Myristica fragrans promotes ABCA1 expression and cholesterol efflux in THP-1-derived macrophages

Myristica fragrans is a traditional herbal medicine and has been shown to alleviate the development of atherosclerosis.However,the anti-atherogenic mechanisms of M.fragrans are still to be addressed.In this study,we explored the effect of M.fragrans on lipid metabolism and inflammation and its mechanisms in THP-1-derived macrophages.The quantitative polymerase chain reaction and western blot analysis results showed that M.fragrans promotes cholesterol efflux from THP-1-derived macrophages and reduces intracellular total cholesterol,cholesterol ester,and free cholesterol contents in a dose-and a time-dependent manner.Further study found that liver X receptor alpha(LXRα)antagonist GGPP significantly blocked the upregulation of ABCA1 expression with M.fragrans treatment.In addition,chromatin immunoprecipitation assay confirmed that GATA binding protein 3(GATA3)can bind to the LXRαpromoter,and inhibition of GATA3 led to the downregulation of LXRαand ATP-binding cassette subfamily A member 1 expression.Furthermore,M.fragrans reduced lipid accumulation,followed by decreasing tumor necrosis factor-α,interleukin(IL)-6,and IL-1βand increasing IL-10 produced by THP-1-derived macrophages.Therefore,M.fragrans is identified as a valuable therapeutic medicine for atherosclerotic cardiovascular disease.     

Cyclic AMP-specific phosphodiesterase 4 inhibitors promote ABCA1 expression and cholesterol efflux.

ATP cassette binding protein 1 (ABCA1) controls the apolipoprotein-mediated cholesterol efflux pathway and determines plasma HDL levels. Although cAMP is known to promote ABCA1 expression and cholesterol efflux from cells, it has not been determined whether cyclic nucleotide phosphodiesterase (PDE) isoforms regulate this pathway. We show that rolipram and cilomilast, inhibitors of cAMP-specific PDE4, increase apolipoprotein A-I (apoA-I)-mediated cholesterol efflux up to 80 and 140% in human THP-1 and mouse J774.A1 macrophages, respectively, concomitant with an elevation of cAMP levels. The EC(50) value was estimated to be 1 to 2 microM for both inhibitors. Rolipram and cilomilast also increase ABCA1 protein expression in THP-1 and J774.A1 macrophages. Thus, PDE4 inhibitors cause parallel increases in cAMP levels, ABCA1 expression and apoA-I-mediated cholesterol efflux. PDE4 inhibitors may provide a novel strategy for the treatment of cardiovascular disease by mobilizing cholesterol from atherosclerotic lesions.     

Quercetin enhances ABCA1 expression and cholesterol efflux through a p38-dependent pathway in macrophages

ATP-binding cassette transporter A1 (ABCA1) plays a crucial role in exporting cholesterol from macrophages, a function relevant to its involvement in the prevention of atherosclerosis. Quercetin, one of flavonoids, has been described to reduce atherosclerotic lesion formation. This study is aimed to investigate the effect of quercetin on regulation of ABCA1 expression and to explore its underlying mechanisms in macrophages. The results show that quercetin markedly enhanced cholesterol efflux from macrophages in a concentration-dependent manner, which was associated with an increase in ABCA1 mRNA and protein expression. Remarkably, quercetin is able to stimulate the phosphorylation of p38 by up to 234-fold at 6 h via an activation of the transforming growth factor β-activated kinase 1 (TAK1) and mitogen-activated kinase kinase 3/6 (MKK3/6). Inhibition of p38 with a pharmacological inhibitor or small hairpin RNA (shRNA) suppressed the stimulatory effects of quercetin on ABCA1 expression and cholesterol efflux. Moreover, knockdown of p38 reduced quercetin-enhanced ABCA1 promoter activity and the binding of specificity protein 1 (Sp1) and liver X receptor α (LXRα) to the ABCA1 promoter using chromatin immunoprecipitation assays. These findings provide evidence that p38 signaling is essential for the regulation of quercetin-induced ABCA1 expression and cholesterol efflux in macrophages.     

A kinetic model to evaluate cholesterol efflux from THP-1 macrophages to apolipoprotein A-1

The kinetics (0 to 3 h) of cholesterol efflux to delipidated apolipoprotein A-1 were investigated, and the experimental data were best fitted to a mathematical model that involves two independent pathways of cholesterol efflux. The first pathway with a rate constant of 4.6 h(-1) is fast but removes only 3-5% of total cholesterol. After preconditioning apoA-1, it was found that this pathway remains, and hence it is a property of the cholesterol-loaded cells rather than due to modification on the apolipoprotein. This fast initial efflux does not seem to contribute to cholesterol efflux at later stages (>1 h) where a second pathway predominates. However, the fast initial efflux pool can be restored if apoA-1 is withdrawn. The second slower pathway (k(membrane--media) = 0.79 h(-1)) is associated with cholesterol ester hydrolysis whose rate constant could be experimentally verified (k(cal) = 0.43, k(exp) = 0.38 +/- 0.05). The model suggests that two different plasma membrane domains are involved in the two pathways. Loading of the cells with an oxysterol, 7-ketocholesterol (7K), inhibits efflux from both pathways. The model predicts that 7K decreases the initial efflux by decreasing the available cholesterol (by possibly affecting lipid packing), while all rate constants in the second pathway are decreased. In conclusion, the kinetic model suggests that cholesterol efflux to apoA-1 is a two-step process. In the first step, some of the plasma membrane cholesterol contributes to a fast initial efflux (possibly from lipid rafts) and leads to a second pathway that mobilizes intracellular cholesterol mobilization.     

15-Lipoxygenase-mediated modification of high-density lipoproteins impairs SR-BI- and ABCA1-dependent cholesterol efflux from macrophages

Elevated plasma levels of high-density lipoprotein cholesterol (HDL-C) are atheroprotective and HDL-dependent reverse cholesterol transport has been related to this effect. HDL particles may, however, undergo modifications that affect their biological activities. Lipoxygenases (LOs) belong to a family of lipid peroxidizing enzymes; among them, reticulocyte-type 15-lipoxygenase (15-LO-1) appears to play a pathophysiological role in atherosclerosis, as its expression is increased in atherosclerotic plaques and it has been shown to oxidize low-density lipoproteins to an atherogenic form. In this work we investigated the impact of in vitro 15-lipoxygenase-catalyzed modification of HDL3 on their ability to act as cholesterol acceptor and found that 15-LO-modified HDL3 were less effective in mediating cholesterol efflux from lipid-laden J774 cells. A reduced binding of 15-LO-modified HDL3 to scavenger receptor class B, type I (SR-BI), due to HDL apoproteins cross-linking, explained, at least in part, the observed reduction of cholesterol efflux. In addition, ATP-binding cassette transporter A1 (ABCA1)-mediated cholesterol efflux was also reduced, as a consequence of pre-beta-particles loss after HDL3 modification. These results suggest that 15-lipoxygenase might induce structural alterations of HDL3 particles that impair their capability of triggering reverse cholesterol transport.     

Deleterious impact of elaidic fatty acid on ABCA1-mediated cholesterol efflux from mouse and human macrophages

Consumption of trans fatty acids (TFA) increase cardiovascular risk more than do saturated FA, but the mechanisms explaining their atherogenicity are still unclear. We investigated the impact of membrane incorporation of TFA on cholesterol efflux by exposing J774 mouse macrophages or human monocyte-derived macrophages (HMDM) to media enriched or not (standard medium) with industrially produced elaidic (trans-9 18:1) acid, naturally produced vaccenic (trans-11 18:1) acid (34 h, 70 μM) or palmitic acid. In J774 macrophages, elaidic and palmitic acid, but not vaccenic acid, reduced ABCA1-mediated efflux by ~23% without affecting aqueous diffusion, SR-BI or ABCG1-mediated pathways, and this effect was maintained in cholesterol-loaded cells. The impact of elaidic acid on the ABCA1 pathway was weaker in cholesterol-normal HMDM, but elaidic acid induced a strong reduction of ABCA1-mediated efflux in cholesterol-loaded cells (-36%). In J774 cells, the FA supplies had no impact on cellular free cholesterol or cholesteryl ester masses, the abundance of ABCA1 mRNA or the total and plasma membrane ABCA1 protein content. Conversely, TFA or palmitic acid incorporation induced strong modifications of the membrane FA composition with a decrease in the ratio of (cis-monounsaturated FA+polyunsaturated FA):(saturated FA+TFA), with elaidic and vaccenic acids representing each 20% and 13% of the total FA composition, respectively. Moreover, we demonstrated that cellular ATP was required for the effect of elaidic acid, suggesting that it contributes to atherogenesis by impairing ABCA1-mediated cholesterol efflux in macrophages, likely by decreasing the membrane fluidity, which could thereby reduce ATPase activity and the function of the transporter.     

Deleterious impact of elaidic fatty acid on ABCA1-mediated cholesterol efflux from mouse and human macrophages

Consumption of trans fatty acids (TFA) increase cardiovascular risk more than do saturated FA, but the mechanisms explaining their atherogenicity are still unclear. We investigated the impact of membrane incorporation of TFA on cholesterol efflux by exposing J774 mouse macrophages or human monocyte-derived macrophages (HMDM) to media enriched or not (standard medium) with industrially produced elaidic (trans-9 18:1) acid, naturally produced vaccenic (trans-11 18:1) acid (34 h, 70 μM) or palmitic acid. In J774 macrophages, elaidic and palmitic acid, but not vaccenic acid, reduced ABCA1-mediated efflux by ~ 23% without affecting aqueous diffusion, SR-BI or ABCG1-mediated pathways, and this effect was maintained in cholesterol-loaded cells. The impact of elaidic acid on the ABCA1 pathway was weaker in cholesterol-normal HMDM, but elaidic acid induced a strong reduction of ABCA1-mediated efflux in cholesterol-loaded cells (− 36%). In J774 cells, the FA supplies had no impact on cellular free cholesterol or cholesteryl ester masses, the abundance of ABCA1 mRNA or the total and plasma membrane ABCA1 protein content. Conversely, TFA or palmitic acid incorporation induced strong modifications of the membrane FA composition with a decrease in the ratio of (cis-monounsaturated FA + polyunsaturated FA):(saturated FA + TFA), with elaidic and vaccenic acids representing each 20% and 13% of the total FA composition, respectively. Moreover, we demonstrated that cellular ATP was required for the effect of elaidic acid, suggesting that it contributes to atherogenesis by impairing ABCA1-mediated cholesterol efflux in macrophages, likely by decreasing the membrane fluidity, which could thereby reduce ATPase activity and the function of the transporter.     

普伐他汀联合罗格列酮上调THP-1巨噬细胞ABCA1表达

目的：观察普伐他汀与罗格列酮联合应用对人巨噬细胞株（THP-1）源性巨噬细胞三磷酸腺苷结合盒转运体A1（ABCA1）表达的影响。方法：THP-1细胞经160 nmol/L佛波酯（PMA）孵育24 h,诱导分化成巨噬细胞,分别与普伐他汀及罗格列酮单独或联合作用24 h,提取各组细胞总RNA和蛋白质,分别采用RT-PCR和Western blot检测ABCA1的mRNA和蛋白的表达。结果：普伐他汀增强过氧化物酶体增殖物激活受体γ（PPARγ）mRNA表达,但抑制肝X受体（LXR）mRNA表达（P〈0.05）,对ABCA1的表达不产生明显效应（P〉0.05）;罗格列酮单独或与普伐他汀联合作用均可引起ABCA1表达明显增加,同时PPARγ及LXRαmRNA表达亦上调（P〈0.05））。结论：普伐他汀与罗格列酮联合应用能上调巨噬细胞ABCA1的表达。     

cAMP induces ABCA1 phosphorylation activity and promotes cholesterol efflux from fibroblasts

ATP-binding cassette transporter A1 (ABCA1) plays a crucial role in apoA-I lipidation, a key step in reverse cholesterol transport. cAMP induces apoA-I binding activity and promotes cellular cholesterol efflux. We investigated the role of the cAMP/protein kinase A (PKA) dependent pathway in the regulation of cellular cholesterol efflux. Treatment of normal fibroblasts with 8-bromo-cAMP (8-Br-cAMP) increased significantly apoA-I-mediated cholesterol efflux, with specificity for apoA-I, but not for cyclodextrin. Concomitantly, 8-Br-cAMP increased ABCA1 phosphorylation in a time-dependent manner. Maximum phosphorylation was reached in <10 min, representing a 260% increase compared to basal ABCA1 phosphorylation level. Forskolin, a known cAMP regulator, increased both cellular cholesterol efflux and ABCA1 phosphorylation. In contrast, H-89 PKA inhibitor reduced cellular cholesterol efflux by 70% in a dose-dependent manner and inhibited almost completely ABCA1 phosphorylation. To determine whether naturally occurring mutants of ABCA1 may affect its phosphorylation activity, fibroblasts from subjects with familial HDL deficiency (FHD, heterozygous ABCA1 defect) and Tangier disease (TD, homozygous/compound heterozygous ABCA1 defect) were treated with 8-Br-cAMP or forskolin. Cellular cholesterol efflux and ABCA1 phosphorylation were increased in FHD but not in TD cells. Taken together, these findings provide evidence for a link between the cAMP/PKA-dependent pathway, ABCA1 phosphorylation, and apoA-I mediated cellular cholesterol efflux.     

Regulation of cholesterol efflux from macrophages

PURPOSE OF REVIEW: The lipid efflux pathway is important for both HDL formation and the reverse cholesterol transport pathway. This review is focused on recent findings on the mechanism of lipid efflux and its regulation, particularly in macrophages. RECENT FINDINGS: Significant progress has been made on understanding the sequence of events that accompany the interaction of apolipoproteins A-I with cell surface ATP-binding cassette transporter A1 and its subsequent lipidation. Continued research on the regulation of ATP-binding cassette transporter A1 and ATP-binding cassette transporter G1 expression and traffic has also generated new paradigms for the control of lipid efflux from macrophages and its contribution to reverse cholesterol transport. In addition, the mobilization of cholesteryl esters from lipid droplets represents a new step in the control of cholesterol efflux. SUMMARY: The synergy between lipid transporters is a work in progress, but its importance in reverse cholesterol transport is clear. The regulation of efflux implies both the regulation of relevant transporters and the cellular trafficking of cholesterol.     

Synthetic amphipathic helical peptides promote lipid efflux from cells by an ABCA1-dependent and an ABCA1-independent pathway

In order to examine the necessary structural features for a protein to promote lipid efflux by the ABCA1 transporter, synthetic peptides were tested on ABCA1-transfected cells (ABCA1 cells) and on control cells. L-37pA, an l amino acid peptide that contains two class-A amphipathic helices linked by proline, showed a 4-fold increase in cholesterol and phospholipid efflux from ABCA1 cells compared to control cells. The same peptide synthesized with a mixture of l and d amino acids was less effective than L-37pA in solubilizing dimyristoyl phosphatidyl choline vesicles and in effluxing lipids. In contrast, the 37pA peptide synthesized with all d amino acids (D-37pA) was as effective as L-37pA. Unlike apoA-I, L-37pA and D-37pA were also capable, although at a reduced rate, of causing lipid efflux independent of ABCA1 from control cells, Tangier disease cells, and paraformaldehyde fixed ABCA1 cells. The ability of peptides to bind to cells correlated with their lipid affinity. In summary, the amphipathic helix was found to be a key structural motif for peptide-mediated lipid efflux from ABCA1, but there was no stereoselective requirement. In addition, unlike apoA-I, synthetic peptides can also efflux lipid by a passive, energy-independent pathway that does not involve ABCA1 but does depend upon their lipid affinity.     

ABCA1 mediates concurrent cholesterol and phospholipid efflux to apolipoprotein A-I

Prior studies provide data supporting the notion that ATP binding cassette transporter A1 (ABCA1) promotes lipid efflux to extracellular acceptors in a two-step process: first, ABCA1 mediates phospholipid efflux to an apolipoprotein, and second, this apolipoprotein-phospholipid complex accepts free cholesterol in an ABCA1-independent manner. In the current study using RAW264.7 cells, ABCA1-mediated free cholesterol and phospholipid efflux to apolipoprotein A-I (apoA-I) were tightly coupled to each other both temporally and after treatment with ABCA1 inhibitors. The time course and temperature dependence of ABCA1-mediated lipid efflux to apoA-I support a role for endocytosis in this process. Cyclodextrin treatment of RAW264.7 cells partially inhibited 8Br-cAMP-induced efflux of free cholesterol and phospholipid to apoA-I. ABCA1-expressing cells are more sensitive to cell damage by high-dose cyclodextrin and vanadate, leading to increased lactate dehydrogenase leakage and phospholipid release even in the absence of the acceptor apoA-I. Finally, we could not reproduce a two-step effect on lipid efflux using conditioned medium from ABCA1-expressing cells pretreated with cyclodextrin.     

Enhanced apoA-I-dependent cholesterol efflux by ABCA1 from sphingomyelin-deficient Chinese hamster ovary cells

ATP binding cassette protein A1 (ABCA1) plays a major role in cholesterol homeostasis and high density lipoprotein (HDL) metabolism. It is proposed that ABCA1 reorganizes the plasma membrane and generates more loosely packed domains that facilitate apoA-I-dependent cholesterol efflux. In this study, we examined the effects of the cellular sphingomyelin level on HDL formation by ABCA1 by using a Chinese hamster ovary-K1 mutant cell line, LY-A, which has a missense mutation in the ceramide transfer protein CERT. When LY-A cells were cultured in Nutridoma-BO medium and sphingomyelin content was reduced, apoA-I-dependent cholesterol efflux by ABCA1 from LY-A cells increased 1.65-fold compared with that from LY-A/CERT cells stably transfected with human CERT cDNA. Exogenously added sphingomyelin significantly reduced the apoA-I-dependent efflux of cholesterol from LY-A cells, confirming that the decrease in sphingomyelin content in the plasma membrane stimulates cholesterol efflux by ABCA1. The amount of cholesterol available to cold methyl-beta-cyclodextrin (MbetaCD) extraction from LY-A cells was increased by 40% by the expression of ABCA1 and was 1.6-fold higher than that from LY-A/CERT cells. This step in ABCA1 function, making cholesterol available to cold MbetaCD, was independent of apoA-I. These results suggest that the function of ABCA1 could be divided into two steps: (i) a flopping step to move phosphatidylcholine and cholesterol from the inner to outer leaflet of the plasma membrane, where cholesterol becomes available to cold MbetaCD extraction, and (ii) a loading step to load phosphatidylcholine and cholesterol onto apoA-I to generate HDL.     

Placental ABCA1 and ABCG1 transporters efflux cholesterol and protect trophoblasts from oxysterol induced toxicity

ATP-binding cassette (ABC) transporters ABCA1 and ABCG1 mediate the efflux of cholesterol and other sterols. Both transporters are expressed on the fetal capillaries of the placenta and are involved in maternal-to-fetal cholesterol delivery. In this study, we report that ABCA1 and ABCG1 are also present on the syncytiotrophoblast, the maternal facing placental membrane. Syncytial ABCA1 expression is apical, suggesting a role in cholesterol efflux to the mother, while ABCG1 is expressed basolaterally indicating transport to the fetus. Silencing of ABCA1 expression in primary trophoblasts in culture, or pharmacological antagonism by glyburide, decreased cholesterol efflux to apolipoprotein A-I (apoA-I) compared to controls, while ABCG1-silencing decreased cholesterol efflux to high density lipoproteins (HDL). In contrast, treatment with endogenous or synthetic LXR α/β ligands such as T0901317 increased ABCA1 and ABCG1 expression and enhanced cholesterol efflux to apoA-I and HDL, respectively, while treatment with pharmacological PPAR-α or -γ ligands was without effect. Trophoblasts transfected with ABCA1 or ABCG1 siRNA were more sensitive to toxic oxysterols substrates (25-hydroxycholesterol and 7-ketocholesterol) compared to mock-transfected cells, while prior treatment with T0901317 reduced oxysterol-mediated toxicity. These results identify syncytial ABCA1 and ABCG1 as important, inducible cholesterol transporters which also prevent placental accumulation of cytotoxic oxysterols.     

ABCA1 promotes the efflux of bacterial LPS from macrophages and accelerates recovery from LPS-induced tolerance

Macrophages play important roles in both lipid metabolism and innate immunity. We show here that macrophage ATP-binding cassette transporter A1 (ABCA1), a transporter known for its ability to promote apolipoprotein-dependent cholesterol efflux, also participates in the removal of an immunostimulatory bacterial lipid, lipopolysaccharide (LPS). Whereas monocytes require an exogenous lipoprotein acceptor to remove cell-associated LPS, macrophages released LPS in the absence of an exogenous acceptor by a mechanism that was driven, in part, by endogenous apolipoprotein E (apoE). Agents that increased ABCA1 expression increased LPS efflux from wild-type but not ABCA1-deficient macrophages. Preexposure of peritoneal macrophages to LPS for 24 h increased the expression of ABCA1 and increased LPS efflux with a requirement for exogenous apolipoproteins due to suppression of endogenous apoE production. In contrast, LPS preconditioning of ABCA1-deficient macrophages significantly decreased LPS efflux and led to prolonged retention of cell-surface LPS. Although the initial response to LPS was similar in wild-type and ABCA1-deficient macrophages, LPS-induced tolerance was greater and more prolonged in macrophages that lacked ABCA1. Our results define a new role for macrophage ABCA1 in removing cell-associated LPS and restoring normal macrophage responsiveness.     

Cytotoxic constituents from Brazilian red propolis and their structure-activity relationship

Several classes of flavonoids [flavanoids (1-10), flavonol (11), isoflavones (12-18), isoflavanones (19-22), isoflavans (23-26), chalcones (27-30), auronol (31), pterocarpans (32-37), 2-arylbenzofuran (38), and neoflavonoid (39)] and lignans (40-42) isolated from the MeOH extract of Brazilian red propolis were investigated for their cytotoxic activity against a panel of six different cancer cell lines including murine colon 26-L5 carcinoma, murine B16-BL6 melanoma, murine Lewis lung carcinoma, human lung A549 adenocarcinoma, human cervix HeLa adenocarcinoma, and human HT-1080 fibrosarcoma cell lines. Based on the observed results, structure-activity relationships were discussed. Among the tested compounds, 7-hydroxy-6-methoxyflavanone (3) exhibited the most potent activity against B16-BL6 (IC(50), 6.66microM), LLC (IC(50), 9.29microM), A549 (IC(50), 8.63microM), and HT-1080 (IC(50), 7.94microM) cancer cell lines, and mucronulatol (26) against LLC (IC(50), 8.38microM) and A549 (IC(50), 9.9microM) cancer cell lines. These activity data were comparable to those of the clinically used anticancer drugs, 5-fluorouracil and doxorubicin, against the tested cell lines, suggesting that 3 and 26 are the good candidates for future anticancer drug development.     

Chemical composition and microbicidal activity of extracts from Brazilian and Bulgarian propolis

AIMS: The chemical composition of ethanol extracts from a Brazilian (Et-Bra) and a Bulgarian (Et-Blg) propolis, and their activity against the protozoan Trypanosoma cruzi, several fungi and bacteria species were determined. METHODS AND RESULTS: The chemical composition was determined by high temperature high resolution gas chromatography coupled to mass spectrometry. Microbiological activity was assayed in vitro against T. cruzi, Candida albicans, Sporothrix schenckii, Paracoccidioides brasiliensis, Neisseria meningitidis, Streptococcus pneumoniae and Staphylococcus aureus. CONCLUSIONS: Et-Bra and Et-Blg, although with totally distinct compositions, were active against T. cruzi and the three species of fungi. Et-Blg was more effective than Et-Bra against bacteria, particularly N. meningitidis and Strep. pneumoniae. SIGNIFICANCE AND IMPACT OF THE STUDY: Although with different classes of components, both propolis extracts showed microbicidal activity. For the bactericidal activity it was possible to establish a positive correlation with the high content of flavonoids of the Bulgarian extract.     

ABCA1 is the cAMP-inducible apolipoprotein receptor that mediates cholesterol secretion from macrophages

Lipid-poor high density lipoprotein apolipoproteins remove cholesterol and phospholipids from cells by an active secretory pathway controlled by an ABC transporter called ABCA1. This pathway is induced by cholesterol and cAMP analogs in a cell-specific manner. Here we provide evidence that increased plasma membrane ABCA1 accounts for the enhanced apolipoprotein-mediated lipid secretion from macrophages induced by cAMP analogs. Treatment of RAW264 macrophages with 8-bromo-cAMP caused parallel increases in apoA-I-mediated cholesterol efflux, ABCA1 mRNA and protein levels, incorporation of ABCA1 into the plasma membrane, and binding of apoA-I to cell-surface ABCA1. All of these parameters declined to near base-line values within 6 h after removal of 8-bromo-cAMP, indicating that ABCA1 is highly unstable and is degraded rapidly in the absence of inducer. Thus, ABCA1 is likely to be the cAMP-inducible apolipoprotein receptor that promotes removal of cholesterol and phospholipids from macrophages.