Published online before print October 28, 2004, doi: 10.1161/01.ATV.0000148707.93054.7d
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© 2004 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Statins Inhibit Synthesis of an Oxysterol Ligand for the Liver X Receptor in Human Macrophages With Consequences for Cholesterol Flux
From the School of Biotechnology and Biomolecular Sciences (J.W., A.J.B.), The University of New South Wales and Centre for Vascular Research at The University of New South Wales (C.M.Q.), Sydney, Australia.
Correspondence to Andrew J. Brown, PhD, School of Biotechnology and Biomolecular Sciences, Biological Sciences Building D26, University of New South Wales, Sydney, 2052, Australia. E-mail aj.brown{at}unsw.edu.au
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Abstract |
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Objective— Cholesterol efflux from macrophages in the artery wall, a key cardioprotective mechanism, is largely coordinated by the nuclear oxysterol-activated liver X receptor, LXR
. We investigated the effect of statins on LXR target gene expression and cholesterol efflux from human macrophages. Methods and Results— In human macrophages (THP-1 cell line and primary cells), the archetypal statin, compactin, greatly reduced mRNA levels of 2 LXR target genes, ABCA1 and ABCG1 mRNA, as well as decreased cholesterol efflux. Commonly prescribed statins also downregulated LXR target gene expression in THP-1 cells. We provide several lines of evidence indicating that statins decrease expression of LXR target genes by inhibiting the synthesis of an oxysterol ligand for LXR, 24(S),25-epoxycholesterol. When THP-1 cells were cholesterol-loaded via incubation with acetylated low-density lipoprotein, synthesis of 24(S),25-epoxycholesterol was greatly reduced and the downregulatory effect of compactin on ABCA1 mRNA levels and cholesterol efflux was lost.
Conclusions— Our results suggest that statins may downregulate cholesterol efflux from nonloaded human macrophages by inhibiting synthesis of an oxysterol ligand for LXR. Further work is needed to determine how relevant our observations are to arterial foam cells in vivo.
We show that statins downregulate key genes involved in cholesterol efflux from nonloaded human macrophages. Furthermore, statin treatment drastically reduced cholesterol efflux from these cells. Moreover, we identify a likely mechanism as inhibition of the synthesis of 24(S),25-epoxycholesterol, an oxysterol ligand for the liver X receptor.
Key Words: statins • human macrophage • liver X receptor • 24(S),25-epoxycholesterol • THP-1 cells • human monocyte-derived macrophages • pleiotropic
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Introduction |
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Statins are highly effective in lowering serum cholesterol concentrations and in reducing the risk of coronary heart disease and stroke.1 There is a growing body of clinical and experimental evidence that statins exert additional benefits beyond cholesterol reduction.2,3 Intensive efforts are underway to study the pleiotropic, cholesterol-independent effects of statins on the vasculature.2,3
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The macrophage is a key vascular cell involved in the development of atherosclerosis. Cholesterol-laden macrophages (foam cells) have essential functions in all phases of atherosclerosis, from development of the fatty streak to processes that ultimately contribute to plaque rupture and myocardial infarction. Because mammalian cells cannot degrade the sterol fused-ring structure, excess sterols undergo elimination from the body principally by biliary excretion. Therefore, macrophages must export cholesterol to extracellular acceptors for transport to the liver.4
The liver X receptor (LXR), NR1H3 or LXR, plays an important role in coordinating cholesterol efflux from the macrophage. As a member of the nuclear receptor family of ligand-dependent transcription factors, LXR activates transcription of target genes in response to the binding of certain oxidized forms of cholesterol (oxysterols).5,6 LXR forms a heterodimer with the retinoid X receptors to bind to specific response elements in the promoters or enhancers of target genes. The genes encoding several important proteins that facilitate cholesterol removal from macrophages are targets of LXR, including ABCA1, ABCG1, apolipoprotein E (apoE), and LXR itself. ABCA1 and ABCG1 are members of the ATP-binding cassette superfamily of transporter proteins. Mutations in ABCA1 were recently identified as the basis for Tangier disease, a rare autosomal disorder characterized by very low levels of high-density lipoprotein and premature atherosclerosis. Genetic and biochemical evidence indicate that ABCA1 is important for mediating efflux of cholesterol and phospholipids from macrophage-foam cells in atherosclerotic lesions.4,7 Less is known about the half-transporter, ABCG1, but it is also implicated in facilitating cholesterol efflux from macrophages.7
The crystal structure of the LXR ligand-binding domain has been solved. The topography of the pocket suggests a common anchoring of certain oxysterols with oxygenated side chains.8 Different oxysterol ligands for LXR have been proposed to be produced in a tissue-specific manner; eg, 24(S),25-epoxycholesterol (24,25EC), until recently, was detected only in the liver, 24(S)-hydroxycholesterol in the brain, and 20(S)-hydroxycholesterol and 22(R)-hydroxycholesterol in the adrenals. 27-Hydroxycholesterol was proposed as one candidate ligand for LXR activation in macrophages.9 However, others have reported that 27-hydroxycholesterol is not an efficient activator of human LXR.10 Therefore, the identity of an oxysterol ligand(s) for LXR, endogenously produced by the human macrophage, remains unclear.
It is commonly assumed that oxysterol LXR ligands will be produced from preformed cholesterol, as believed to be the case for 27-hydroxycholesterol. However, synthesis of an oxysterol ligand could also occur by de novo synthesis in the mevalonate pathway, as was shown for hepatic synthesis of 24,25EC. Forman et al11 have shown that statins can reduce the constitutive activity of the LXR– retinoid X receptor- heterodimer in cotransfected CV-1 cells. Therefore, we set out to investigate the effect of statins on the expression of LXR target genes in human macrophages.
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Methods |
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Reagents and Cell Culture
Chemicals and reagents used are detailed elsewhere (please see http://atvb.ahajournals.org). Cells were grown at 37°C in a 5% CO2 atmosphere in RPMI 1640 supplemented with penicillin/streptomycin 100 U/100 µg/mL, L-glutamine (2 mmol/L), and various sera as described. As a model for human macrophages, we used the widely used monocytic cell line THP-1, differentiated with phorbol 12-myristate 13-acetate. Human monocyte-derived macrophages (HMDM) were prepared from white cell buffy coat concentrates from healthy donors as described.12 For detailed culturing conditions and full Methods, please see online supplement.
Cholesterol Efflux
After prelabeling THP-1 cells or HMDMs with [3H]-cholesterol (1 µCi/mL), efflux was determined by incubating the cells for 24 hours with media containing bovine serum albumin (0.1% v/v) in the presence or absence of apoAI (25 µg/mL) while maintaining treatment(s). Cholesterol efflux was expressed as the radioactivity appearing in the media as a percentage of total radioactivity (cells plus media).
Thin-Layer Chromatography
Thin-layer chromatography (TLC) was conducted for assessment of cholesterol and 24,25EC synthesis using a method detailed by Morand et al13 with minor modifications. Cells were incubated in the presence or absence of inhibitors together with [14C]-acetate (2 µCi/well; 6-well plates; 24 hours). For visualization, TLC plates were exposed to X-ray film (–80°C, 48 to 96 hours) or analyzed by phosphoimaging.
RNA Extraction and mRNA Quantitation
Cells were harvested for total RNA using Tri Reagent according to the manufacturer’s instructions (Sigma) and quantitative ("real-time") reverse transcriptase-polymerase chain reaction (QRT-PCR) was performed using an ABI 7700 Sequence Detector and analyzed using ABI Prism Sequence Detector Soft-ware v1.6.3 (PE Biosystems) as detailed online.
Western Blotting
To measure ABCA1 protein expression, membrane fractions were prepared as described14 and samples (50 µg per lane) were analyzed by SDS-PAGE (ABCA1, 7.5%; transferrin receptor, 10%). Protein was transferred onto nitrocellulose membrane and immunoblotted for ABCA1 and transferrin receptor.
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Results |
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Compactin Decreases Expression of LXR Target Genes, ABCA1 and ABCG1, in THP-1 Human Macrophages
We hypothesized that if oxysterol ligands for LXR are derived from de novo synthesis, inhibition of the committed step in this pathway, catalyzed by 3-hydroxy-3-methylglutaryl (HMG)-coenzyme A (CoA) reductase, should reduce LXR ligand production and, hence, expression of LXR target genes. Cells were treated with varying concentrations of the archetypal statin, compactin (also called mevastatin), for 24 hours before cell harvest and RNA extraction. Figure 1A shows that statin treatment reduced mRNA levels of 2 LXR target genes, ABCA1 and ABCG1, in a concentration-dependent fashion. To exclude the possibility that the statin was exerting a nonspecific effect, we measured the expression of 2 non-LXR target genes that have previously been shown to increase with statin treatment.15 We confirmed that mRNA expression of the low-density lipoprotein (LDL) receptor and HMG-CoA reductase increased in a concentration-dependent manner (Figure 1B). Maximal effects for all genes examined were observed at 5 µmol/L compactin, a concentration that was used in subsequent experiments.
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Compactin Decreases ABCA1 Protein Levels and Cholesterol Efflux From THP-1 Human Macrophages
To determine whether the statin-induced reduction of ABCA1 translates to decreased protein levels, we incubated cells in the presence and absence of compactin (5 µmol/L) and measured ABCA1 protein levels in membrane fractions by Western blotting. Two bands were observed migrating in the vicinity of the deduced molecular weight of ABCA1 (
220 kDa) in agreement with others.16 Compactin treatment greatly reduced ABCA1 protein levels (Figure 2A) in concordance with the downregulatory effect of the statin at the mRNA level (Figure 1A). Another plasma membrane-bound protein, the transferrin receptor, was probed as a test for specificity and found to be unaffected by compactin treatment (Figure 2A). We then tested whether a diminished protein level of ABCA1 resulted in reduced function. Cells were radio-labeled with [3H]-cholesterol and cholesterol efflux was induced by incubating with the cholesterol acceptor, apoAI, for 24 hours. Compactin treatment did not affect total radio-labeling or cell protein levels (data not shown). Figure 2B shows that cholesterol efflux induced by apoAI was ablated in the presence of compactin. These results suggest that compactin inhibited apoAI induced cholesterol efflux from THP-1 human macrophages by decreasing ABCA1 mRNA and protein expression levels.
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24(S),25-Epoxycholesterol Is a Potent Activator of LXR Target Genes in THP-1 Human Macrophages
In agreement with previous studies in cotransfected CV-1 cells5 and a ligand-binding assay,6 we showed that 24,25EC is a potent activator of LXR target genes in THP-1 macrophages. Of a panel of natural oxysterol ligands tested, 24,25EC upregulated the LXR target genes, ABCA1 and ABCG1, to the greatest extent. Another LXR target gene, LXR, responded to LXR ligands and decreased with compactin treatment (please see online supplement).
24(S),25-Epoxycholesterol Is an Important LXR Ligand Produced in THP-1 Human Macrophages
24,25EC is derived from a shunt in the mevalonate pathway in which 2,3(S)-monooxidosqualene (MOS), rather than undergoing cyclization to lanosterol, is converted to 2,3(S):22(S),23-dioxidosqualene (DOS) (Figure 3A). DOS is then cyclized into 24(S),25-epoxylanosterol, which ultimately leads to the formation of 24,25EC. Because the cyclase preferentially cyclizes DOS over MOS, incomplete inhibition of oxidosqualene cyclase explains how the squalene epoxides can be channeled into 24,25EC, a finding observed in HepG2 liver cells13 and recently extended to the murine macrophage cell line, J774A.1.17 We repeated this observation in [14C]-acetate–labeled J774A.1 murine macrophages using a different cyclase inhibitor, GW534511X (Figure 3B), and further extended this finding to the human macrophage cell line, THP-1 (Figure 3C). Identification of 24,25EC was confirmed chemically and by mass spectrometry (please see online supplement). In THP-1 cells, levels of synthesized 24,25EC increased in the presence of low concentrations of cyclase inhibitor (0.1 to 1.0 nM) but decreased at higher concentrations (100 to 1000 nM) (Figure 3C). This profile was similar to the mRNA levels of ABCA1 and ABCG1 observed in response to increasing concentrations of the cyclase inhibitor (Figure 3D). THP-1 human macrophages also produced 24,25EC under control or basal conditions (Figure 3C and 3E). Densitometry of the phosphorimages indicated that under basal conditions, THP-1 macrophages synthesized 24,25EC in a ratio of 0.9:100 relative to cholesterol. Cholesterol and 24,25EC were the only 2 sterols detected under basal conditions (data not shown). Treatment with compactin decreased synthesis of both 24,25EC and cholesterol (Figure 3E), again reflecting the LXR target gene expression data (Figure 1A). 24,25EC production, in the presence of either compactin or the cyclase inhibitor, was strongly correlated with the expression of LXR target genes, ABCA1 and ABCG1 (Figure 3F). Together, these data indicate that compactin may decrease expression of LXR target genes by inhibiting production of the potent LXR ligand, 24,25EC.
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Exogenous 24(S),25-Epoxycholesterol Overcomes Compactin-Induced Reduction of LXR Target Gene Expression in THP-1 Human Macrophages
To further explore how compactin decreases expression of LXR target genes, we tested whether the effect could be reversed by the addition of mevalonate, the product of HMG-CoA reductase. Exogenous mevalonate restored transcription of the LXR target genes, ABCA1 and ABCG1 (Figure 4A and 4B). Also, we tested if mevalonate addition could overcome blockade of an enzyme distal to HMG-CoA reductase (squalene epoxidase) using the inhibitor GR144000X (Figure 3A). At the concentration used (5 µmol/L), GR144000X completely blocked synthesis of both 24,25EC and cholesterol (data not shown). Exogenous mevalonate failed to restore transcription of ABCA1 (Figure 4A) and ABCG1 (Figure 4B) in the presence of the squalene epoxidase inhibitor. Together, these data indicate that the LXR ligand is produced downstream of this enzyme. We then tested if addition of 24,25EC reversed the effect of inhibiting either HMG-CoA reductase or squalene epoxidase. When either enzyme was inhibited, the addition of 24,25EC normalized expression of ABCA1 and ABCG1 (Figure 4C and 4D) and cholesterol efflux (data not shown), lending further support to the contention that 24,25EC is a significant LXR ligand in human macrophages whose generation is inhibited by compactin.
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Effect of Other Statins on Expression of LXR Target Genes in THP-1 Human Macrophages
We used compactin in our investigations because it is the archetypal statin. To ensure that the suppression of ABCA1 and ABCG1 expression is not restricted to compactin, we tested a panel of statins, most of which are in clinical use. 24,25EC synthesis and expression of ABCA1 and ABCG1 mRNA displayed a marked dose-related decrease with all statins tested (please see online supplement). Therefore, the downregulation of LXR target genes that contribute to cholesterol efflux represents a general effect of statins.
Effect of Compactin on Expression of LXR Target Genes in and Cholesterol Efflux From Human Monocyte-Derived Macrophages
We determined if compactin had comparable effects in primary human macrophages to those we observed in THP-1 cells. Although cholesterol and 24,25EC were synthesized under our culturing conditions (10% whole serum) (Figure 5A), the 24,25EC band was very faint, and the ratio of 24,25EC relative to cholesterol was considerably less than observed for nonloaded THP-1 cells (0.2:100). Partial inhibition of oxidosqualene cyclase with 1 nM GW534511X greatly enhanced 24,25EC synthesis (Figure 5A), clearly demonstrating that primary human macrophages can produce this oxysterol ligand for LXR. Compactin treatment decreased both cholesterol and 24,25EC synthesis, and these effects were maximal at 5 µmol/L. Compactin treatment (5 µmol/L) also significantly decreased ABCA1 mRNA expression (Figure 5B) and cholesterol efflux (Figure 5C). Addition of 24,25EC greatly increased ABCA1 mRNA levels and cholesterol efflux and abolished the compactin effect. Therefore, our key findings in THP-1 cells were also observed in primary human macrophages.
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Effect of Compactin on Expression of LXR Target Genes in and Cholesterol Efflux From THP-1 Human Macrophages Loaded With Cholesterol
Up to this point, our studies have been performed in nonloaded THP-1 macrophages and HMDMs. Cholesterol-laden macrophages are arguably more relevant to atherogenesis. However, cholesterol loading might be expected to shut down synthesis of cholesterol and 24,25EC. Therefore, we tested whether statins also decrease ABCA1 mRNA levels in THP-1 macrophages that have been loaded with cholesterol via incubation with acetylated low-density lipoprotein (AcLDL). Consistent with the lack of 24,25EC synthesis observed with AcLDL-loading, compactin had little effect on mRNA levels of ABCA1. Furthermore, compactin treatment had no effect on apoAI-stimulated cholesterol efflux from AcLDL-loaded THP-1 cells (please see online supplement). Therefore, the inhibitory effect of statins on cholesterol efflux is lost with extensive cholesterol loading of macrophages.
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Discussion |
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Statins are a structurally related group of HMG-CoA reductase inhibitors that are widely used to treat hypercholesterolemia. However, there is growing interest in the action of statins beyond cholesterol reduction. For example, statins have been reported to exert a number of cholesterol-independent effects on macrophages such as inhibiting secretion of matrix metalloproteinases2 and downregulating scavenger receptor class A expression.18 In support of recent studies,19,20 we showed that statins decrease expression of several key LXR target genes that are involved in cholesterol removal from the macrophage. ABCA1 is particularly important in facilitating cholesterol efflux from the macrophage as evidenced from the virtually absent high-density lipoprotein cholesterol levels and the increased atherosclerosis seen in ABCA1 deficiency (Tangier disease).4,7 We demonstrated that the statin-mediated reduction in ABCA1 mRNA levels produced a drastic change in function, namely, a marked reduction in ABCA1 protein levels and ablation of cholesterol efflux to apoAI. The effect was observed both in a human macrophage cell line (THP-1) as well as in primary human macrophages (HMDMs). Furthermore, we provided compelling evidence that statins inhibit these processes by interfering with the generation of an oxysterol ligand for LXR.
We presented several lines of evidence implicating 24,25EC as a significant LXR ligand in the human macrophage. 24,25EC was a potent activator of LXR target genes in human macrophages, superior to other natural oxysterol ligands tested, and comparable to a potent synthetic ligand. In an experiment using exogenous mevalonate, we showed that endogenous LXR ligand was produced de novo, downstream from HMG-CoA reductase and squalene epoxidase. Squalene epoxidase is a secondary rate-limiting enzyme in sterol biosynthesis and converts squalene to MOS and catalyzes the conversion of MOS to DOS in the initial step of the shunt pathway, which ultimately forms 24,25EC (Figure 3A). Consequently, we showed that exogenous 24,25EC restored transcriptional activity of LXR target genes both in the presence of compactin or an inhibitor of squalene epoxidase. Moreover, in experiments using compactin and an oxidosqualene cyclase inhibitor, we showed that there was a strong linear relationship between 24,25EC synthesis and LXR target gene expression. Taken together, our data indicate that 24,25EC is an endogenous LXR ligand produced by human macrophages and that statins interfere with this production.
Our data have potential implications for the clinical use of statins considering that oxysterol activation of LXR has been ascribed a significant anti-atherogenic role. Whereas most administered statins are cleared rapidly by the liver,21 their pleiotropic vascular effects suggest that extrahepatic cells such as the macrophage are also exposed to statins. Considering that peak plasma concentrations achieved for most statins range from 0.1 to 1 µmol/L,2,21 effects in the present study were observed at therapeutically relevant concentrations (0.05 to 0.5 µmol/L).
Statins decrease cholesterol synthesis and downregulate scavenger receptor class A expression,18 effects that would be predicted to be anti-atherogenic. We observed that statins upregulated the LDL receptor and HMG-CoA reductase. We also observed that statins downregulated key efflux pathways (ABCA1, ABCG1) in nonloaded human macrophages. Reduced cholesterol efflux would be predicted to be pro-atherogenic. However, the effect of statins was lost when macrophages were extensively cholesterol-loaded. These conflicting observations beg the question: do statins accentuate or ameliorate macrophage cholesterol accumulation within the arterial wall?
In this initial report, we have not attempted to measure the effect of statins on cellular cholesterol status. From the literature, statins appear to have varying effects on macrophage cholesterol levels, depending on culturing conditions.22,23 In the present study, AcLDL-loading of THP-1 cells tended to increase ABCA1 expression in agreement with previous studies,19 but drastically inhibited the mevalonate pathway, including synthesis of 24,25EC. These results suggest that human macrophages may produce different ligands for LXR, depending on the supply of exogenous cholesterol versus the activity of the shunt pathway. 27-hydroxycholesterol is unlikely to be a significant ligand in THP-1 cells because these cells, unlike primary human macrophages, have very low expression of CYP27A1 and produce negligible 27-hydroxycholesterol (Quinn CM, Brown AJ, Kritharides L, Jessup W, unpublished observations).
Further work is required to evaluate the role of cholesterol status on the effects of statins on LXR target genes, and to determine how relevant our observations are to arterial foam cells in vivo. In terms of future studies to assess the clinical implications of the effect of statins on LXR target genes, studies in mice may not be particularly helpful, considering the substantial differences in lipid metabolism between mice and humans, particularly regarding the regulation of LXR.19
Although there is no doubt that statins exert a net benefit, their efficacy potentially may be negated to some extent by reducing LXR ligand formation and hence impairing reverse cholesterol transport, at least in nonloaded human macrophages. With the evolving interest in the cholesterol-independent vascular effects of statins, it is imperative that we explore and understand all interactions between statins and the macrophage, even those that may be potentially negative.
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Acknowledgments |
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This work was supported by grants from National Heart Foundation of Australia (G01S 0409) and National Health and Medical Research Council (Atherosclerosis Program 222722). Inhibitors of the cholesterol synthesis pathway and synthetic nuclear receptor ligands were generously provided by Glaxo Smith-Kline. We thank Ingrid Gelissen for invaluable help with the Western blotting.
Received May 10, 2004; accepted September 17, 2004.
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[Abstract/Free Full Text]
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