Published online before print May 3, 2007, doi: 10.1161/ATVBAHA.107.144121
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© 2007 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Expression of Human OSBP-Related Protein 1L in Macrophages Enhances Atherosclerotic Lesion Development in LDL Receptor–Deficient Mice
From the Department of Molecular Medicine (D.Y., M.J., CE., V.M.O.), National Public Health Institute, Biomedicum, Helsinki, Finland; the Division of Biopharmaceutics (R.B.H., T.J.C.V.B., M.V.E.), Leiden/Amsterdam Center for Drug Research, Gorlaeus Laboratories, Leiden, The Netherlands; and the The Departments of General Internal Medicine and Human Genetics (K.W.v.D.), Leiden University Medical Center, Leiden, The Netherlands.
Correspondence Vesa M. Olkkonen, Department of Molecular Medicine, National Public Health Institute, Biomedicum, P.O. Box 104, FI-00251 Helsinki, Finland. E-mail vesa.olkkonen{at}ktl.fi
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Abstract |
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Objective— The purpose of this study was to assess the role of macrophage OSBP-related protein 1L (ORP1L) in the development of atherosclerosis.
Methods and Results— C57BL/6 mice overexpressing human ORP1L in macrophages driven by scavenger receptor A promoter were generated. Bone marrow (BM) of the mice was transplanted into LDLr–/– animals, and aortic root lesion area in the recipients was determined after Western-type diet feeding. The recipients of ORP1L BM displayed 2.1-fold increase (P<0.001) in lesion size as compared with recipients of wild-type littermate BM. Macrophages of the ORP1L BM recipients showed a decrease in ABCG1 and APOE mRNAs and proteins, and an increase in PLTP message; also the plasma PLTP activity was elevated. The effect of ORP1L on cholesterol efflux was assessed using macrophages loaded with [3H]cholesterol oleate-acLDL or labeled with [3H]cholesterol. The ORP1L transgenic macrophages displayed 30% reduction (P<0.01) in cholesterol efflux to HDL2, but not to apoA-I. ORP1L was shown to bind 25- and 22(R)-hydroxycholesterol, identifying it as an oxysterol binding protein. Furthermore, ORP1L attenuated the response of ABCG1 mRNA to 22(R)-hydroxycholesterol, the effect on ABCA1 being less pronounced.
Conclusions— The results demonstrate that macrophage ORP1L can act as a modulator of atherosclerotic lesion development and provide clues to the underlying mechanism.
LDLr–/– animals that received bone marrow of mice expressing human ORP1L in macrophages displayed a 2.1-fold increase in aortic root lesion size relative to controls. Decreased macrophage ABCG1 and apoE expression and cholesterol efflux to HDL2, as well as increased PLTP expression, provide plausible explanations for the increased lesion size.
Key Words: ABCG1 • apolipoprotein E • atherosclerosis • cholesterol efflux • macrophage • ORP1L • oxysterol binding protein • PLTP
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Introduction |
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Lipid-loaded monocyte-derived macrophage foam cells are characteristic constituents of the early atherosclerotic lesion, the fatty streak, and are present at all stages of lesion development.1 Macrophages also play a central role in the inflammatory signaling within the plaque,2 whereas hydrolytic enzymes secreted by macrophages and other inflammatory cell types have been suggested to influence plaque structure and stability.3 In addition to cholesterol, several oxysterols, 27-carbon oxygenated derivatives of cholesterol, are enriched in the atherosclerotic plaques in both humans and in animal models.4,5 Oxysterols have cytotoxic, proapoptotic, and proinflammatory effects and facilitate monocyte differentiation into macrophages. They have therefore been suggested to adversely affect lesion development and stability.5,6 However, certain oxysterols act as agonists of liver X receptors, transcription factors that facilitate cholesterol efflux from macrophages and removal from the circulation via the reverse cholesterol transport process,7 thus having beneficial properties in terms of atherogenesis.
Oxysterol binding protein (OSBP), a cytosolic receptor for oxysterols, was isolated and molecularly cloned in the 1980s.8–10 Families of proteins (OSBP-related proteins [ORP]) displaying sequence homology to the carboxy-terminal sterol binding domain of OSBP are present in practically all eukaryotic organisms.11 The mammalian ORP have been implicated as sterol sensors that regulate cellular functions ranging from sterol and neutral lipid metabolism to vesicle transport and cell signaling.12 However, until now, their role in the development of atherosclerosis has not been assessed.
We have previously shown that one of the human ORP proteins, ORP1L, is expressed in macrophages and, moreover, is upregulated on the differentiation of human monocytes into macrophages,13 observations suggesting that ORP1L may play a role in atherogenesis. In the present study we generated transgenic C57BL/6 mice that overexpress ORP1L in macrophages, driven by scavenger receptor A promoter. Using the bone marrow transplantation technique, we examined the effect of macrophage expression of human ORP1L on the size of aortic root lesions in LDLr–/– animals that were fed a Western-type diet. The results demonstrated a marked increase of lesion size in recipients of ORP1L transgenic bone marrow as compared with recipients of wild-type littermate bone marrow.
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Materials and Methods |
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Antibodies and Other Reagents
The reagents used are specified in the supplemental materials (available online at http://atvb.ahajournals.org).
Generation of the Transgenic Mice
Transgenic C57B/6J mice carrying the human ORP1L cDNA under control of the macrophage-specific SR-A promoter were generated as described (see supplemental materials).
Bone Marrow Transplantation
Bone marrow from ORP1L transgenic mice or gene-negative littermate controls was transplanted into homozygous LDL receptor knockout (LDLr–/–) mice as described (see supplemental materials).
Histological Analysis of the Aortic Root
To analyze the development of atherosclerosis at the aortic root, transplanted LDLr–/– mice were euthanized after 9 weeks on the Western-type diet. The area of aortic root atherosclerotic lesions was analyzed as described (see supplemental materials).
Preparation and acLDL-Loading of Human Primary Macrophages
Human primary macrophages were differentiated from buffy coat mononuclear cells using granulocyte-macrophage colony stimulating factor (GM-CSF), and loaded with acLDL as described (see supplemental materials).
Analysis of Plasma Lipids and Lipoproteins
Plasma lipid and lipoprotein analysis was performed as described (see supplemental materials).
mRNA Quantification
Total RNA was isolated from peritoneal or RAW264.7 cells and selected mRNAs quantified by real-time RT-PCR as described (see supplemental materials). The gene-specific primers used are listed in supplemental Table I.
Determination of Plasma PLTP Activity
PLTP activity was determined as previously described.14
Analysis of Macrophage Cholesterol Efflux
Peritoneal cells from 20-week-old male ORP1L TG mice or age-matched wild-type C57BL/6 animals were loaded for 24 hours with [3H]cholesterol oleate-labeled acLDL or labeled for 24 hours with [3H]cholesterol (see supplemental materials). Efflux of the radioactive cholesterol to human apoA-I or human HDL2 was determined as described in the supplemental materials.
In Vitro Assay for Oxysterol Binding by ORP1L
The oxysterol binding capacity of ORP1L in the cytosol of transfected HEK293 cells was determined as described (see supplemental materials).
Preparation of Recombinant Adenoviruses and Transduction of RAW264.7 Cells
Recombinant adenoviruses expressing GFP (AdGFP) or ORP1L (AdORP1L) were generated and used for transduction of RAW264.7 cells as described (see supplemental materials).
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Results |
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The ORP1L Transgenic Animals
To generate transgenic (TG) mice that selectively express human ORP1L in macrophages, we used an expression construct in which the ORP1L cDNA is under control of the scavenger receptor A (SR-A) promoter. Expression of the transgene in the peritoneal macrophages of the gene-positive animals was verified by RT-PCR with primers specific for the human ORP1L mRNA (data not shown) and by Western blotting with ORP1L antibodies. For the present study we selected transgenic F0 progeny which, assuming that the antibodies used recognize equally the mouse and human proteins, express human ORP1L at levels 15-fold higher than the endogenous mouse ORP1L level (Figure 1A). The expression of the transgenic ORP1L was compared with that in primary human monocyte-macrophages before and after loading with acLDL (Figure 1B). The acLDL loading increased ORP1L protein in the human macrophages by 75% to 80%. The ORP1L level in the TG mouse peritoneal macrophages was similar to that in the acLDL-loaded human cells. The endogenous ORP1L level in mouse peritoneal macrophages appeared markedly lower than that in the in vitro differentiated human macrophages.
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Macrophage ORP1L Enhances Atherosclerotic Lesion Development in LDLr–/– Mice
To assess the role of macrophage ORP1L in atherosclerotic lesion development, we used bone marrow (BM) transplantation to selectively express human ORP1L in hematopoietic cells. BM from transgenic C57BL/6 mice that express human ORP1L in macrophages was transplanted into LDLr–/– mice (ORP1L 
LDLr–/–), which represent an established model for the development of atherosclerosis. LDLr–/– mice transplanted with BM from nontransgenic control littermates were used as controls (WT LDLr–/–). Successful reconstitution of the transplanted bone marrow was verified by PCR with human ORP1L-specific primers using genomic DNA from the bone marrow of WT LDLr–/– or ORP1L LDLr–/– animals (supplemental Figure I). To induce atherosclerotic lesion development, the transplanted mice were allowed to recover for 8 weeks and then fed a Western-type diet for 9 weeks, followed by analysis of atherosclerotic lesion size in the aortic root. Expression of human ORP1L in macrophages induced a 2.1-fold increase in lesion size [271±23x103 µm2 in ORP1L LDLr–/– mice (n=19) versus 130±23x103 µm2 in WT LDLr–/– mice (n=17, P<0.001; Figure 2A)]. The macrophage content of the lesions of ORP1L LDLr–/– mice was 51±4% and the collagen content 2.3±0.5% (Figure 2B and 2C). These values did not differ significantly from those determined for the WT LDLr–/– mice (46±4% and 1.9±0.9%, respectively). No difference was observed in the plasma total or free cholesterol, triglyceride, or choline-containing phospholipid concentrations between the ORP1L LDLr–/– and WT LDLr–/– mice before or after the Western-type diet feeding (supplemental Table II), nor in the plasma lipoprotein profiles of the animals (data not shown).
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ORP1L Downregulates ABCG1 and ApoE and Induces PLTP
To investigate the mechanisms underlying the increase of lesion size in recipients of ORP1L BM, we quantified the mRNAs for 12 genes involved in macrophage lipid metabolism or inflammatory signaling, in peritoneal macrophages of the BM recipients. The mRNAs for ABCG1, ABCG5, and APOE were significantly downregulated in the cells from ORP1L LDLr–/– mice as compared with WT LDLr–/– controls (supplemental Figure II). Moreover, the PLTP and interleukin-1ß (IL-1ß) mRNAs were induced. To verify the downregulation of ABCG1 and apoE at the protein level, the peritoneal cells were analyzed by Western blotting. A 54% decrease in ABCG1 and 68% decrease in apoE in the ORP1L LDLr–/– mice, as compared with controls, was observed (Figure 3A through 3C). Determination of plasma PLTP activity revealed a 30% increase in the ORP1L LDLr–/– animals as compared with controls (22.92±1.65 µmol/mL/h versus 17.61±0.72 µmol/mL/h; P<0.05).
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Macrophage ORP1L Impairs Cholesterol Efflux to Spherical High-Density Lipoproteins (HDL)
The downregulation of ABCG1 and apoE, which participate in cellular cholesterol efflux,15–17 led us to investigate whether ORP1L overexpression affects macrophage cholesterol efflux. Peritoneal macrophages from ORP1L TG and age-matched control C57BL/6 mice were loaded with [3H]cholesterol oleate-labeled acLDL or with free [3H]cholesterol, and the efflux of [3H]cholesterol to apoA-I or HDL2 was measured. Independent of the labeling method, the efflux from ORP1L TG macrophages to HDL2 was significantly reduced (acLDL, by 31%, P<0.01; free cholesterol, by 28%, P<0.01) as compared with controls, whereas no difference was observed in cholesterol efflux to apoA-I (Figure 3D and 3E).
ORP1L Is an Oxysterol Binding Protein
To study the mechanisms underlying the ORP1L effects, we investigated whether the protein is able to bind oxysterols. HEK293 cells were transfected with the human ORP1L cDNA, the rabbit OSBP cDNA (as a reference), or the plain vector. Thereafter, cytosolic extracts of the cells were assayed for [3H]25OHC or [3H]22(R)OHC binding capacity. ORP1L-containing cytosol showed similar 25OHC binding activity as OSBP (Figure 4). The ORP1L signal was competed 65% to 80% by a 40-fold excess of unlabeled 25OHC and was markedly higher than background 25OHC binding in lysate of mock-transfected cells. With [3H]22(R)OHC, an established ligand of LXR, ORP1L displayed a stronger specific signal than with 25OHC, whereas OSBP failed to bind this oxysterol above background levels.
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ORP1L Modulates the Response of ABCA1 and ABCG1 mRNAs to 22(R)OHC
To test the hypothesis that ORP1L could modulate the response of LXR target genes to oxysterols, we treated adenovirally transfected mouse RAW264.7 macrophages for 6 hours with increment concentrations of 22(R)OHC, and quantified the ABCG1 and ABCA1 mRNA levels in the cells (Figure 5). The baseline level of ABCG1 but not ABCA1 mRNA was in AdORP1L-infected cells significantly reduced (by 53%; P<0.01), similar to the macrophages of ORP1L BM recipient mice. Although both mRNAs displayed a dose-dependent induction in cells infected with the control virus (AdGFP), the response of the ABCG1 message to 0.625 µmol/L 22(R)OHC was markedly attenuated in AdORP1L-transduced cells (relative difference to AdGFP-transduced cells 66%, P<0.001; Figure 5A). The difference was not significant at the higher concentrations of the oxysterol. Attenuation of the ABCA1 mRNA response by ORP1L at 0.625 µmol/L 22(R)OHC was detectable but clearly less pronounced (31%, P<0.05) than the effect on ABCG1.
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Discussion |
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The present study demonstrates that overexpression of human ORP1L in macrophages increases the size of atherosclerotic lesions in LDLr–/– mice. Peritoneal macrophages isolated from recipients of the ORP1L transgenic bone marrow displayed reduced expression of ABCG1, ABCG5, and APOE, with impairment of cholesterol efflux to spherical HDL, as well as increased PLTP mRNA and plasma activity. Of these, the changes in ABCG1, apoE, and PLTP may provide explanations for the increase in lesion size. Moreover, the fact that the peritoneal cells of the ORP1L bone marrow recipients showed an increase of IL-1ß mRNA expression indicates that also inflammatory signaling by the transgenic macrophages could be affected.
ABCG1 has a critical role in cholesterol efflux to spherical HDL and thereby prevents lipid accumulation in hepatocytes and macrophages.18–20 Therefore, we find it likely that the observed impairment of macrophage cholesterol efflux to spherical HDL is at least in part attributable to reduced ABCG1 expression. However, bone marrow transplantation studies addressing the effects of macrophage ABCG1 deficiency on atherogenesis have yielded controversial results.21–23 Moreover, crossing of ABCG1 transgenic mice with LDLr–/– animals revealed increased atherosclerosis attributable to ABCG1 overexpression in the liver and macrophages, despite enhanced cholesterol efflux from macrophages.24 Therefore, it is difficult to firmly define the functional consequences of the reduced macrophage ABCG1 expression observed in the present study.
ApoE plays a major antiatherogenic role by facilitating the clearance of chylomicron remnants from circulation via LDL-receptor related protein. It is also associated with subpopulations of HDL, can act as an activator of lecithin-cholesterol acyltransferase (LCAT), and mediates the hepatic uptake of HDL via LDL receptors, functions important for the reverse cholesterol transport process.15 Furthermore, apoE-containing large HDL particles act as acceptors for macrophage cholesterol efflux, especially in cholesterol ester transfer protein (CETP)–deficient animal models and human subjects.16,25 Bone marrow transplantation studies addressing the role of macrophage apoE show that expression of human apoE in macrophages of apoE-deficient mice is atheroprotective,26 whereas transplantation of apoE-deficient macrophage stem cells into wild-type mice promotes atherosclerosis.27 Thus, the reduction of apoE may contribute to the increase of lesion size observed in the ORP1L BM recipients.
The role of PLTP in the development of atherosclerotic lesions is far from clear. Systemic PLTP deficiency was reported to alleviate atherosclerosis via reduction of apolipoprotein B secretion,28 improvement of the anti-inflammatory properties of HDL,29,30 and increased protection of LDL from oxidation.31 However, bone marrow transplantation studies addressing the effect of macrophage PLTP deficiency on lesion development have yielded controversial results,32–34 whereas increased PLTP expression seems invariably proatherogenic.35,36 In the light of these investigations, it is plausible that the observed increase of macrophage PLTP expression and activity in plasma may contribute to the enhancement of lesion development in the ORP1L BM recipients.
We have previously shown that ORP1L interacts directly with the small GTPase Rab7 on late endosomes (LE) and modifies the subcellular distribution and membrane trafficking functions of the LE.37 The protein has been suggested to act as a sensor that relays signals from lipid cues to the late endocytic membrane trafficking machineries.12,37 Importantly, we now show that the protein also binds oxysterols. ORP1L is shown to bind both 25OHC and 22(R)OHC, whereas OSBP included as a reference failed to bind 22(R)OHC above background levels. This suggests that different ORPs may have distinct effects on cellular lipid metabolism attributable to differences in ligand specificity.
The ABCG1, ABCG5, PLTP, and APOE genes are subject to transcriptional regulation by the LXR.7 In addition to the control of cellular cholesterol efflux and the reverse cholesterol transport process, the LXR also display antiinflammatory activity by repressing, presumably via an indirect mechanism, a set of proinflammatory genes that include IL-1ß.38,39 A tempting possibility is that excess ORP1L could interact with cellular oxysterols, resulting in altered expression of LXR targets. This hypothesis is corroborated by the finding that ORP1L modulated in RAW264.7 cells the response of ABCG1 mRNA to the exogenously added LXR agonist 22(R)OHC. Why ORP1L had only a minor effect on ABCA1 remains to be investigated. On the other hand, disturbance of the normal endocytic pathway function by excess ORP1L37 could alter the intracellular trafficking of LDL-derived cholesterol and thus its conversion into oxysterols by sterol hydroxylases located in mitochondria and in the endoplasmic reticulum.40 However, the facts that ORP1L overexpression did not change ABCA1 mRNA abundance and that the PLTP message was elevated in ORP1L BM recipients suggest that the observed effects of ORP1L are complex and not attributable to a uniform stimulatory or inhibitory impact of ORP1L on the LXR. We have previously shown that ORP1L overexpression in nonmacrophage cells also transfected with LXR and RXR plasmids, mildly enhanced an LXRE-dependent reporter in the presence of 22(R)OHC or a nonsterol LXR agonist.13 However, because of differences in the experimental systems used and in the content of individual oxysterol species present in different cell types, it is difficult to directly compare the reporter assay data and the present one.
A change in endocytic pathway function caused by ORP1L and a resulting disturbance of intracellular cholesterol trafficking could directly affect the availability of cholesterol for efflux from the plasma membrane. There is increasing evidence that manipulation of endocytic membrane trafficking, for instance by overexpression of small Rab GTPases, can alter cholesterol efflux from cells.41,42 However, the fact that ORP1L failed to enhance the transfer of cholesterol to apoA-I suggests that the availability of cholesterol for efflux in general was not altered, arguing for a specific effect mediated via distinct target proteins such as ABCG1.
The present study is the first investigation addressing the impact of the OSBP-related protein family on atherogenesis, and demonstrates that these proteins are promising targets for the development of drugs affecting the development of atherosclerotic lesions. Our work also provides clues to the mechanisms by which ORP1L induces an increase of plaque size, and motivates future work to elucidate the role of the entire ORP family in cardiovascular diseases.
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Acknowledgments |
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We are grateful to Sari Nuutinen, Seija Puomilahti, and Pirjo Ranta for skilled technical assistance, to Jari Metso and Mikko Muilu for help with lipid and lipoprotein analysis, and to Shuhei Nakanishi for preparing the primary human macrophages. The labeled acLDL was kindly provided by Riikka Vikstedt.
Sources of Funding
This work was supported by The Netherlands Organization of Scientific Research (grant 917.66.301 to M.v.E.), The Netherlands Heart Foundation (grant 2001T041 to M.v.E.), The Academy of Finland (grants 206298, 113013, 118720 to V.M.O.), The Sigrid Juselius Foundation (to M.J. and V.M.O.), The Finnish Foundation for Cardiovascular Research (to M.J. and V.M.O.), The Magnus Ehrnrooth Foundation (to C.E.), and The Finnish Society of Sciences and Letters (to C.E. and V.M.O.).
Disclosures
None.
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Footnotes |
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Original received January 22, 2007; final version accepted April 16, 2007.
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