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. Author manuscript; available in PMC: 2014 Sep 9.
Published in final edited form as: Circulation. 2012 Apr 17;125(15):1905–1919. doi: 10.1161/CIRCULATIONAHA.111.066589

Cholesterol efflux and atheroprotection: Advancing the concept of reverse cholesterol transport

Robert S Rosenson 1, H Bryan Brewer Jr 2, W Sean Davidson 3, Zahi A Fayad 4, Valentin Fuster 1, James Goldstein 5, Marc Hellerstein 6, Xian-Cheng Jiang 7, Michael C Phillips 8, Daniel J Rader 9, Alan T Remaley 10, George H Rothblat 8, Alan R Tall 11, Laurent Yvan-Charvet 11
PMCID: PMC4159082  NIHMSID: NIHMS504802  PMID: 22508840

High density lipoprotein has been proposed to have several anti-atherosclerotic properties, including mediating macrophage cholesterol efflux, anti-oxidant capacity, anti-inflammatory properties, nitric oxide promoting activity and transport of proteins with their own intrinsic biological activities (1). HDL particles are critical acceptors of cholesterol from lipid-laden macrophages, and thereby participate in the maintenance of net cholesterol balance in the arterial wall and in the reduction of pro-inflammatory responses by arterial cholesterol loaded macrophages. The pathways that regulate HDL-mediated macrophage cholesterol efflux and disposition of cholesterol involve cell membrane bound transporters, plasma lipid acceptors, plasma proteins and enzymes, and hepatic cellular receptors (Figure 1). From the earliest proposed concept for HDL mediated cholesterol efflux (2,3), the concentration of the cholesterol content in HDL particles has been considered a surrogate measurement for the efficiency of the “reverse cholesterol transport” (RCT) process; however, macrophage-derived cholesterol represents a minor component of the cholesterol transported by HDL particles (4–7). One important pathway for cholesterol-mediated efflux from macrophage foam cells involves interaction between the ATP-binding cassette transporter A1 (ABCA1) with cholesterol-deficient and phospholipid-depleted apoA-I complexes (preβ migrating HDL or very-small HDL [HDL-VS]) (Figure 2) (1,8). Subsequently, the ATP-binding cassette transporter G1 (ABCGI) mediates macrophage cholesterol efflux through interactions with spherical, cholesterol-containing alpha HDL particles (small HDL, medium HDL [HDL-M], large HDL [HDL-L] and very large (HDL-VL) (Figure 3) (1). In contrast, the scavenger receptor class B type I (SR-BI) is a multifunctional receptor, which mediates bidirectional lipid transport in the macrophage, which is dependent upon the content of cholesterol in lipid-laden macrophages. A more established role for SR-BI in cholesterol trafficking involves selective uptake of cholesteryl esters from mature HDL by the liver. Recent studies suggest that polymorphisms in SR-BI contribute to the functional capacity of this cholesterol disposition pathway (9), thereby providing important insights concerning involvement of this receptor in RCT.

Figure 1.

Figure 1

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Metabolic pathways that regulate HDL

Figure 2.

Figure 2

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Schematic diagram of ABCA1 transporter

Figure 3.

Figure 3

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Schematic diagram of cholesterol efflux via ABCG1, SRB1 and passive diffusion

In this review, we discuss the molecular and cellular pathways involved in macrophage cholesterol efflux and cholesterol disposition, as well as recent clinical trials aimed at better understanding HDL function. Specifically, we address new advances in HDL biology that challenge long-standing misperceptions regarding HDL and cholesterol efflux from arterial wall and non-arterial wall sites through the use of specific terminology that addresses the various tissue locations involved in cholesterol efflux and elimination (Table 1). However, non-macrophage arterial wall efflux and non-arterial wall cholesterol efflux will not be addressed in this review. Critical to understanding the processes that facilitate arterial cholesterol efflux, recent experimental studies establish that increased fecal sterol excretion is not necessarily a pre-requisite for HDL mediated macrophage cholesterol efflux and atheroprotection (10,11). Thus, this new information necessitates revision of initial models of RCT in order to foster accurate description of the critical steps required for effective HDL-mediated atheroprotection.

Table 1.

Key Concepts

  • Reverse cholesterol transport is comprised of multiple components

    • ○ Macrophage-specific arterial wall efflux

    • ○ Non-macrophage arterial wall efflux

    • ○ Non-arterial wall efflux

    • ○ Lipoprotein transport

    • ○ Hepatic cholesterol uptake (Hepatobiliary excretion)

    • ○ Direct excretion into small intestine

    • ○ Fecal excretion

  • HDL-C is not necessarily an adequate surrogate for macrophage cholesterol efflux

  • Fecal excretion of cholesterol is not necessarily a pre-requisite for assessing the cholesterol efflux from the arterial wall

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Evolution of the Reverse Cholesterol Transport Concept

Nearly 50 years ago, Glomset proposed a concept of RCT in overall flux of cholesterol from the entire periphery to the liver and its ultimate fecal excretion (2,3). RCT is also sometimes used to refer to specific steps or specific cell types in this process, thus sometimes causing confusion. In order to enhance communication concerning cholesterol efflux pathways, we propose specific terminology that distinguishes between the various macrophage and non-macrophage sites involved in cholesterol efflux and elimination (Table 1).

Emergence of HDL cholesterol as a Biomarker of Reverse Cholesterol Transport

The emphasis on the cholesterol content of HDL in Glomset’s initial model of RCT (2,3) promulgated the use of HDL-C concentration as a biomarker for cholesterol efflux from tissues (3). Even though cholesterol efflux from the lipid-laden macrophage contributes a minor amount of the cholesterol content to the HDL particles, HDL-C has been found to be inversely related to cardiovascular disease risk (12) and to be positively correlated with the beneficial effect of lipid modifying therapies, including statins (13). Yet, the value of HDL-C as a biomarker may be limited because: 1) a small percentage of HDL-C is derived from peripheral tissues, 2) inaccuracy of direct HDL-C measurements routinely used by most clinical laboratories versus more established but technically more demanding analytical methods, and 3) potential confounding of the cardiovascular risk relationships after statistical adjustment for LDL particle concentration (1).

Efforts to refine biomarkers of RCT have encompassed measurement of specific HDL subclasses based on physical and chemical properties (1). However, the use of multiple static measures of the pool size of HDL-C is likely an inadequate approach for the characterization of a dynamic process that involves the active flux and passive transport mechanisms from lipid-laden macrophages, HDL modifying enzymes and transporters, as well as hepatic cholesterol receptors (1). For these reasons, there is a critical need to identify new and clinically measurable biomarkers that accurately relay information concerning flux through the RCT pathway.

HDL Structure and Composition

HDL Structure

Localized conformational features in apoA-I structure may be of key importance for the interaction of HDL with plasma enzymes, receptors or exposure to oxidants (Table 2). Analysis of different size spherical particles reconstituted with a neutral lipid ester core, revealed almost identical patterns, suggesting similar structures (14) that were consistent with the ‘trefoil’ model in which three apoA-I molecules arrange into a 3-D cage structure that stabilizes HDL lipids (Figure 1). Data consistent with these models was also obtained using HDL isolated directly from human plasma and separation into five distinct density subfractions, using density gradient ultracentrifugation (15). HDL particles predominantly containing apoA-I (LpA-I) isolated by immunoaffinity chromatography from plasma, showed a strikingly similarity to the cross-linking pattern observed with reconstituted HDL forms, indicating a similar apoA-I secondary and tertiary structure. Also, despite variations in particle size and apoA-I molecules per particle, there were no systematic changes in cross-linking patterns between the density subfractions. Combining this information with detailed compositional studies of the LpA-I subpopulations, human plasma HDL particle structure appears to be primarily based on the common intermolecular interactions inherent to the double belt and trefoil models. To account for changes in particle size, a twisting motion of the resident apoA-I molecules has been postulated similar to what has been described in molecular dynamics studies (16). These models hold interesting implications for apoA-I conformation and how it interacts with HDL and plasma-remodeling factors, as well as for the association of other HDL associated proteins that may also alter particle function.

Table 2.

Composition of HDL Lipoprotein Acceptors

HDL-VL HDL-L HDL-M HDL-S HDL-VS Free-Apo
HDL2b HDL2a HDL3a HDL3b HDL3c Pre-b HDL Apo AI
Density (g/mL) Composition (%) 1,063–1,090 1,090–,120 1,120–1,150 1,150–1,180 1,180–1,210 x x
TG 4 4 3 2 1 0 0
FC 4 3 2 1 0.1 0.1 0
CE 29 27 25 23 17 0 0
PL 30 33 29 24 16 16 0
Proteins 33 34 41 50 66 84 100
Apolipoproteins
ApoA-I (mol/mol HDL) 3.6 4.1 4.4 3.7 3 1 1
ApoA-II (mol/mol HDL) 0.8 1.1 1.4 1 0.4 0 0
Other Apo ApoC, D, E ApoC, D x ApoE
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Reviewed in reference 1.

HDL Protein Composition

Approximately 65% of HDL protein mass is apoA-I with another 12–15% apoA-II; however, recent proteomic studies (17–20) have identified up to 50 less abundant proteins in HDL, with many linked to functions such as complement regulation, protease inhibition and innate immunity (1). One view of the complexity of the HDL proteome is that apoA-I acts as an organizing scaffold that stabilizes lipids and allows the attachment of these minor proteins onto the particles. Alternatively, although apoA-I containing particles may represent a majority of HDL, other proteins could potentially generate independent particles that co-isolate with HDL particles, and are therefore similarly classified as “HDL”. The majority of these minor proteins associate with the densest (and hence smallest) HDL populations (21). About 13% of the HDL particle surface is phospholipid-covered and is available for binding by protein-lipid interaction. However, the complete particle surface is available for binding because protein-apoA-I interactions are also possible. This suggests that the term “HDL” refers to a constellation of distinct protein and lipid constructs that share a similar density (20,21), but may vary widely in function (22), as originally suggested by Alaupovic and colleagues (23). Indeed, it is now recognized that specific HDL subpopulations serve highly specialized functions (22). It follows that some of these subspecies may play particularly protective roles in cardiovascular disease and therefore represent important targets for mechanistic investigations.

HDL Lipid Composition

HDL is also heterogeneous in regard to its lipidome and exists in distinct subpopulations that differ in their lipid content (1,15,24–26 (Table 2). Among the minor bioactive lipid components, the abundance of sphingosine-1 phosphate (S1P) per HDL particle is asymmetric across the HDL spectrum, with preferential enrichment in HDL-S (small HDL) as compared to HDL-M (medium HDL), HDL-L (large HDL) and HDL-VL (very-large HDL) subfractions. Sphingomyelin (SM) decreases binding of apoE to HDL, thus the reduced content of sphingomyelin in HDL-L and HDL-VL may explain their role in apoE-mediated cholesterol efflux. Additionally, increased SM/phosphatidylcholine (PC) ratio decreased the binding and activity of LCAT in reconstituted HDL particles (27–29).

Cellular Cholesterol Efflux

The removal of excess cholesterol from macrophage derived foam cells present in the atherosclerotic plaque (2) has been incorporated into the concept of RCT (Figure 1). There are multiple pathways by which excess cholesterol in foam cells can be removed by HDL: 1) aqueous diffusion, 2) ABCA1 (Figure 2), 3) ABCG1, 4) SR-BI, and 5) by endogenous production of lipid-poor apolipoprotein E (apoE) (Table 3, Figure 3) (30). The relative contributions of these pathways to cholesterol efflux from mouse peritoneal macrophages and from cholesterol-loaded human macrophages have been determined (Table 3) (31,32). In cholesterol-normal murine macrophages, the aqueous diffusion pathway is predominant, whereas in cholesterol-loaded macrophages the contributions of the ABC transporters predominate (31). Relative contributions of the efflux pathways are ABCA1 35%, aqueous diffusion 35%, ABCG1 21% and SR-BI 9%. In cholesterol-loaded human macrophages the relative contributions of these pathways to cholesterol efflux are different; the ABCA1 pathway remains predominant but ABCG1 does not contribute to efflux and the SR-BI pathway is relatively more important (32).

Table 3.

Pathways for Macrophage-Specific Cholesterol Efflux

Efflux Pathway Energetics Preferred HDL Acceptor Characteristics
Aqueous diffusion Passive HDL-L~ HDL-M~ HDL-S

  • Process is bidirectional
SR-BI Passive HDL-L>HDL-M>HDL-S

  • Process is bidirectional

  • Creates labile pool of cholesterol for efflux

  • High affinity binding permits cholesterol transfer from plasma membrane to bound HDL particles
ABCG1 Active HDL-L~ HDL-M~ HDL-S
E-HDL

  • Process is unidirectional

  • No high affinity binding

  • Creates and enlarges labile pool of plasma membrane cholesterol for efflux
ABCA1 Active HDL-VS (preβ1-HDL)
Lipid poor apoE

  • Unidirectional process

  • HDL-VS (preβ HDL) interaction with high affinity ABCA1 receptor

  • Active transport from the late endocytic compartment of the endoplasmic reticulum to plasma membrane with formation of HDL-S
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Aqueous Diffusion

The rate-limiting step is desorption of free cholesterol (FC) molecules from the cell plasma membrane into the surrounding aqueous phase. Interactions of FC molecules with neighboring phospholipid (PL) molecules influence the rate (the rate is increased by higher PL unsaturation and decreased by a higher membrane SM content (33). Collision of the desorbed FC molecules with HDL particles diffusing in the extracellular aqueous space leads to their rapid uptake into the lipoprotein acceptor. The human HDL subclasses HDL-L, HDL-M and HDL-S are equally effective acceptors in this pathway, because the efflux process is not affected significantly by alterations in HDL particle size (34).

ABCA1-dependent cholesterol efflux pathway

The concentration of the ABCA1 transporter in the plasma membrane determines the rates of PL and FC efflux and nascent HDL particle formation. The primary acceptor for cellular cholesterol efflux via the ABCA1 pathway includes cholesterol-deficient and phospholipid depleted apoA-I complexes (preβ-1-HDL mobility on two-dimensional gel electrophoresis or HDL-VS) (35,36) (Figure 2). The binding of apoA-I to ABCA1 prevents its intracellular degradation and increases the level of ABCA1 transporter in the plasma membrane. The ABCA1 transporter and apoA-I have an intracellular pathway, which facilitates the mobilization of cholesterol from the late endocytic compartment to the cell membrane (37). The ABCA1 transporter-apoA-I interaction has been proposed to lead to solubilization of an exovesiculated membrane domain, which results in the formation of a heterogeneous population of nascent HDL particles that are discoidal in shape and contain FC molecules (38,39).

Elucidation of the ABCA1 transporter and HDL-VS (preβ-HDL), as the major ligand for the ABCA1 transporter, provided a unique opportunity to quantitate the effect of expanding the HDL-VS (preβ-HDL) pool size by intravenous infusion on cholesterol efflux and coronary atherosclerosis quantitated by the IVUS technique (40–43). HDL, as well as the reconstituted lipid-poor apoA-I complex, are also effective anti-inflammatory agents (44,45). Thus, the infusion of preβ-HDL also reduces vascular inflammation providing a second potential mechanism for intravenous HDL therapy in reducing coronary atherosclerosis (44,45).

The initial clinical data to suggest that infusions of HDL-VS (preβ-HDL) would be effective in decreasing coronary atherosclerosis was provided by the apoA-I Milano infusion study (40). In the combined 36 patients who received apoA-I Milano infusions, total atheroma volume and the 10 mm most diseased segment decreased when compared to the atherosclerosis quantitated at baseline. However, the data were not significant compared to the control saline infusion, possibly because of the limited sample size.

Two additional HDL infusion clinical trials, ERASE Trial (41) and Selective Delipidation Trial (42) confirmed that infusion of preβ-HDL reduced coronary atherosclerosis. The combined results from the acute HDL infusions studies add support to the concept that increasing preβ-HDL may be an effective approach to reduce coronary atheroma burden, with stabilization of the plaque and reduction in clinical cardiovascular events.

HDL is normally cardioprotective because of its ability to promote cellular cholesterol efflux and mediate RCT. However, HDL can become dysfunctional for example by posttranslational modification of apoA-I (46). Myeloperoxidase-induced oxidative damage of apoA-I, which is seen in patients with established cardiovascular disease, impairs its ability to promote cholesterol efflux via the ABCA1 pathway (47).

ABCG1-dependent cholesterol efflux pathway

A second transporter, ABCG1 is also involved in controlling intracellular cholesterol homeostasis. Expression of ABCG1 enhances efflux of cholesterol to HDL by increasing the pool of plasma membrane FC and reorganizing it so that it can desorb more readily into the extracellular medium (Figure 1) (48,49). Larger HDL2 (HDL-VL, HDL-L) are similarly effective to smaller HDL3 (HDL-M, HDL-S, HDL-VS) particles as acceptors from ABCG1 (Table 3). Unlike ABCA1, FC efflux does not require direct binding of HDL to ABCG1 (49, 50).

The ATP binding cassette transporters, ABCA1 and ABCG1, are increased by LXR transcription factors (51–53), which play a pivotal role in modulating cholesterol efflux by both the ABCA1 and ABCG1 transporters. In vivo, LXRs are activated by specific oxysterols in cholesterol-loaded cells (54). ABCA1 and ABCG1 are key target genes of LXRs in macrophages. While ABCA1 promotes cholesterol efflux to cholesterol-deficient and phospholipid-depleted apolipoprotein A-I and E complexes, ABCG1 promotes efflux to HDL particles (35,36,50). Increased expression of the ABCA1 and ABCG1 transporters is associated with redistribution of cholesterol from the inner to the outer leaflet of the plasma membrane, facilitating cholesterol efflux from cholesterol-loaded foam cells to HDL particles (55). LXRs also increase the endogenous expression of macrophage apoE, which increase cholesterol efflux by interaction with the ABCA1 transporter (53).

New insights into the coordinated participation of ABCA1 and ABCG1 in mediating macrophage cholesterol efflux have recently evolved from animal studies. Single deficiency of ABCA1 in mice results in a moderate increase in atherosclerosis, and deficiency of ABCG1 has no effect; however, combined deficiency resulted in markedly accelerated lesion development (56). Double knockout (DKO) macrophages showed markedly defective cholesterol efflux to HDL and apoA-I (57), and also increased inflammatory responses when treated with lipopolysaccharide (57).

Cholesterol homeostasis has also recently been investigated with microRNAs (miRNA), which are small endogenous non-protein coding RNAs that are post-transcriptional regulators of genes involved in physiological processes (58–60). MiR-33, an intronic miRNA located within the gene encoding sterol-regulatory element binding factor-2 (SREBF-2), inhibits both hepatic expression of ABCA1 and ABCG1, reducing HDL-C concentrations (58,61), as well as ABCA1 expression in macrophages, thus resulting in decreased cholesterol efflux (57). Antagonism of MiR-33 by oligonucleotides raised HDL-C and reduced atherosclerosis in a mouse model, and thus may represent a novel approach to enhancing macrophage cholesterol efflux and raising HDL-C levels in the future (62).

Scavenger Receptor Class B Type 1

SR-BI is an 82-kDa integral membrane protein that controls the structure and composition of plasma HDL. SR-BI mediates bidirectional flux (e.g., efflux) of unesterified, or ‘free’ cholesterol (FC) between cells and HDL or other acceptors (63–65).

While SR-BI bone marrow deficiency leads to accelerated atherosclerosis (66–68), the physiological role of SR-BI-mediated arterial macrophage-specific cholesterol efflux in vitro is unclear (65,68,69); At least, SR-BI did not contribute to macrophage RCT in vivo (method described below) (70) and thus, a role for SR-BI in other bone marrow cell populations, such as platelets, may finally emerge to be the relevant role of SR-BI to atherosclerosis (71). By contrast, hepatic SR-BI clearly has an indirect role in atherosclerosis by modulating changes in the composition and structure of HDL particles (72).

Carriers of the first reported mutation of SR-BI in humans (P297S mutation) had increased HDL-C levels but reduced capacity for cholesterol efflux from macrophages without increased severity of atherosclerosis that may have resulted from the small numbers of carriers studied (9).

Endogenous production of apolipoprotein E

In addition to the apoA-I containing HDL, apoE-HDL (E-HDL) plays a pivotal role in RCT. Major sites of synthesis of apoE include the liver and macrophages. E-HDL facilitates both the efflux of cholesterol from the macrophage as well as the delivery of cholesterol to the liver. Lipid poor apoE secreted by the macrophage binds to the ABCA1 transporter and removes excess macrophage cholesterol. E-HDL also facilitates cholesterol efflux from the macrophage by the ABCG1 transporter and LCAT present on the E-HDL particle converts cholesterol to cholesteryl esters. E-HDL particles can deliver cholesterol to the liver through the interaction with both the SR-B1 and LDL receptors. The molecular structure of the E-HDL particles permits the expansion of the CE core and the development of large E-HDL particles. An increase in E-HDL is seen in CETP-deficient patients and in patients treated with CETP inhibitors. These large E-HDL particles containing LCAT are very effective ligands for cholesterol efflux by the ABCG1 pathway and may play an important role in reducing atherosclerosis in the patients treated with CETP inhibitors (73,74).

Enzymatic Modulation of HDL Remodeling in the Various Stages of Reverse Cholesterol Transport

Role of Lecithin:Cholesterol Acyl Transferase

LCAT, a 63 kDa hepatically-synthesized glycoprotein, mediates a two-step reaction in which a fatty acid is cleaved from the sn-2 position of phospholipids and transesterified to the 3-β-hydroxyl group on the A-ring to form cholesteryl ester. Apo A-I activates LCAT (75,76), and the LCAT reaction largely occurs on very-small HDL (HDL-VS) and small HDL (HDL-S) particles (1), transforming these particles into the larger spherical alpha-migrating forms of HDL (HDL-M, HDL-L and HDL-VL) (Figure 3).

Because of the role of LCAT in maintaining HDL-C levels, it is generally believed to be anti-atherogenic. As discussed earlier, Glomset proposed that the esterification of cholesterol would drive the net efflux or removal of cholesterol from cells, because esterification would ‘trap lipoprotein bound cholesterol” and prevent the back exchange of cholesterol from HDL to cells (2,3). LCAT enhances cholesterol efflux by ABCG1 (50) and by passive exchange (77).

However, evidence from various animal models of either over or under expression of LCAT has been controversial in regard to fecal excretion and the atheroprotective role of LCAT as extensively discussed elsewhere (78). The reason of these discrepancies in animal models have not yet been fully understood but may involve levels of overexpression of LCAT, and difference in species, including lack of CETP expression in mice (see paragraph below).

It has also been speculated that the overall effect of LCAT on atherosclerosis may be modulated by other lipid modifying genes or by different diets. Indeed, LCAT-KO mice exhibited decreased atherosclerosis when fed on a high cholesterol-cholate diet (79) but increased atherosclerosis in an apoE-KO background fed a more “Western” high fat diet (80). In addition to its effect on HDL-C, increased LCAT expression in various animal models was found to lower LDL-C (81,82), which often better correlated with atherosclerosis. For example, LCAT transgenic rabbits defective in the LDL-receptor had high HDL-C and LDL-C and did not show protection against diet-induced atherosclerosis (83).

Thus, by contrast to the initial hypothesis proposed by Glomset (2,3), it remains uncertain whether targeting LCAT activity might become a pharmaceutical approach in humans to raise HDL-C, promote macrophage RCT and prevent atherosclerosis. Indeed, similar to what was observed in animal models, LCAT deficiency in humans has not been consistently associated with accelerated atherosclerosis (78) even when HDL-C levels are low. This lack of association has been attributed to the associated low LDL-C levels in these patients. Recent carotid imaging studies in heterozygous patients with LCAT deficiency showed, however, increased atherosclerosis and higher CRP levels (84,85), although the opposite finding was reported in an earlier study (86). Development of new vascular imaging as measures of HDL functionality, as proposed in this manuscript, may potentially clarify the role of this key enzyme of the RCT in humans (87).

Role of Cholesterol Ester Transfer Protein

Human plasma CETP is a 476-residue hydrophobic glycoprotein that catalyzes the transfer of cholesteryl ester (CE), generated by lecithin:cholesterol acyltransferase (LCAT) in HDL, to other lipoproteins. A CETP gene mutation due to an intron 14 splicing defect was the first mutation described in the Japanese population (88,89). Homozygosity for this mutation results in absence of CETP in plasma, dramatic elevations in HDL-C and apoA-I levels, and moderate reductions in LDL-C and apoB levels (73). Based on this phenotype, CETP inhibition was proposed as a possible strategy to increase HDL levels in humans and reduce atherosclerosis (88,89).

Similar to LCAT animal models, variable results on atherosclerosis have been obtained in mice most likely because of the need to overexpress CETP in this animal model naturally lacking CETP (90,91). In contrast, in almost all instances CETP inhibition in the rabbit, a species naturally containing CETP has resulted in reduced lesions (90).

In humans, potent CETP inhibitors have been developed that cause marked increase in HDL-C levels and smaller decrease in LDL-C levels (92–95). The premature termination of the ILLUMINATE study with torcetrapib created concerns regarding CETP mediated increases in HDL-C as a viable therapeutic approach. Based on current data, the increase in adverse outcomes observed with torcetrapib was most likely due to off target toxicity rather than the inhibition of CETP. Post hoc analysis have shown that despite the adverse off-target effect of torcetrapib, there was a significant inverse relationship between the change in HDL-C levels and the primary measure of atherosclerosis, i.e., the percent of atheroma volume (96). The future role for CETP inhibitors without the same off-target effects, such as dalcetrapib and anacetrapib (97), is under investigation in phase III clinical trials. However, these two molecules have significant different effects on plasma lipoprotein metabolism (97).

While anacetrapib is a potent inhibitor of CETP activity, dalcetrapib is a partial inhibitor or modulator of CETP activity. The reason for this difference is not fully understood but could be related to the mode of binding of both molecules (covalent vs. noncovalent binding of dalcetrapib to CETP Cys13 vs. noncovalent biding of anacetrapib to CETP) (97–99). As a consequence, by promoting strong inhibition of CETP-mediated CE/TG transfer activity within HDL (97,98), in vitro anacetrapib treatment was reported to reduce preβ-HDL (HDL-VS) formation (98). There has been concern that the absence of increased small preβ HDL in CETP deficiency (100) may not mediate efficient cholesterol efflux to ABCA1, since preβ HDL (HDL VS) is the key receptor for the ABCA1 transporter. Indeed, the hydrolysis of triglycerides secondary to CETP-mediated CE-TG exchange results in the release of lipid-poor apoA-I. It is possible that the regeneration of these acceptors for ABCA1 is impaired in CETP deficiency (101). However, in vivo studies with enhanced formation of large spherical HDL enriched in LCAT and apoE was associated with effective ABCG1-dependent net cholesterol efflux (102), similar to what was observed in plasma samples from CETP deficiency patients (73). Although cell culture studies have limitations, these data provide evidence that anacetrapib enhanced function of HDL in humans.

In contrast, by being a modulator of CETP-mediated CE/TG transfer, dalcetrapib treatment only modestly promotes formation large spherical HDL enriched in apoE (personal communication Eric Niesor). However, dalcetrapib maintains efficient preβ HDL particle formation (98). This could explain why dalcetrapib enhances RCT in hamsters (98) and prevents atherosclerosis in other animal models with CETP expression (99).

Role of Phospholipid Transfer Protein

PLTP, a member of lipid transfer/lipopolysaccharide binding proteins (103), mediates transfer of phospholipids from apoB-containing lipoproteins to HDL. Active and inactive forms of PLTP are present in the circulation (104,105). The active form of PLTP is associated with apoAI but not apoE, whereas the inactive form is associated with apoA-I and apoE (106). The various PLTP complexes contribute to variation in plasma PLTP activity (107).

In transgenic and gene knockout mice, the association between PLTP and HDL cholesterol levels has been inconsistent (108,109). Furthermore, murine macrophage cholesterol efflux models have not clarified the involvement of PLTP in RCT (110–112). However, several investigators have shown that recombinant PLTP promotes cholesterol efflux in the presence of HDL (113). An in vivo analysis suggests that systemic elevations in PLTP concentrations and not macrophage specific PLTP expression are responsible for impaired macrophage RCT (104). The contribution of hepatic synthesis of PLTP on plasma lipids was investigated in a murine model that specifically expresses PLTP in the liver (114). On a PLTP-null background, hepatic overexpression of PLTP was responsible for increased plasma PLTP activity, and increased VLDL production and circulating concentrations of apoB-containing lipoproteins and HDL-C. In this study, there were no changes in apoA-I levels. In a recent study, human PLTP transgenic rabbits fed a cholesterol-rich diet showed a significant increase in non-HDL-C, no change in HDL-C, and increased formation of aortic fatty streaks as compared to non-transgenic littermates (115).

Role of Endothelial lipase

Endothelial lipase (EL) is a phospholipase, which belongs to the lipoprotein lipase (LPL) gene family (116). The sequence homology of the lid domain, which determines the specificity of lipases, largely differs between EL and LPL or HL. EL is unique among these lipases, because it is primarily synthesized by vascular endothelial cells, and to a lesser extent by macrophages and smooth muscle cells.

EL acts primarily as a phospholipase and hydrolyzes HDL-phospholipids at the sn-1 position. EL overexpression accelerates renal apoAI catabolism (114). In mice, inhibition of EL increases plasma HDL-C levels (117), whereas HDL-C levels decrease in mice that overexpress EL (118). In humans, plasma EL mass was inversely correlated with plasma HDL-C levels and positively correlated with atherosclerosis and features of the metabolic syndrome (119).

EL appears to have a variety of functions, which may modulate atherosclerosis. Thus, the net effect from EL inhibition on atherosclerosis may be complicated and varied among tissues or cells where EL is expressed, or the presence of inflammation. However, a low frequency EL coding variant in humans that was shown to be loss-of-function and is strongly associated with increased HDL-C levels was not associated with reduced CVD risk. (120).

Role of Hepatic Lipase

Hepatic lipase (HL), a 65-kDa sized glycoprotein, is synthesized primarily by the liver where it is bound to proteoglycans (121) and also by macrophages (122). HL has two principal effects on lipoprotein metabolism (Fig. 2). HL promotes the conversion of chylomicrons to remnants as well as VLDL to LDL. It appears, however, to primarily act on smaller size apoB-containing lipoproteins (121). Increased HL activity is associated with increased amount of the more pro-atherogenic small dense LDL (123). In addition, HL acts on large lipid-rich forms of HDL-L (α-HDL) and converts them into smaller subspecies, including preβ-HDL (121). Consistent with these findings, patients with a genetic deficiency of HL have increased concentrations of IDL-C and higher HDL-C levels (124,125).

Data from various animal models of either over or under expression of HL have been inconsistent with regard to atherosclerosis (126), although as expected HDL-C was inversely related to HL activity. An in vivo RCT model in mice involving intraperitonal macrophages radiolabeled with cholesterol showed that HL deficiency in mice increased the amount of the radiotracer in plasma and raised HDL-C but there was no increase fecal cholesterol excretion (127).

In patients, the role of HL in atherosclerosis has been controversial, because it has properties that can be considered both pro-atherogenic and anti-atherogenic, namely increasing small dense LDL and increasing the cholesterol content of HDL respectively. Because of the smaller number of patients reported, it is difficult to assess the impact of HDL in patients with a genetic deficiency of HL (121,128). Because of the role of HL in promoting hepatic uptake of lipids, it may be that higher levels of HDL-C in subjects with lower HL activity may inhibit the hepatic uptake step of the RCT pathway (129).

Liver Receptors

Hepatic expression of scavenger receptor class B type I (SR-BI) is a positive regulator of macrophage reverse cholesterol transport in vivo (130). CETP-mediated HDL cholesterol exchange to LDL particles, and subsequent clearance by hepatic LDL receptors is a second arm of the RCT pathway. SR-BI binds to HDL via apoA-I and mediates selective uptake of HDL-C, primarily from large cholesterol-enriched HDL particles, by a poorly understood process that differs markedly from classic cellular endocytic uptake of lipoproteins (e.g., LDL binding and internalization via LDL receptors) (126,131–133) (Figure 1). The lipid-depleted HDL particles then dissociate and re-enter the circulation. SR-BI also enhances efflux to HDL by creating a pool of activated cholesterol in the membrane.

Experimental Animal Models of RCT

In order to selectively assay the macrophage-specific RCT pathway, a technique in mice was developed in which macrophages are loaded with cholesterol and labeled with a 3H-cholesterol tracer ex vivo and injected intraperitoneally. Plasma specimens are obtained periodically for measurement of radioactivity levels in plasma and HDL fractions; and feces are collected continuously for measurement of fecal [3H] neutral sterols and [3H] bile acids. The 3H-cholesterol is effluxed to HDL-based acceptor particles that enter the plasma compartment. The appearance of tracer can be followed in plasma over time and the amount of macrophage-derived radiolabeled tracer excreted in feces can be quantitated as a estimate of macrophage-to-feces RCT. Quantification of bile acids and neutral sterols can be incorporated in the study to ascertain the net balance of fecal bile acids and neutral sterols. A variation of this model involves injection of [3H] cholesterol macrophages into the peritoneal cavity of Golden Syrian hamsters (98), an attractive model because unlike mice hamsters naturally express CETP. Both cholesterol loaded J774 macrophages as well as macrophages isolated from the mouse peritoneal cavity following [3H] cholesterol injection have been employed in these hamster studies. The immunologic response of the hamsters to the murine macrophages and the potential impact on the RCT process has not been assessed.

Using this macrophage to feces approach, apoA-I overexpression was shown to promote (130) and apoA-I deficiency to impair (134) macrophage RCT, consistent with the atheroprotective role of apoA-I. Multiple studies have assessed macrophage-specific RCT in the setting of genetic and pharmacologic manipulation of mice, and the effects on RCT (in contrast to the effects on HDL-C) are largely consistent with the effects of the same interventions on atherosclerosis (135). Overall, the dynamic rate of macrophage RCT correlates much better than steady-state plasma HDL-C level with atherosclerosis, suggesting that it is measuring an atheroprotective process and could be used to predict the anti-atherosclerotic effects of a novel HDL-targeted intervention. Thus, methods for assessing the integrated rate of macrophage RCT in animals have provided insights into the molecular regulation of the process. Animal studies of macrophage RCT suggest that promotion of cholesterol efflux from macrophages is a potential therapeutic approach to preventing or regressing atherosclerotic vascular disease.

Recently, however, two experimental studies demonstrate fecal cholesterol excretion is not always a pre-requisite for macrophage cholesterol efflux. For instance, infusion of rHDL stimulated cholesterol efflux from extrahepatic tissues and resulted in net flux to the liver without increasing fecal cholesterol excretion (10). Intravenous infusion of the 5A peptide, an apoA-I mimetic peptide, complexed with phospholipid increased cholesterol efflux, measured in vivo by a stable isotope kinetic technique, from ABCA1 and ABCG1-transfected macrophages and reduced atherosclerosis in apoE-KO mice, without changing net fecal excretion of neutral sterols or bile acids (11).

Human Models of Cholesterol Efflux

Robust and sensitive methods for assessing integrated RCT in humans are needed in order to advance insights gained in animals into the human realm and to assess novel therapies targeted toward HDL and RCT (136,137). A comparison of the contribution of efflux pathways of high and low efficiency HDL demonstrated that the increased cholesterol efflux observed in the high efficiency sera was largely attributed to greater efflux via the ABCA1 pathway (137). These observations indicate that HDL quality, particular in terms of HDL subfraction distribution, is a more important parameter in regulating efflux than is total HDL-C or apoA-I. Thus, the demonstration that cholesterol efflux capacity is associated with atherosclerosis further support the use of the measurement of HDL efflux in guiding the development of new HDL-target therapies for humans. While this ex vivo approach supports the concept that the capacity of HDL in promoting efflux is more important than its concentration, a more effective approach would be to develop a clinical method to determine cholesterol flux in humans and in particular the efflux from cholesterol loaded macrophages in coronary plaques. As discussed above, at present one potential approach is the quantification of the mass of fecal sterol and bile acid excretion as a surrogate for RCT. For example, an acute intravenous bolus infusion of pro-apoA-I in humans was found to result in a significant increase in fecal sterol excretion, suggesting promotion of RCT (138), however no increase in fecal sterol excretion in the steady state was reported in patients receiving CETP inhibitors (139). However, this approach is not macrophage-specific, is unlikely to be very sensitive, and may have limited utility in the chronic steady state setting due to counter-regulatory pathways involved in biliary cholesterol excretion and fecal sterol absorption.

An isotope kinetic modeling technique has been developed that involves the intravenous infusion of stable isotopically labeled cholesterol for ~24 hours, with frequent blood sampling for analysis of plasma free cholesterol, red blood cell cholesterol and plasma cholesterol-ester isotope enrichments by mass spectrometry. In addition, stool is collected over subsequent days during oral sitostanol intake, for isolation of fecal bile acid and neutral sterols for mass and isotope enrichments. Simulation modeling (SAAM) is used to calculate the rate of whole body efflux of free cholesterol from tissues into the plasma compartment, after correcting for red blood cell exchange with plasma free cholesterol. Also calculated are the esterification rates of free cholesterol to cholesterol-ester, clearance of cholesterol-ester from the blood; and flux from plasma cholesterol into fecal bile acids and neutral sterols (140). Absolute and relative RCT flux rates in humans have proven to be of interest. Esterification is ~1.3 mg/kg/hr (~2 g/d), which is of similar magnitude as total fecal excretion of sterols, suggesting that the irreversible LCAT step in plasma may be flux generating for sterol excretion from the whole body. Moreover, esterification represents a substantial fate (~40%) of the 3.2 mg/kg/hr (~5g/d) non-erythrocyte-derived free cholesterol efflux into plasma. Interestingly, exchange of red blood cell with plasma free cholesterol (~2.5mg/kg/hr) is of comparable magnitude as non-red cell efflux, potentially providing a non-lipoprotein fallback mechanism for cholesterol carriage and transport in the RCT pathway. Flux of plasma free cholesterol into fecal sterols was 3.4% and 13.4% over 7 days into fecal bile acids and neutral sterols, respectively. Coefficient of variation of the measurement was 10–15% in humans. The consequences of hypoalphalipoprotemia due to ABCAI or ApoAI genetic alterations were explored in a Dutch population (141). Among low HDL-C participants, there was ~40% reduction in efflux despite normal esterification and fecal excretion rates. However, not all hypoalphalipoproteinemia subjects had low efflux.

As with fecal sterol excretion, this method is not macrophage-specific. Accordingly, it remains to be established whether this method, which measures whole body cholesterol efflux and therefore includes non-arterial wall and non-macrophage arterial wall efflux (Table 1), will have utility in determining cholesterol efflux specifically from cholesterol loaded coronary macrophages in humans following therapeutic intervention. Furthermore, its ability to differentiate between hepatic and peripheral (non-hepatic) tissues as the source of cholesterol efflux has not been definitively proven, although prior human data with radiolabeled cholesterol (142) suggests that hepatic and plasma free cholesterol pools are likely to be fully equilibrated after 24 hours of continuous labeled cholesterol infusion, so that the liver will not contribute to measured flux rates. Other metrics of the RCT pathway generated by this stable isotope kinetic modeling approach, including plasma cholesterol-ester production and clearance rates, plasma cholesterol flux into specific neutral sterols and bile acids, and the quantitative role of the red cell membrane as a lipoprotein-independent pathway for cholesterol carriage, are also potentially useful. The combination of a macrophage-specific assay with other components of whole-body RCT has resulted in an improved understanding of cholesterol efflux pathways.

Vascular Imaging of Atherosclerosis

Although certain ex vivo HDL measures (qualitative and quantitative) are more highly correlated with atherosclerosis than HDL-C, new vascular imaging modalities provide opportunities for direct in vivo assessment of HDL-mediated cholesterol efflux. The ideal invasive tool for characterization of vascular plaque would provide a complete roadmap of atherosclerotic burden throughout the coronary tree and provide per plaque lesion specific data characterizing the architecture, composition and dynamic biology of each plaque. Specific parameters should include: (1) extent of luminal stenosis; (2) lesion length; (3) coronary blood flow reserve through any given narrowing; (4) intramural plaque architecture including atheroma burden, eccentricity, and local vascular remodeling; (5) plaque composition, specifically lipid content; (6) fibrous cap thickness; and (7) presence of inflammation (143–145).

Certain vascular imaging modalities may be particularly useful techniques for investigation into the processes that regulate cholesterol flux within the vessel wall (143). Structural changes in the vessel wall include overall measures of vessel wall thickness to specific measures of plaque size, composition and inflammatory burden (143–145). The composition and the inflammatory activity of the atheromatous plaque have important implications for clinical events (154). The studies that have evaluated the effects of HDL modifying therapies on non-invasive and invasive imaging modalities of atherosclerosis are summarized in Appendix 1.

Non-invasive imaging of atherosclerosis can be utilized to assess efficacy as well as provide pathophysiological information on the mechanism of action of novel of HDL-C–raising drugs. Much effort has been made over the past decades to develop ultrasound, MRI, and most recently FDG-PET to provide efficacy measures that can be used to assist in decision-making and whether or not to proceed with novel anti-atherogenic drugs in costly and time-consuming mortality and morbidity trials. The current armamentarium of imaging modalities is capable of providing insight in drug effects on atherosclerosis progression and composition, endothelial function, and vessel wall inflammation and will play a crucial role in evaluating emerging HDL-C–raising compounds. Recently, advanced vascular imaging was used to investigate the effects of the CETP inhibitor/modulator dalcetrapib on carotid plaque progression and inflammation (146). After 24 months, there was a significant reduction in carotid total vessel area with dalcetrapib compared to placebo. Although there were there were no treatment differences in carotid inflammation by FDG-PET, reductions in plaque inflammatory index were correlated with increases in HDL-C.

Prospective clinical studies will indicate which of these features identified by vascular imaging provides an accurate prediction of future coronary events. The High-Risk Plaque (HRP) BioImage Study, a total of 6,104 men 55 to 80 years of age and women 60 to 80 years of age without evidence of atherothrombotic disease but presumed to be at increased risk for near-term atherothrombotic events have been enrolled in a prospective trial of comprehensive risk assessment in a dedicated mobile facility equipped with advanced imaging tools (147).

Proposed Updated Concept of Reverse Cholesterol Transport

In this review, we endorse the continued use of the terminology “reverse cholesterol transport” to describe whole body cholesterol efflux from peripheral tissues to its ultimate disposition in the feces. However, this terminology is imprecise with regard to an assessment of changes in the cholesterol loaded vascular macrophage and its use has led to substantial confusion in the field of HDL biology. The adoption of a nomenclature that identifies the specific component of RCT will improve communication of experimental animal models and human translational studies that investigate various aspects of tissue-specific cholesterol efflux. The use of the term, “macrophage RCT”, more precisely describes the cholesterol removal from the cholesterol-loaded macrophage that is ultimately removed in the feces. Quantitation of fecal sterols and bile acids rather than radioactivity alone provides a more definitive analysis of sterol balance in these studies. At present, quantitation of macrophage RCT can only be ascertained in animal models; however, studies are underway to develop methods for use in humans. The ultimate choice in the evaluation of therapeutic agents for this aspect of HDL functionality is direct quantitation of cholesterol efflux from the vascular macrophage. Recent studies have established that the fraction of HDL-C coming from these cells is a very small and most likely does not change HDL-C levels. Furthermore, cholesterol efflux from macrophages because of is relatively small pool size would not be expected to significantly alter the total mass of fecal sterol or bile acid excretion on a mass basis. Thus, both HDL-C or fecal sterol and bile acid loss may be either insensitive or ineffective methods to quantitate cholesterol changes in vascular macrophage, which has been proposed to reduce cardiovascular events. At present in vitro quantitation of serum efflux capacity or plasma preβ-HDL assays have been use to assess the effectiveness of plasma HDL to reduce macrophage cholesterol content. However, the recycling and flux through the preβ-HDL to HDL-L (α1-HDL) pathway cannot be determined by the static quantitation of serum efflux capacity or preβ-HDL assays thus limiting the effectiveness of this approach. At this time, the most effective approach to determine the effect of agents on vascular cholesterol content will involve invasive and noninvasive imaging techniques. Great progress is currently being made in imaging methodology and effective approaches to the quantitation of vascular plaque may be available in the near future. Ultimately, these advanced vascular imaging techniques will require validation with clinical cardiovascular events.

Supplementary Material

Acknowledgments

Funding sources

This work emanated from a CME activity sponsored by Medical Education Resources in Littleton CO. MER received funding from Genentech, Inc. The funding agency had no input in the content of the manuscript.

Footnotes

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Disclosures: Dr. Rosenson has served on advisory boards and received consulting fees and honorarium from Abbott Labs (modest), Amgen (modest), Amaryn (modest), Astra Zeneca (modest), Genentech (modest), Grain Foods Advisory Council (modest), LipoScience (modest), GlaxoSmithKline (modest), Residual Risk Reduction Initiative (modest) and Sanofi Aventis (significant), and he has stock ownership in LipoScience, Inc (significant). Dr. Brewer, Jr. serves on advisory boards, received consulting fees and honoraria from Abbott (modest), Eli Lilly & Co (modest), Merck (significant), Pfizer, Roche (significant), and Sanofi-Aventis (modest); speaker’s bureau for Astra Zeneca (modest), Abbott (modest) Merck (modest) Pfizer (modest) and Roche (modest); and ownership interest in InfraRedDx Inc. (significant), Medicines Company (significant) and NDL Therapeutics (significant). Dr. Davidson serves on the Speaker’s Bureau and received honorarium from Abbott Labs and Merck (moderate). Dr. Fayad has served on advisory boards and received honorarium from Roche (significant) and research support from Bristol Myers Squibb (significant), GlaxoSmithKline (significant), Merck (significant), Roche (significant) and VBL (significant). Dr. Fuster reports no disclosures. Dr. Goldstein serves on advisory board and receives honorarium from InfraReDx, Inc. (significant) and has stock ownership in InfraReDx Inc. (significant). Dr. Hellerstein is co-founder and chief of the scientific advisory board for KineMed Inc. (significant) and has stockownership in KineMed Inc (significant). Dr. Jiang reports no disclosures. Dr. Phillips reports no disclosures. Dr. Remaley receives research support from Alpha Care-CRADA (modest) and KineMed, Inc. (significant). Dr. Rader serves as a consultant and receives honorarium from Ainlam (moderate), Astra Zeneca (moderate), Daiichi Sankyo (moderate), Eli Lilly & Co (moderate), Glaxo Smith Kline (moderate), Johnson & Johnson (significant), Merck (significant), Novartis (moderate), Omthera (moderate), Pfizer (moderate), Regeneron (moderate), Sanofi Aventis (moderate), and has has stock ownership in Aegerion Pharmaceuticals (significant) and Vascular Strategies (significant). Dr. Rothblat has stock ownership in Vascular Strategies (significant). Dr. Tall serves on advisory boards for CSL (modest), Merck (modest), Regulus (modest) and Roche (modest), speaker’s bureau for Merck (modest), and receives honorarium form Novartis (modest). Dr. Yvan-Charvet reports no disclosures.

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