties of apoA-I and their relationship to the anti-inflammatory properties of this apolipoprotein are not known.

Conclusions

  1. Top of page
  2. Abstract.
  3. Introduction
  4. Composition and structure of HDLs
  5. Metabolism of A-I HDLs
  6. Functions of A-I HDLs
  7. Conclusions
  8. Conflict of interest
  9. References

The long-established inverse relationship between the concentration of HDL cholesterol and the risk of developing cardiovascular is almost certainly related to several protective properties of HDLs. These include the ability of HDLs to promote the efflux of cholesterol from macrophages and foam cells in the artery wall and to the anti-inflammatory/antioxidant properties of these lipoproteins. All of these functions appear to involve apoA-I that may therefore be central to the role of HDLs in protecting against vascular disease. These observations provide further support to the view that apoA-I should be measured as a component of the assessment of cardiovascular risk in humans.

References

  1. Top of page
  2. Abstract.
  3. Introduction
  4. Composition and structure of HDLs
  5. Metabolism of A-I HDLs
  6. Functions of A-I HDLs
  7. Conclusions
  8. Conflict of interest
  9. References
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