Published online before print October 27, 2005, doi: 10.1161/01.ATV.0000193513.29074.52
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© 2006 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Glucocorticoid Receptor Regulates ATP-Binding Cassette Transporter-A1 Expression and Apolipoprotein-Mediated Cholesterol Efflux From Macrophages
From the First Department of Internal Medicine (M.A., S.S., A.Y., N.I., M.O., N.T., K.N., M.K., F.O.), National Defense Medical College, Tokorozawa, and the Mitsukoshi Health and Welfare Foundation (H.N.), Tokyo, Japan.
Correspondence to Makoto Ayaori, First Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Japan 359-8513. E-mail ayaori{at}ba2.so-net.ne.jp
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Objective— The ATP-binding cassette transporter-A1 (ABCA1) regulates cholesterol efflux from cells and is involved in high-density lipoprotein metabolism and atherogenesis. The objective of this study was to investigate the effect of dexamethasone (Dex) and other glucocorticoid receptor (GR) ligands on apolipoprotein AI–mediated cholesterol efflux from macrophages and ABCA1 expression in them.
Methods and Results— Dex, a GR agonist, decreased ABCA1 mRNA levels in a dose- and time-dependent fashion, and RU486, a GR antagonist, reversed the inhibitory effect of Dex. The effects of Dex and RU486 on ABCA1 protein levels and apolipoprotein AI–mediated cholesterol efflux from the macrophages were consistent with these changes in mRNA levels. Transfected RAW264.7, together with a human ABCA1 promoter–luciferase construct, inhibited transcriptional activity by Dex and overexpression of human GR. Transrepression by GR was not mediated by liver X receptor (LXR), because there were no differences in the effects of the GR ligands on promoter activity between a reporter construct with mutations at the LXR binding site and one without the mutations, and no changes were brought about in ABCG1 and ABCG4 expression by GR ligands.
Conclusions— Our results showed that GR ligands affected ABCA1 expression and cholesterol efflux from macrophages, which are regulated by GR through a LXR-independent mechanism.
Several nuclear receptors regulate ABCA1 expression to maintain intracellular cholesterol. The present study showed that glucocorticoid receptor (GR) agonist and antagonist, respectively, attenuated and stimulated cholesterol efflux from macrophages by apolipoprotein and ABCA1 expression, which are regulated by GR at a transcriptional level through an LXR-independent mechanism.
Key Words: ABCA1 • dexamethasone • GR • cholesterol • macrophage
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Multiple lines of evidence suggest that long-term use of glucocorticoids is associated with increased risk of developing atherosclerotic disease.1 It has been reported that glucocorticoid treatment can cause cardiovascular complications in patients with rheumatoid arthritis2 and systemic lupus erythematosus3 receiving such treatment and that patients with Cushing’s syndrome had a higher incidence of cardiovascular disease (CVD).4 In this regard, it has been noted that glucocorticoid treatment causes hypertension, as well as impaired glucose and lipid metabolism,1 which are classical risk factors for CVD. Other than this, glucocorticoids have been observed to directly affect the vascular wall with respect to cholesterol metabolism in the cells involved in atherogenesis.
Macrophage-derived foam cells containing accumulations of cholesteryl ester (CE) as lipid droplets are characteristically present in atherosclerotic plaque. In this connection, several investigators have reported that dexamethasone (Dex) induced CE accumulation in macrophages by enhancing scavenger receptor and acyl coenzyme A:cholesterol O–acyltransferase activity and reducing cholesterol esterase activity.5,6
Cholesterol efflux is a pivotal event in maintaining intracellular cholesterol levels and preventing the formation of macrophage-derived foam cells. Furthermore, the ATP-binding cassette transporter A1 (ABCA1) has been identified as a defective gene in Tangier disease,7–9 which is characterized by an extremely low level of circulating high-density lipoprotein (HDL), and accumulation of CE in various tissues, which is concentrated in macrophage-derived foam cells. In addition, ABCA1 has been shown recently to play an important role in apolipoprotein AI (apoAI)–mediated cholesterol efflux from peripheral cells10 and macrophages. Thus, given the key role of ABCA1 in facilitating cholesterol efflux, it would be of interest to determine how the ABCA1 gene itself is regulated. The expression of ABCA1 is greatly regulated by cAMP and sterols.11–13
Oxysterols and 9-cis-retinoic acid (9cRA) bind liver X receptor (LXR) and retinoid X receptor (RXR), respectively, to form heterodimers, which bind to conserved consensus cis-element, direct repeat 4 (DR4), in the ABCA1 promoter region, resulting in the activation of transcription.14,15 LXR, RXR, and the glucocorticoid receptor (GR) are all nuclear receptors that have been shown to play important physiological roles in macrophages.16 Recent studies have demonstrated that the peroxisome proliferator–activated receptor-
upregulates LXR expression resulting in elevated ABCA1 levels in macrophages17 and that thyroid hormone receptor (TR) attenuated ABCA1 expression is dependent on LXR/RXR,18 but it is still unclear whether it is glucocorticoids or GRs that influence cholesterol efflux and ABCA1 expression in macrophages.
In the present study, we found that the GR agonist Dex decreased apoAI-mediated cholesterol efflux and ABCA1 expression in macrophages, whereas the GR antagonist RU486 increased them, with ABCA1 expression in macrophages being regulated via GR.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The Methods section can be found in an online supplement available at http://atvb.ahajournals.org.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Inhibitory Effect of GR Agonist Dex on ABCA1 Expression in THP-1 Macrophages and Restoration of Expression by GR Antagonist RU486
ABCA1 mRNA levels in the THP-1 macrophages decreased in a dose-dependent manner 6 hours after treatment with Dex and were restored by concomitant treatment with RU486, actually showing an increase compared with basal levels (Figure 1A). When the macrophages were treated with acetyl LDL (AcLDL) and the LXR/RXR agonists, 22HC and 9cRA, respectively, ABCA1 mRNA levels dramatically increased compared with basal levels. In this experiment, Dex attenuated ABCA1 mRNA levels, and RU486 restored them in the presence of AcLDL and the LXR and RXR agonists (Figure 1B and 1C).
|
P<0.05 vs Dex 1 µmol/L. P values were calculated using Mann–Whitney U test.Figure 1D shows that treatment with RU486 increased ABCA1 mRNA levels in a dose-dependent manner in the presence of untreated FBS but did not increase these levels in the presence of dextran-coated charcoal FBS. These findings indicate that increased ABCA1 expression because of RU486 stems from the endogenous glucocorticoid effect. We also investigated the effect of another GR agonist, triamcinolone, noting the attenuation of ABCA1 mRNA levels and antagonization by RU486 (Figure 1E). We also examined the changes in ABCA1 mRNA levels in THP-1 macrophages with time after treatment with Dex, finding that ABCA1 mRNA levels were slightly elevated after 2 hours and were then clearly lower at 4 hours and thereafter (Figure 2A). In the presence of untreated FBS, RU486 had increased ABCA1 mRNA levels after 2 hours, and the increase was maintained up to 6 hours (Figure 2B). Levels had decreased at 16 hours after treatment with RU486.
|
Effects of GR Ligands on ABCA1 Protein Levels and ApoAI-Mediated Cholesterol Efflux
Figure 3A shows the ABCA1 protein levels after treatment with Dex or RU486 in the presence and absence of AcLDL. Dex decreased ABCA1 protein levels and RU486 restored them, even after stimulation of ABCA1 expression by AcLDL. We also examined the effects of the GR ligands on apoAI-mediated cholesterol efflux from THP-1 macrophages. Dex significantly reduced cholesterol efflux attributed to apoAI, and RU486 attenuated this inhibitory effect (Figure 3B), which was consistent with the changes in ABCA1 mRNA and protein levels.
|
Effects of GR Ligands on ABCA1 mRNA in HMDM and RAW264.7 Cells
We conducted experiments using human monocyte-derived macrophages (HMDM) and murine RAW264.7 cells to investigate whether Dex exerted inhibitory effects on ABCA1 and mRNA levels in other lines of the macrophages. By means of quantitative real-time RT-PCR, Dex was shown to significantly reduce ABCA1 mRNA levels in HMDM, and they were restored by RU486 (Figure IA, available online at http://atvb.ahajournals.org). In RAW 264.7 cells (Figure IB), Dex also reduced ABCA1 mRNA levels, and they were restored by RU486.
Regulation of ABCA1 Promoter Activity by GR Ligands through GR
To investigate whether GR ligands regulate ABCA1 mRNA levels in macrophages at the transcriptional level, a human ABCA1 promoter luciferase reporter construct spanning –940 to +110 bp (ABCA1-Luc) was transfected into RAW264.7 cells, and luciferase assay was performed. Dex inhibited ABCA1 promoter activity in a dose-dependent fashion, and RU486 completely restored it as shown in Figure 4A. In the case of overexpression of GR, ABCA1 promoter activity increased in the absence of Dex but decreased in its presence in a dose-dependent manner (Figure 4B). We also observed that when macrophages were treated with actinomycin D, the GR ligands had no effect on ABCA1 mRNA levels or mRNA stability (data not shown). These data suggest that GR ligands regulate ABCA1 expression in macrophages at the transcriptional level through GR.
|
P<0.05 vs control with pCMX empty vector; 
P<0.05 vs wild-type with 22HC. P values were calculated using Mann–Whitney U test.
Alteration of ABCA1 Promoter Activity by GR Ligands Independent of LXR
To investigate whether the effects of GR ligands on ABCA1 promoter activity are associated with LXR- and RXR-dependent transcriptional regulation, we used a mutant reporter construct, DR4mut (Figure 4C). The LXR ligand 22HC failed to induce promoter activity for DR4mut, whereas it increased promoter activity in the case of the wild-type reporter construct ABCA1-Luc (Figure 4D). There were no differences in the changes in promoter activity because of GR ligands between ABCA1-Luc and DR4mut.
ABCG1 and ABCG4 are reportedly involved in cholesterol efflux from macrophages19,20 and are also known to be LXR-responsive genes.21–23 Figure IIA and IIB (available online at http://atvb.ahajournals.org) show that GR ligands did not affect mRNA levels of ABCG1 and ABCG4 in THP-1 macrophages, although they had been increased by LXR and RXR ligands. The above findings clearly demonstrate that transcriptional regulation in ABCA1 by GR ligands is independent of LXR. We also studied the effect of GR ligands on mRNA levels for scavenger receptor class B, type 1, which is reportedly involved in HDL-mediated cholesterol efflux,24 but noted no change in levels (Figure IIC).
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
We demonstrated that a GR agonist and antagonist, respectively, inhibited and stimulated ABCA1 expression in several lines of macrophages and apoAI-mediated cholesterol efflux from THP-1 macrophages, which were regulated through GR. Glucocorticoids have been reported to be associated with an increased risk of CVD presumably because of their unfavorable effects with respect to classical CVD risk factors, such as hypertension, impaired glucose, and lipid metabolism.1 Other than these effects, glucocorticoids have been reported to directly affect the vascular wall with respect to cholesterol metabolism in the cells involved in atherogenesis. Hirsch and Mazzone5 reported that Dex enhanced the degradation of AcLDL in macrophages through increased lipoprotein binding, which could mean enhanced scavenger receptor activity. Cheng et al6 reported that Dex increased cholesterol O–acyltransferase activity and decreased neutral cholesterol esterase activity, resulting in greater accumulation of CE in macrophages. The homeostasis of intracellular cholesterol in peripheral cells is mainly maintained through its influx and efflux. Cholesterol efflux should be more important to macrophages than other types of cells, because macrophages express scavenger receptor class A, which is not downregulated by excess intracellular cholesterol. However, the effects of glucocorticoids on cholesterol efflux from macrophages have still to be investigated. Our study demonstrated the inhibitory effect of Dex on ABCA1 expression levels (Figures 1, 2, and 3
A; Figure I) and apoAI-specific cholesterol efflux from macrophages (Figure 3B), which might be part of the reason for CE accumulation observed in previous studies. However, scavenger receptor class B, type 1 was not affected by the GR ligands, as mentioned above (Figure IIC). Petrichenko et al25 reported that Dex decreased cholesterol efflux mediated by HDL from vascular smooth muscle cells, and Stein et al26 observed that Dex decreased HDL-mediated cholesterol efflux from skeletal muscle in mice, suggesting that altered ABCA1 expression was involved. It has been reported that glucocorticoid therapy increases serum HDL cholesterol levels.27 Because GR is expressed in most organs, we investigated whether GR ligands affected ABCA1 expression in other types of cells. GR ligands did not change ABCA1 mRNA levels in NIH 3T3 cells, and Dex brought about a slight increase in levels in both HepG2 and Caco-2 cells, which was reversed by RU486 (data not shown). These results indicate that ABCA1 expression is regulated by GR ligands in a cell-specific manner, and partly explain the reason for the elevation of HDL cholesterol levels by glucocorticoids. Given that the contribution of ABCA1 in macrophages to serum HDL cholesterol levels is minimal, as reported by Haghpassand et al,28 decreased ABCA1 expression in macrophages because of glucocorticoids is unlikely to affect HDL cholesterol levels.
GR agonists regulate gene expression in various ways, at the transcriptional,29 posttranscriptional,30–32 and posttranslational levels.33 The classical mode of gene regulation by glucocorticoids, which accounts for most cases of positive gene regulation, is known to be mediated by interaction of ligand-activated GR with positive control elements, which are present in single or multiple copies upstream of or within target genes. However, compared with positive regulation of gene transcription by GR, negative regulation seems to be more complicated as described below. Dex reportedly destabilizes the mRNA of some genes presumably by affecting RNA binding proteins, which associate with 3'-untranslated lesions to stabilize mRNA.30–32 Lasa et al34 reported that Dex caused sustained expression of mitogen-activated protein kinase phosphatase 1 and phosphatase-mediated inactivation of mitogen-activated protein kinase p38, resulting in destabilization of Cox-2 mRNA. Kaplan et al35 reported that a p38 inhibitor decreased ABCA1 expression in macrophages, and this inhibitory effect was not at the transcriptional level. In our study, the GR ligands did not affect ABCA1 mRNA levels or alter mRNA stability when macrophages were treated with actinomycin D (data not shown). Regarding transcriptional regulation, Dex inhibited ABCA1 promoter activity in a dose-dependent manner, and RU486 antagonized the inhibitory effects of Dex in this respect (Figure 4), which is consistent with the changes in mRNA levels observed. We also found that overexpression of GR decreased ABCA1 promoter activity in the presence of Dex. These findings indicate that GR ligands regulate ABCA1 expression in macrophages at the transcriptional level through GR.
We also observed a stimulatory effect of overexpression of GR in the absence of Dex (Figure 4B). Xiao and DeFranco36 reported that overexpression of unliganded and liganded GR, respectively, activated and inactivated heat shock factor, a transcription factor that transactivates heat shock protein genes, such as hsp90 and hsp70. They suggested that the mechanism for increased transcriptional activity was unliganded GR-induced depletion of hsp70, which inactivates heat shock factor, resulting in activation of heat shock factor. In our study, overexpression of unliganded GR
might have affected unknown protein-regulated events involving ABCA1 expression, as Xiao and DeFranco36 observed in the case of heat shock factor. Another possible mechanism is the reciprocal effects on transcriptional activity of liganded and unliganded receptors reported by Tagami et al.37 They reported that transcription of genes, which was inhibited by liganded TR, was reciprocally activated by unliganded TR with enhancement by overexpression of nuclear corepressors. Because Xiao and DeFranco36 clearly showed that unliganded GR was present not only in the cytosol but also in the nucleus, unliganded GR might stimulate ABCA1 promoter activity through the mechanism reported by Tagami et al.37 Because we did not fully clarify the mechanism for the inhibitory effect of GR on ABCA1 transcription, it remains unclear whether activated GR is directly associated with the transcriptional machinery involved in ABCA1 expression. Given the cell-specific regulation of ABCA1 expression by GR ligands, GR might affect pathways recruited by macrophage-specific proteins associated with ABCA1 expression.
Dex treatment caused the transient increase in ABCA1 mRNA levels from 1 to 2 hours after beginning the experiment, and the levels gradually decreased from 4 hours onwards (Figure 2A). We also observed a difference in the times of maximal changes in ABCA1 expression between Dex and RU486, which were at 6 hours and 2 hours after treatment, respectively. The dependence on endogenous glucocorticoids (Figure 1D) indicates that RU486 exerts a competitive effect on ABCA1 expression through GR antagonization. However, it is possible that different mechanisms are involved in the respective effects of Dex and RU486 and that they are the reason for the early and late times of maximal changes in ABCA1 expression. As described above, both liganded and unliganded GR reportedly affected not only gene transcription through binding control elements of target genes but also protein–protein interaction and intracellular protein distribution. Therefore, several mechanisms could be involved in the changes in ABCA1 expression attributed to GR ligands. Additional study will be needed to clarify the mechanism for the transient increase in ABCA1 expression because of Dex.
There are 2 main mechanisms for the negative regulation of gene transcription by GR, 1 of them involving interference with DNA binding of upstream or general transcription factors and the other a repression mechanism, which is independent of DNA binding. Ligand-activated GRs have been reported to interact with activator protein-1 (AP-1)38 and nuclear factor 
B (NF-B),39,40 resulting in decreased transcription of AP-1– and NF-B–responsive genes involved in inflammation. The ABCA1 promoter has been found to have consensus sequences for AP-1 and NF-kB.10,13 However, although GRs can affect ABCA1 promoter activity by interfering with AP-1 and NF-B, Kaplan et al35 reported that lipopolysaccharides induced ABCA1 expression in macrophages without activating transcription. Thus, additional studies will be needed to ascertain whether the inhibitory effect of GR on ABCA1 transcription is mediated though AP-1 and NF-B.
Accumulating evidence indicates that LXR regulates many genes involved in cholesterol homeostasis in cells, such as ABCA1, ABCG1, and ABCG4. Recently, several investigators have demonstrated interactions between LXR and other nuclear receptors. TR has been reported recently to inhibit ABCA1 promoter activity through competition between TR/RXR and LXR/RXR heterodimers.18 Small heterodimer partner, an unusual nuclear receptor, because it does not have the typical DNA binding domain, has been reported to act as a corepressor for several nuclear receptors, including LXR. Brendel et al41 reported that small heterodimer partner attenuated ABCA1 and ABCG1 promoter activities by interacting with LXR. Our study revealed that GR-mediated transcriptional inhibition in ABCA1 is independent of LXR (Figure 4). In addition, the expression of other LXR target genes, ABCG1 and ABCG4, were not affected by GR ligands (Figure IIA and IIB).
Other recent studies have reported transcriptional regulation for both ABCA1 and ABCG1, not only by LXR and RXR and cholesterol loading, but also by zinc finger protein 202.42 Moreover, Lorkowski et al43 have reported that macrophages from patients with Tangier disease showed a compensated increase in ABCG1 expression. Although such evidence led us to believe that these 2 genes share similar mechanisms of regulation, we observed differences in the mechanisms of regulation of ABCA1 and ABCG1, and other researchers have also found this to be the case. Therefore, these genes may have their own unique functions, like that of ABCA1 in apoptosis.44
As other possible mechanisms for GR-mediated transrepression of ABCA1, there is the stimulation of ABCA1 expression in macrophages by transforming growth factor (TGF) ß,45 and inhibition of smad-dependent transactivation through the binding of smad3 by GRs.46 To determine whether GR-mediated transrepression in ABCA1 is associated with the TGF-ß signaling pathway, we investigated the effect of a neutral antibody against TGF-ß on the changes in ABCA1 mRNA levels by GR agonists. The presence of the antibody, however, caused no changes in ABCA1 mRNA levels (data not shown).
Our study indicated that the attenuated cholesterol efflux and ABCA1 expression in macrophages could contribute to glucocorticoid-associated cardiovascular risk. Additional investigation of the mechanisms by which GR regulates ABCA1 expression would, therefore, provide important information for the study of compounds that facilitate cholesterol efflux.
Received March 12, 2005; accepted August 5, 2005.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Nashel DJ. Is atherosclerosis a complication of long-term corticosteroid treatment? Am J Med. 1986; 80: 925–929.[CrossRef][Medline] [Order article via Infotrieve]
2. Kalbak K. Incidence of arteriosclerosis in patients with rheumatoid arthritis receiving long-term corticosteroid therapy. Ann Rheum Dis. 1972; 31: 196–200.
3. Salmon JE, Roman MJ. Accelerated atherosclerosis in systemic lupus erythematosus: implications for patient management. Curr Opin Rheumatol. 2001; 13: 341–344.[CrossRef][Medline] [Order article via Infotrieve]
4. Etxabe J, Vazquez JA. Morbidity and mortality in Cushing’s disease: an epidemiological approach. Clin Endocrinol (Oxf). 1994; 40: 479–484.[Medline] [Order article via Infotrieve]
5. Hirsch LJ, Mazzone T. Dexamethasone modulates lipoprotein metabolism in cultured human monocyte-derived macrophages. Stimulation of scavenger receptor activity. J Clin Invest. 1986; 77: 485–490.[Medline] [Order article via Infotrieve]
6. Cheng W, Kvilekval KV, Abumrad NA. Dexamethasone enhances accumulation of cholesteryl esters by human macrophages. Am J Physiol. 1995; 269: E642–E648.
7. Brooks-Wilson A, Marcil M, Clee SM, Zhang LH, Roomp K, van Dam M, Yu L, Brewer C, Collins JA, Molhuizen HO, Loubser O, Ouelette BF, Fichter K, Ashbourne-Excoffon KJ, Sensen CW, Scherer S, Mott S, Denis M, Martindale D, Frohlich J, Morgan K, Koop B, Pimstone S, Kastelein JJ, Genest J Jr, Hayden MR. Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency. Nat Genet. 1999; 22: 336–345.[CrossRef][Medline] [Order article via Infotrieve]
8. Bodzioch M, Orso E, Klucken J, Langmann T, Bottcher A, Diederich W, Drobnik W, Barlage S, Buchler C, Porsch-Ozcurumez M, Kaminski WE, Hahmann HW, Oette K, Rothe G, Aslanidis C, Lackner KJ, Schmitz G. The gene encoding ATP-binding cassette transporter 1 is mutated in Tangier disease. Nat Genet. 1999; 22: 347–351.[CrossRef][Medline] [Order article via Infotrieve]
9. Rust S, Rosier M, Funke H, Real J, Amoura Z, Piette JC, Deleuze JF, Brewer HB, Duverger N, Denefle P, Assmann G. Tangier disease is caused by mutations in the gene encoding ATP-binding cassette transporter 1. Nat Genet. 1999; 22: 352–355.[CrossRef][Medline] [Order article via Infotrieve]
10. Wang N, Silver DL, Thiele C, Tall AR. ATP-binding cassette transporter A1 (ABCA1) functions as a cholesterol efflux regulatory protein. J Biol Chem. 2001; 276: 23742–23747.
11. Takahashi Y, Smith JD. Cholesterol efflux to apolipoprotein AI involves endocytosis and resecretion in a calcium-dependent pathway. Proc Natl Acad Sci U S A. 1999; 96: 11358–11363.
12. Oram JF, Lawn RM, Garvin MR, Wade DP. ABCA1 is the cAMP-inducible apolipoprotein receptor that mediates cholesterol secretion from macrophages. J Biol Chem. 2000; 275: 34508–34511.
13. Santamarina-Fojo S, Peterson K, Knapper C, Qiu Y, Freeman L, Cheng JF, Osorio J, Remaley A, Yang XP, Haudenschild C, Prades C, Chimini G, Blackmon E, Francois T, Duverger N, Rubin EM, Rosier M, Denefle P, Fredrickson DS, Brewer HB Jr. Complete genomic sequence of the human ABCA1 gene: analysis of the human and mouse ATP-binding cassette A promoter. Proc Natl Acad Sci U S A. 2000; 97: 7987–7992.
14. Costet P, Luo Y, Wang N, Tall AR. Sterol-dependent transactivation of the ABC1 promoter by the liver X receptor/retinoid X receptor. J Biol Chem. 2000; 275: 28240–28245.
15. Repa JJ, Turley SD, Lobaccaro JA, Medina J, Li L, Lustig K, Shan B, Heyman RA, Dietschy JM, Mangelsdorf DJ. Regulation of absorption and ABC1-mediated efflux of cholesterol by RXR heterodimers. Science. 2000; 289: 1524–1529.
16. Valledor AF, Ricote M. Nuclear receptor signaling in macrophages. Biochem Pharmacol. 2004; 67: 201–212.[CrossRef][Medline] [Order article via Infotrieve]
17. Chawla A, Boisvert WA, Lee CH, Laffitte BA, Barak Y, Joseph SB, Liao D, Nagy L, Edwards PA, Curtiss LK, Evans RM, Tontonoz P. A PPAR gamma-LXR-ABCA1 pathway in macrophages is involved in cholesterol efflux and atherogenesis. Mol Cell. 2001; 7: 161–171.[CrossRef][Medline] [Order article via Infotrieve]
18. Huuskonen J, Vishnu M, Pullinger CR, Fielding PE, Fielding CJ. Regulation of ATP-binding cassette transporter A1 transcription by thyroid hormone receptor. Biochemistry. 2004; 43: 1626–1632.[CrossRef][Medline] [Order article via Infotrieve]
19. Klucken J, Buchler C, Orso E, Kaminski WE, Porsch-Ozcurumez M, Liebisch G, Kapinsky M, Diederich W, Drobnik W, Dean M, Allikmets R, Schmitz G. ABCG1 (ABC8), the human homolog of the Drosophila white gene, is a regulator of macrophage cholesterol and phospholipid transport. Proc Natl Acad Sci U S A. 2000; 97: 817–822.
20. Wang N, Lan D, Chen W, Matsuura F, Tall AR. ATP-binding cassette transporters G1 and G4 mediate cellular cholesterol efflux to high-density lipoproteins. Proc Natl Acad Sci U S A. 2004; 101: 9774–9779.
21. Venkateswaran A, Repa JJ, Lobaccaro JM, Bronson A, Mangelsdorf DJ, Edwards PA. Human white/murine ABC8 mRNA levels are highly induced in lipid-loaded macrophages. A transcriptional role for specific oxysterols. J Biol Chem. 2000; 275: 14700–14707.
22. Kennedy MA, Venkateswaran A, Tarr PT, Xenarios I, Kudoh J, Shimizu N, Edwards PA. Characterization of the human ABCG1 gene: liver X receptor activates an internal promoter that produces a novel transcript encoding an alternative form of the protein. J Biol Chem. 2001; 276: 39438–39447.
23. Engel T, Lorkowski S, Lueken A, Rust S, Schluter B, Berger G, Cullen P, Assmann G. The human ABCG4 gene is regulated by oxysterols and retinoids in monocyte-derived macrophages. Biochem Biophys Res Commun. 2001; 288: 483–488.[CrossRef][Medline] [Order article via Infotrieve]
24. Trigatti BL, Krieger M, Rigotti A. Influence of the HDL receptor SR-BI on lipoprotein metabolism and atherosclerosis. Arterioscler Thromb Vasc Biol. 2003; 23: 1732–1738.
25. Petrichenko IE, Daret D, Kolpakova GV, Shakhov YA, Larrue J. Glucocorticoids stimulate cholesteryl ester formation in human smooth muscle cells. Arterioscler Thromb Vasc Biol. 1997; 17: 1143–1151.
26. Stein O, Dabach Y, Hollander G, Ben-Naim M, Halperin G, Stein Y. Dexamethasone impairs cholesterol egress from a localized lipoprotein depot in vivo. Atherosclerosis. 1998; 137: 303–310.[Medline] [Order article via Infotrieve]
27. Zimmerman J, Fainaru M, Eisenberg S. The effects of prednisone therapy on plasma lipoproteins and apolipoproteins: a prospective study. Metabolism. 1984; 33: 521–526.[CrossRef][Medline] [Order article via Infotrieve]
28. Haghpassand M, Bourassa PA, Francone OL, Aiello RJ. Monocyte/macrophage expression of ABCA1 has minimal contribution to plasma HDL levels. J Clin Invest. 2001; 108: 1315–1320.[CrossRef][Medline] [Order article via Infotrieve]
29. Adcock IM. Glucocorticoid-regulated transcription factors. Pulm Pharmacol Ther. 2001; 14: 211–219.[CrossRef][Medline] [Order article via Infotrieve]
30. Korhonen R, Lahti A, Hamalainen M, Kankaanranta H, Moilanen E. Dexamethasone inhibits inducible nitric-oxide synthase expression and nitric oxide production by destabilizing mRNA in lipopolysaccharide-treated macrophages. Mol Pharmacol. 2002; 62: 698–704.
31. Garcia-Gras EA, Chi P, Thompson EA. Glucocorticoid-mediated destabilization of cyclin D3 mRNA involves RNA-protein interactions in the 3'-untranslated region of the mRNA. J Biol Chem. 2000; 275: 22001–22008.
32. Dixon DA, Kaplan CD, McIntyre TM, Zimmerman GA, Prescott SM. Post-transcriptional control of cyclooxygenase-2 gene expression. The role of the 3'-untranslated region. J Biol Chem. 2000; 275: 11750–11757.
33. Kritsch KR, Murali S, Adamo ML, Ney DM. Dexamethasone decreases serum and liver IGF-I and maintains liver IGF-I mRNA in parenterally fed rats. Am J Physiol Regul Integr Comp Physiol. 2002; 282: R528–36.
34. Lasa M, Abraham SM, Boucheron C, Saklatvala J, Clark AR. Dexamethasone causes sustained expression of mitogen-activated protein kinase (MAPK) phosphatase 1 and phosphatase-mediated inhibition of MAPK p38. Mol Cell Biol. 2002; 22: 7802–7811.
35. Kaplan R, Gan X, Menke JG, Wright SD, Cai TQ. Bacterial lipopolysaccharide induces expression of ABCA1 but not ABCG1 via an LXR-independent pathway. J Lipid Res. 2002; 43: 952–959.
36. Xiao N, DeFranco DB. Overexpression of unliganded steroid receptors activates endogenous heat shock factor. Mol Endocrinol. 1997; 11: 1365–1374.
37. Tagami T, Madison LD, Nagaya T, Jameson JL. Nuclear receptor corepressors activate rather than suppress basal transcription of genes that are negatively regulated by thyroid hormone. Mol Cell Biol. 1997; 17: 2642–2648.[Abstract]
38. Herrlich P. Cross-talk between glucocorticoid receptor and AP-1. Oncogene. 2001; 20: 2465–2475.[CrossRef][Medline] [Order article via Infotrieve]
39. Almawi WY, Melemedjian OK. Negative regulation of nuclear factor-kappaB activation and function by glucocorticoids. J Mol Endocrinol. 2002; 28: 69–78.[Abstract]
40. McKay LI, Cidlowski JA. Molecular control of immune/inflammatory responses: interactions between nuclear factor-kappa B and steroid receptor-signaling pathways. Endocr Rev. 1999; 20: 435–459.
41. Brendel C, Schoonjans K, Botrugno OA, Treuter E, Auwerx J. The small heterodimer partner interacts with the liver X receptor alpha and represses its transcriptional activity. Mol Endocrinol. 2002; 16: 2065–2076.
42. Porsch-Ozcurumez M, Langmann T, Heimerl S, Borsukova H, Kaminski WE, Drobnik W, Honer C, Schumacher C, Schmitz G. The zinc finger protein 202 (ZNF202) is a transcriptional repressor of ATP binding cassette transporter A1 (ABCA1) and ABCG1 gene expression and a modulator of cellular lipid efflux. J Biol Chem. 2001; 276: 12427–12433.
43. Lorkowski S, Kratz M, Wenner C, Schmidt R, Weitkamp B, Fobker M, Reinhardt J, Rauterberg J, Galinski EA, Cullen P. Expression of the ATP-binding cassette transporter gene ABCG1 (ABC8) in Tangier disease. Biochem Biophys Res Commun. 2001; 283: 821–830.[CrossRef][Medline] [Order article via Infotrieve]
44. Hamon Y, Broccardo C, Chambenoit O, Luciani MF, Toti F, Chaslin S, Freyssinet JM, Devaux PF, McNeish J, Marguet D, Chimini G. ABC1 promotes engulfment of apoptotic cells and transbilayer redistribution of phosphatidylserine. Nat Cell Biol. 2000; 2: 399–406.[CrossRef][Medline] [Order article via Infotrieve]
45. Argmann CA, Van Den Diepstraten CH, Sawyez CG, Edwards JY, Hegele RA, Wolfe BM, Huff MW. Transforming growth factor-beta1 inhibits macrophage cholesteryl ester accumulation induced by native and oxidized VLDL remnants. Arterioscler Thromb Vasc Biol. 2001; 21: 2011–2018.
46. Song CZ, Tian X, Gelehuter TD. Glucocorticoid receptor inhibits transforming growth factor-beta signaling by directly targeting the transcriptional activation function of Smad3. Proc Natl Acad Sci U S A. 1999; 96: 11776–11781.
This article has been cited by other articles:
 |
|
 |
|
  N. Iwamoto, S. Abe-Dohmae, M. Ayaori, N. Tanaka, M. Kusuhara, F. Ohsuzu, and S. Yokoyama ATP-Binding Cassette Transporter A1 Gene Transcription Is Downregulated by Activator Protein 2{alpha}: Doxazosin Inhibits Activator Protein 2{alpha} and Increases High-Density Lipoprotein Biogenesis Independent of {alpha}1-Adrenoceptor Blockade Circ. Res., July 20, 2007; 101(2): 156 - 165. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||