Published online before print October 25, 2007, doi: 10.1161/CIRCRESAHA.107.161711
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© 2008 American Heart Association, Inc.
Integrative Physiology |
Coexistence of Foam Cells and Hypocholesterolemia in Mice Lacking the ABC Transporters A1 and G1
From the Division of Biopharmaceutics 9R.O., M.H., Y.Z., J.K., T.J.C.V.B., M.V.E.), Leiden/Amsterdam Center for Drug Research, Leiden University, The Netherlands; the Centre for Vascular Research (W.J., I.C.G., L.K.), School of Medical Sciences, University of New South Wales, Sydney, Australia; INSERM U551 (W.L.g., M.J.C., T.H.), Paris, France; Université Pierre et Marie Curie-Paris6 (W.L.G., M.J.C., T.H.), UMR S551 Paris, France; and Centre d’Immunologie de Marseille Luminy (G.C.), Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique, Université de la Méditerranée, Marseille, France.
Correspondence to Ruud Out, Gorlaeus laboratories, Einsteinweg 55, 2300RA, Leiden, The Netherlands. E-mail r.out{at}lacdr.leidenuniv.nl
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
The concept that macrophages can become foam cells as a result of a disturbed balance between the uptake of cholesterol from lipoproteins and cholesterol efflux is generally accepted. ABCA1 and ABCG1 are two cholesterol transporters that may act sequentially to remove cellular cholesterol, but currently their combined role in vivo is unknown. We report here that targeted disruption of both ABCA1 and ABCG1 in mice, despite severe plasma hypocholesterolemia, leads to massive lipid accumulation and foam cell formation of tissue macrophages. A complete ablation of cellular cholesterol efflux in vitro is observed, whereas in vivo macrophage-specific reverse cholesterol transport to the feces is markedly decreased. Despite the massive foam cell formation of tissue macrophages, no lipid accumulation was observed in the vascular wall, even in mice of 1 year old, indicating that the double knockout mice, possibly because of their hypocholesterolemia, lack the trigger to attract macrophages to the vessel wall. In conclusion, even under hypocholesterolemic conditions macrophages can be converted into foam cells, and ABCA1 and ABCG1 play an essential role in the prevention of foam cell formation.
Key Words: ABC transporter • reverse cholesterol transport • cholesterol efflux • macrophage • foam cell
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Macrophages are implicated in the pathological deposition of cholesterol during atherogenesis as a result of the uptake of native (eg, VLDL) or modified (eg, oxidized LDL) lipoproteins1–3. Because macrophages are incapable of limiting the uptake of lipoproteins, these cells rely on cholesterol efflux mechanisms for maintaining cellular cholesterol homeostasis.4,5 In 1999, 3 groups reported that the molecular defect in Tangier Disease, an autosomal recessive disorder that is characterized by severe HDL deficiency and deposition of cholesteryl esters in cells of the reticuloendothelial system, was caused by mutations in the ABCA1 gene.6–8 Mice in which the ABCA1 gene was deleted were equally characterized by low circulating levels of serum high-density lipoproteins (HDL).9–11 HDL is responsible for the transport of cholesterol from peripheral cells (including macrophages) to the liver, bile, and feces in the pathway of reverse cholesterol transport.12 Although macrophages from ABCA1 knockout mice display attenuated cholesterol efflux in vitro,9 these mice do not exhibit excessive lipid accumulation and accelerated atherosclerotic lesion development when fed a regular chow diet.10 More recently, a second ABC-transporter, ABCG1, was identified as a key transporter in macrophages for cholesterol efflux to HDL.13–15 Furthermore, targeted disruption of ABCG1 in mice was without effect on serum cholesterol levels and no striking phenotype was noted on a regular chow diet, whereas a high-fat diet was required to induce tissue lipid accumulation.15
Recent in vitro evidence suggests that ABCA1 and ABCG1 may act sequentially to facilitate efflux of cellular cholesterol.16,17 However, as deficiency of either the ABCA1 or ABCG1 gene alone results in expression of a relatively mild phenotype, we generated ABCA1/ABCG1 double knockout (dKO) mice to analyze the potential synergistic role of these transporters in mediating cellular cholesterol homeostasis.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Animals
ABCA1-deficient10 and ABCG1-deficient (Deltagen Inc, San Carlos, California) mice (both backcrossed more than 7 times on a C57BL/6J background) were mated to generate F1 heterozygotes. Heterozygote F1 animals were crossbred to obtain the ABCA1–/–/ABCG1+/+ (ABCA1 KO), ABCA1+/+/ABCG1–/– (ABCG1 KO), ABCA1–/–/ABCG1–/– (dKO), and ABCA1+/+/ABCG1+/+ (WT) mice. Mice were given unlimited access to food and water. Mice were maintained on sterilized regular chow, containing 4.3% (w/w) fat with no added cholesterol (RM3; Special Diet Services). Animal experiments were performed at the Gorlaeus Laboratories of the Leiden/Amsterdam Center for Drug Research and Central Animal Facility of the Medical Faculty of La Pitié Hospital, Paris in accordance with the National Laws. All experimental protocols were approved by the Ethics Committee for Animal Experiments of Leiden University and the Direction Départementale des Services Vétérinaires, Paris, France, under strict compliance with European Community Regulations.
PCR and Western Blot Analysis
PCR analysis of genomic DNA was performed as described before.18,19 Immunoblotting for ABCA1 and ABCG1 protein was performed by running 2 µg of protein (bone marrow–derived macrophages, see below) on a 7% (Tris Acetate, NuPage) and 10% (Bis-Tris, NuPage) gel, respectively. ABCA1 was detected using a rabbit–anti-mouse ABCA1 polyclonal antibody (Novus) as a primary antibody. ABCG1 was detected using a rabbit–anti-mouse ABCG1 polyclonal antibody (Novus) as a primary antibody. As a secondary antibody a goat–anti-rabbit IgG-HRP (Jackson) was used.
Lipid Analyses
Blood was collected by retro-orbital puncture under anesthesia. The concentrations of total cholesterol in plasma were determined as described before.20 Plasma HDL cholesterol levels were determined by fractionation of 50 µL of plasma from each mouse using a Superose 6 column (3.2x300 mm, Smart-System; Pharmacia).
Peritoneal Leukocyte Analysis
On sacrifice the peritoneal cavity of the mice was lavaged with 10 mL cold PBS to collect peritoneal leukocytes for quantification of macrophage foam cells using an automated Sysmex XT-2000iV Veterinary Heamatology analyzer (Sysmex Corporation). Corresponding samples were cytospun for manual confirmation and stained with Oil red O for detection of lipid accumulation, and counterstained with hematoxylin.
Histological and Tissue Lipid Analysis
Histological analyses were performed as described before20 on seven micrometer cryosections of lung, liver, thymus, and Peyer patches. In addition, a fragment of intestine containing a Peyer Patch was cut longitudinally on the opposite side of the Peyer Patch and stained with Oil red O. Hepatic lipids were extracted as described earlier.21 Atherosclerotic lesion development was quantified in the aortic root of dKO mice of 1 year old as described previously.20
Cellular Cholesterol Efflux Assays
For each mouse, bone marrow cells were isolated from both the femurs and tibias by lavage with phosphate-buffered saline (PBS). Cells were plated and differentiated in Dulbecco’s modified Eagle’s medium (DMEM) supplemented with 10% fetal bovine serum, 2 mmol/L glutamine, 20% L929 cell-conditioned media (as a source of M-CSF), and penicillin-streptomycin for 5 days. Bone marrow–derived macrophages (BMDM) were then cholesterol-loaded for 48 hours with acetylated LDL (50 µg/mL) in DMEM containing BSA (0.1%; wt/vol). The loading medium was removed and the cells washed twice in PBS, then incubated overnight (16 hours) with DMEM containing BSA (0.1%; wt/vol), supplemented with 22-hydroxycholesterol (10 µmol/L) and 9-cis retinoic acid (1 µmol/L). To measure cholesterol efflux, cells were incubated in DMEM/0.1% BSA alone or with lipid-free apoAI (10 µg protein/mL) or HDL2 (10 µg protein/mL) for 24 hours. At 24 hours the media were removed and the cells lysed in 0.1N NaOH. Cell and media samples were also extracted and analyzed for free and esterified cholesterol mass by HLPC, as previously described.22 Cell proteins were measured using the BCA assay (Pierce). For mass analysis, HDL samples were separately analyzed to allow correction for HDL cholesterol present in relevant media samples. Cholesterol efflux is expressed as the percentage of total cell cholesterol present in the medium. Basal efflux to media (in the absence of added acceptors) has been subtracted from the data shown.
In Vivo Macrophage-Specific Reverse Cholesterol Transport Assay
BMDM were prepared as described above and loaded with 50 µg/mL [3H]-cholesterol-labeled acetylated LDL (5 µCi/mL) in fresh differentiation media containing 4 µg/mL 22-hydroxy-cholesterol and 1 µmol/L 9-cis retinoic acid for 48 hours. [3H]-cholesterol labeled-BMDM were washed twice in PBS and harvested by treatment with accutase (PAA) for 15 minutes at 37°C. Cells were spun down at 4°C and resuspended in cold PBS. Radioactivity incorporated in BMDM was determined by double extraction in hexane-isopropanol (3:2), evaporation of the solvent and liquid scintillation counting (Beckman). Male C57BL/6J mice were fed a standard chow diet and housed in separate cages. Mice were injected intraperitoneally with 5x106 [3H]-cholesterol-labeled BMDM in 0.5 mL PBS. Blood was collected at 24 hours after injection by retro-orbital puncture under isoflurane anesthesia and radioactivity in plasma was measured by liquid scintillation counting (Beckman). Mice were euthanized by cervical dislocation, perfused transcardially with PBS and livers were removed and weighed. Radioactivity in homogenized liver samples was counted directly in a scintillation vial (Beckman). Feces were collected, dried at 50°C, weighed and rehydrated at a similar concentration overnight. Fecal samples were then homogenized and radioactivity determined by liquid scintillation counting (Beckman). The amount of [3H]-tracer in plasma, liver, and feces was expressed as a percent of the injected dose.
Statistical Analysis
Statistical analysis between the 4 groups was performed using ANOVA and the Student-Newman-Keuls post-test (GraphPad InStat and Prism software). Statistical analysis on reproduction was performed using the X2-test (GraphPad InStat and Prism software).
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
To analyze the potential synergistic role of the transporters ABCA1 and ABCG1 in mediating cellular cholesterol homeostasis we generated ABCA1/ABCG1 double knockout (dKO) mice. In Figure 1 the verification of the absence of ABCA1 and ABCG1 in the dKO mice is shown at both the DNA and protein level by performing PCR and Western blot analysis, respectively.
|
Similar to ABCA1 KO mice,9–11 nonproductive mating is prevalent in dKO mice. Only 1.75% of the offspring from crosses of ABCA1xABCG1 double heterozygous mice were ABCA1 KO and 1.75% dKO mice, compared with the expected Mendelian rate of 6.25% (
2-test, P<0.05). For WT and ABCG1 KO mice the expected Mendelian rate of 6.25% was observed. Homozygous dKO females and males are fertile. However, as described before for single ABCA1 KO mice9–11 extensive neonatal death has been observed with pups born from dKO mothers within the first 24 to 48 hours after birth. dKO mice born from ABCA1xABCG1 double heterozygous breedings did not appear to have a reduced life expectancy because we have observed that the dKO mice can reach the age of >1 year. No significant differences in body weight between WT, ABCA1 KO, ABCG1 KO, and dKO mice were observed at the age of 6 months (22.1±1.6 g, 23.3±0.3 g, 22.6±0.8, 20.2±0.9, respectively; n
4). In contrast to ABCG1 knockout (KO) mice whose plasma cholesterol and HDL cholesterol concentrations are similar to those of wild-type (WT) mice,15 ABCA1 KO9,10 and dKO mice are severely hypocholesterolemic (Figure 2A). Indeed, when fed a regular chow diet, plasma total cholesterol and HDL-cholesterol concentrations were decreased >80% in dKO mice (Figure 2A). Despite low serum cholesterol levels, ABCA1/ABCG1 dKO mice showed profound changes in tissues rich in macrophages, including the liver, spleen, lung, thymus, lymph nodes, and the Peyer patches. Furthermore, severe hepatosplenomegaly and enlargement of lymph nodes and Peyer patches was observed in dKO mice, whereas no such phenotype was evident in the ABCA1 and ABCG1 single knockout or wild-type animals. The liver (Figure 2C) and spleen (Figure 2D) of the dKO mice contained many pale white foci, whereas the Peyer patches presented as "white marbles" on top of the intestine (Figure 2E and 2F), such morphology is consistent with lipid accumulation. Consequently, cryostat sections of liver, spleen, and Peyer patches showed massive neutral lipid accumulation, as indicated by Oil red O staining (Figure 3). Excessive neutral lipid accumulation was not limited to the liver, spleen, and Peyer Patches however, as Oil red O staining was also consistently greater in thymus (Figure 3) and lymph nodes (not shown) of dKO mice as compared with wild-type and single knockout animals. Within the different tissues of the dKO mice fed a chow diet, Oil red O staining was mainly observed in macrophage-rich areas like the red pulp of the spleen and thymus, as evidenced by colocalization of Oil red O with MOMA-2 macrophage staining (data not shown). Consistent with this finding, Oil red O staining was absent from kidney, a tissue poor in macrophages (data not shown). Furthermore, virtually no Oil red O staining was observed in the liver, spleen, Peyer patches, and thymus of WT, ABCA1 KO, and ABCG1 KO mice on a chow diet. The only organ showing lipid accumulation in single ABCA1 KO and single ABCG1 KO mice were the lungs, in agreement with earlier findings.10,15 However, in the ABCA1/ABCG1 dKO mice, the lipid accumulation was scattered more widely throughout the lung. The foci of neutral lipid accumulation in the liver of dKO mice were concluded to comprise free cholesterol and esterified cholesterol, and not triglycerides or phospholipids, on the basis of selective accumulation of free cholesterol and esterified cholesterol in liver extracts (Figure 2B).
|
|
We subsequently examined the effect of combined deletion of ABCA1 and ABCG1 on foam cell formation within the peritoneal cavity by isolating resident peritoneal leukocytes. The collected cells were analyzed using an automated hematology analyzer with 5-differential leukocyte population counting. The resulting scattergrams are shown in Figure 4A. Interestingly, the isolated peritoneal leukocytes from the dKO animals reveal a group of cells that is shifted to the upper-right of the plot when compared with WT, ABCA1 KO, and ABCG1 KO animals, thereby indicating that this group of cells was larger and contained more abundant granules. To determine whether the increased granularity resulted from enhanced foam cell formation, collected cells were cytospun and stained for lipids with Oil red O (See Figure 4B and 4C for representative photomicrographs). In agreement with the observed shift of the macrophage population in dKO animals, lipid-laden peritoneal cells were more numerous as compared with the corresponding populations in WT, ABCA1 KO, and ABCG1 KO mice (Figure 4D).
|
ABCA1 is involved in the efflux of cholesterol from peripheral tissue macrophages to lipid-free apolipoproteins, and in particular to apoAI,6,7,23 whereas ABCG1 facilitates cellular cholesterol efflux from macrophages to lipidated particles such as mature HDL, but not to lipid-free apolipoproteins.13–15 To directly test the consequence of combined ABCA1 and ABCG1 deficiency on cholesterol efflux, mass efflux experiments were performed. Bone marrow–derived macrophages from WT, ABCA1 KO, ABCG1 KO, and dKO mice were cholesterol-loaded with acetylated LDL, and cholesterol mass efflux to HDL or apoAI was determined. Consistent with a role for ABCA1 in mediating the efflux of cholesterol to lipid-poor apolipoproteins,6,7,23 and for ABCG1 in mediating the efflux of cholesterol to HDL,13–15 mass efflux of cholesterol from macrophages of ABCA1 KO mice to apoAI was almost completely inhibited, whereas mass efflux of cholesterol from macrophages of ABCG1 KO mice to HDL was significantly reduced (–32%; Figure 5A and 5B). Whereas single ABCG1 deficiency did not affect mass cholesterol efflux to apoAI, ABCA1 deficiency led to reduced cholesterol mass efflux to HDL. Most importantly, cholesterol mass efflux to both apoAI and HDL was virtually absent in macrophages isolated from the dKO mice.
|
The relative importance of ABCA1 and ABCG1 in promoting in vivo lipid efflux from macrophages, and thus their effect on attenuating foam cell formation, was further tested by using a macrophage-specific reverse cholesterol transport (RCT) assay.24 By transfer of [3H] cholesterol–labeled bone marrow–derived macrophages to the peritoneal cavity of control C57Bl/6J mice with normal serum lipoprotein levels, the release of [3H]-cholesterol from macrophages obtained from WT, ABCA1 KO, ABCG1 KO, and dKO mice to the plasma and their transport to the liver and ultimately the feces can be quantified. At 24 hours after injection of the [3H]-cholesterol loaded macrophages into the peritoneal cavity, plasma radioactivity derived from the dKO macrophages was significantly lower, while the amount of [3H]-tracer found in the liver, and especially the amount of tracer excreted into the feces, was significantly less as compared with animals that received macrophages from WT, ABCA1 KO, and ABCG1 KO mice (Figure 5C, 5D, and 5E).
Finally, we analyzed the effect of double ABCA1 and ABCG1 deficiency on lipid deposition in the arterial wall. Interestingly, despite massive lipid accumulation in macrophages of different organs, dKO mice did not show any atherosclerotic lesion development (Figure 6). Thus, macrophage lipid-loading is only seen in macrophage-containing organs of double knockouts, while the dKO mice lack the high plasma cholesterol levels needed to trigger arterial wall accumulation of macrophages.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
In the current study we show that on a regular chow diet the combined deletion of ABCA1 and ABCG1 in mice does lead to massive lipid accumulation in peritoneal macrophages as well as macrophage-rich tissues like the liver and spleen, leading to severe hepatosplenomegaly. Furthermore, lymph nodes and Peyer patches were increased in size and display massive lipid-loading in macrophage-rich areas. No such phenotype was evident in the ABCA1 and ABCG1 single knockout or wild-type animals. Single ABCG1 KO mice only showed Oil red O staining in multiple tissues15 and elevated hepatic concentrations of cholesterol, triglycerides, and phospholipids on challenge with a high-fat/high-cholesterol diet for 9 weeks leading to serum cholesterol values of 140 to 170 mg/dL.15 This phenotype is however less severe as compared with that of ABCG1/ABCA1 dKO mice on a chow diet, whose serum cholesterol levels are only
10 mg/dL. The massive formation of tissue macrophage foam cells, despite severe hypocholesterolemia, clearly illustrates the essential combined role of these transporters in maintaining macrophage cellular cholesterol homeostasis. Interestingly, it also suggests that other efflux mechanisms cannot compensate for the absence of these 2 transporters. Three genes are suggested to play a role in cholesterol efflux from macrophages: ABCA1, ABCG1, and SR-BI.5,25 ABCA1 stimulates cholesterol and phospholipid efflux from macrophages to lipid-poor apoAI, but not to mature HDL.26 ABCG1 has been implicated in the efflux of cholesterol to mature HDL.13–15 SR-BI requires a phospholipid-containing acceptor, like mature HDL to induce a concentration gradient dependent efflux of free cholesterol.27,28 In vitro studies showed that the transfer of lipids to apoAI mediated by ABCA1 activity is sufficient to generate an efficient acceptor for ABCG1-mediated cholesterol efflux, which implies that ABCA1 cooperatively works with ABCG1 in cholesterol transport.16,17 The observed dramatic enhancement of macrophage foam cell formation as a result of combined deletion of ABCA1 and ABCG1 as compared with single deletion of ABCA1 and ABCG1 in this study would indeed favor this proposed model, while SR-BI could not prevent the accumulation of lipids. However, SR-BI might efflux from a specific compartment or functionally distinct cellular pools of cholesterol other than ABCG1.29
During the preparation of our manuscript, an article of Wang et al30 appeared, describing the role of ABCA1, ABCG1, and SR-BI in in vitro efflux and in macrophage-specific in vivo reverse cholesterol transport. Whereas macrophage SR-BI was shown not to be involved in promoting macrophage reverse cholesterol transport, combined partial deficiency of ABCA1 and ABCG1 in J774 cells transferred to LXR-stimulated C57BL/6J mice led to a 25% decrease in reverse cholesterol transport from macrophages to the feces.30 We used WT, ABCA1, ABCG1, and dKO mice bone marrow–derived macrophages with the same genetic background as the recipient mice and observed that the combined complete deficiency of ABCA1 and ABCG1 led to a striking 71% decrease in fecal excretion of [3H]-tracer. Also the plasma and liver [3H]-tracer in mice injected with dKO macrophages were significantly decreased compared with mice injected with WT, ABCA1, or ABCG1 KO macrophages, indicating that the reverse cholesterol transport pathway in the complete absence of ABCA1 and ABCG1 was highly impaired.
In this study, we furthermore choose to determine the effect of combined deletion of ABCA1 and ABCG1 on the net efflux of cholesterol by performing mass efflux experiments. It is known from previous studies that absence of ABCA1 results in a decreased efflux of cholesterol from macrophages toward apoAI.26 Accordingly, compared with WT and ABCG1 KO macrophages, we found a 72% decrease in net cholesterol efflux from ABCA1 KO macrophages, whereas in dKO cells the efflux was decreased even slightly more (84%). In agreement with the suggested role for ABCG1 in the efflux of cholesterol to mature HDL13–15 we also found a significant decrease in the net cholesterol efflux from ABCG1 KO macrophages to HDL. In the absence of both ABCA1 and ABCG1 expression, we did observe a complete abolishment of mass cholesterol efflux from dKO macrophages, indicating the essential role of the combined presence of ABCA1 and ABCG1 for cholesterol release from macrophages to HDL. Thus we conclude that the highly impaired efflux capacity of macrophages from dKO mice is likely to be responsible for the massive accumulation of lipids in tissue macrophages observed in dKO mice. Despite the massive foam cell formation of tissue macrophages lacking ABCA1 and ABCG1, no lipid accumulation was observed in the vascular wall. Thus, probably because of the absence of high plasma cholesterol levels no stimulus is available to attract macrophages to the arterial wall thereby preventing atherosclerotic lesion development.
Administration of the LXR agonist GW3965, which induces both ABCA1 and ABCG1 expression, has been shown to increase the rate of RCT from macrophages to feces in vivo.24 The present studies reveal that the combined action of ABCA1 and ABCG1, both key LXR target genes, is critical to maintaining lipid homeostasis in the macrophage. Despite the fact that no atherosclerotic lesion development was observed in dKO mice, targeted upregulation of ABCA1 and ABCG1 expression, for instance by nuclear receptor agonists, may constitute an effective pharmacological approach to the prevention of vascular lipid accumulation.
|
Acknowledgments |
|---|
Sources of Funding
This work was supported by grants from The Netherlands Heart Foundation (Grants 2003B134 [to R.O.], 2001T041 [to M.V.E. and Y.Z.], and 2001B043 [to J.K.]), The Netherlands Organization for Scientific Research (VIDI Grant 917.66.301 [to M.V.E.]), The National Health and Medical Research Council of Australia (to W.J., L.K and I.C.G), and The Heart Foundation of Australia (to W.J., L.K., and I.C.G). W.L.G., T.H., and M.J.C. were supported by INSERM. W.L.G. was the recipient of a PNRC award from INSERM. The authors belong to the European Vascular Genomics Network (http://www.evgn.org), a Network of Excellence supported by the European Community’s Sixth Framework Program for research Priority I (Life Sciences, Genomics, and Biotechnology for Health; contract LSHM-CT-2003-503254).
Disclosures
None.
|
Footnotes |
|---|
*The first three authors contributed equally to this study.
Original received August 10, 2007; revision received October 2, 2007; accepted October 17, 2007.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
- Brown MS, Goldstein JL. Lipoprotein metabolism in the macrophage: implications for cholesterol deposition in atherosclerosis. Annu Rev Biochem. 1983; 52: 223–261.[CrossRef][Medline] [Order article via Infotrieve]
- Krieger M, Herz J. Structures and functions of multiligand lipoprotein receptors: macrophage scavenger receptors and LDL receptor-related protein (LRP). Annu Rev Biochem. 1994; 63: 601–637.[Medline] [Order article via Infotrieve]
- Steinberg D, Parthasarathy S, Carew TE, Khoo JC, Witztum JL. Beyond cholesterol. Modifications of low-density lipoprotein that increase its atherogenicity. N Engl J Med. 1989; 320: 915–924.[Medline] [Order article via Infotrieve]
- Jessup W, Gelissen IC, Gaus K, Kritharides L. Roles of ATP binding cassette transporters A1 and G1, scavenger receptor BI and membrane lipid domains in cholesterol export from macrophages. Curr Opin Lipidol. 2006; 17: 247–257.[Medline] [Order article via Infotrieve]
- Pennings M, Meurs I, Ye D, Out R, Hoekstra M, Van Berkel TJ, Van Eck M. Regulation of cholesterol homeostasis in macrophages and consequences for atherosclerotic lesion development. FEBS Lett. 2006; 580: 5588–5596.[CrossRef][Medline] [Order article via Infotrieve]
- 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]
- 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]
- 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]
- Orso E, Broccardo C, Kaminski WE, Bottcher A, Liebisch G, Drobnik W, Gotz A, Chambenoit O, Diederich W, Langmann T, Spruss T, Luciani MF, Rothe G, Lackner KJ, Chimini G, Schmitz G. Transport of lipids from golgi to plasma membrane is defective in tangier disease patients and Abc1-deficient mice. Nat Genet. 2000; 24: 192–196.[CrossRef][Medline] [Order article via Infotrieve]
- McNeish J, Aiello RJ, Guyot D, Turi T, Gabel C, Aldinger C, Hoppe KL, Roach ML, Royer LJ, de Wet J, Broccardo C, Chimini G, Francone OL. High density lipoprotein deficiency and foam cell accumulation in mice with targeted disruption of ATP-binding cassette transporter-1. Proc Natl Acad Sci U S A. 2000; 97: 4245–4250.
[Abstract/Free Full Text] - Christiansen-Weber TA, Voland JR, Wu Y, Ngo K, Roland BL, Nguyen S, Peterson PA, Fung-Leung WP. Functional loss of ABCA1 in mice causes severe placental malformation, aberrant lipid distribution, and kidney glomerulonephritis as well as high-density lipoprotein cholesterol deficiency. Am J Pathol. 2000; 157: 1017–1029.
[Abstract/Free Full Text] - Glomset JA. The plasma lecithins:cholesterol acyltransferase reaction. J Lipid Res. 1968; 9: 155–167.[Abstract]
- 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.
[Abstract/Free Full Text] - 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.
[Abstract/Free Full Text] - Kennedy MA, Barrera GC, Nakamura K, Baldan A, Tarr P, Fishbein MC, Frank J, Francone OL, Edwards PA. ABCG1 has a critical role in mediating cholesterol efflux to HDL and preventing cellular lipid accumulation. Cell Metab. 2005; 1: 121–131.[CrossRef][Medline] [Order article via Infotrieve]
- Gelissen IC, Harris M, Rye KA, Quinn C, Brown AJ, Kockx M, Cartland S, Packianathan M, Kritharides L, Jessup W. ABCA1 and ABCG1 synergize to mediate cholesterol export to apoA-I. Arterioscler Thromb Vasc Biol. 2006; 26: 534–540.
[Abstract/Free Full Text] - Vaughan AM, Oram JF. ABCA1 and ABCG1 or ABCG4 act sequentially to remove cellular cholesterol and generate cholesterol-rich HDL. J Lipid Res. 2006; 47: 2433–2443.
[Abstract/Free Full Text] - Out R, Hoekstra M, Hildebrand RB, Kruit JK, Meurs I, Li Z, Kuipers F, Van Berkel TJ, Van Eck M. Macrophage ABCG1 deletion disrupts lipid homeostasis in alveolar macrophages and moderately influences atherosclerotic lesion development in LDL receptor-deficient mice. Arterioscler Thromb Vasc Biol. 2006; 26: 2295–2300.[CrossRef][Medline] [Order article via Infotrieve]
- van Eck M, Bos IS, Kaminski WE, Orso E, Rothe G, Twisk J, Bottcher A, Van Amersfoort ES, Christiansen-Weber TA, Fung-Leung WP, Van Berkel TJ, Schmitz G. Leukocyte ABCA1 controls susceptibility to atherosclerosis and macrophage recruitment into tissues. Proc Natl Acad Sci U S A. 2002; 99: 6298–6303.
[Abstract/Free Full Text] - Out R, Hoekstra M, Meurs I, de Vos P, Kuiper J, Van Eck M, Van Berkel TJ. Total body ABCG1 expression protects against early atherosclerotic lesion development in mice. Arterioscler Thromb Vasc Biol. 2007; 27: 594–599.
[Abstract/Free Full Text] - Out R, Hoekstra M, de Jager SC, de Vos P, van der Westhuyzen DR, Webb NR, Van Eck M, Biessen EA, Van Berkel TJ. Adenovirus-mediated hepatic overexpression of scavenger receptor class B type I accelerates chylomicron metabolism in C57BL/6J mice. J Lipid Res. 2005; 46: 1172–1181.
[Abstract/Free Full Text] - Gelissen IC, Brown AJ, Mander EL, Kritharides L, Dean RT, Jessup W. Sterol efflux is impaired from macrophage foam cells selectively enriched with 7-ketocholesterol. J Biol Chem. 1996; 271: 17852–17860.
[Abstract/Free Full Text] - Lawn RM, Wade DP, Garvin MR, Wang X, Schwartz K, Porter JG, Seilhamer JJ, Vaughan AM, Oram JF. The Tangier disease gene product ABC1 controls the cellular apolipoprotein-mediated lipid removal pathway. J Clin Invest. 1999; 104: R25–31.[Medline] [Order article via Infotrieve]
- Naik SU, Wang X, Da Silva JS, Jaye M, Macphee CH, Reilly MP, Billheimer JT, Rothblat GH, Rader DJ. Pharmacological activation of liver X receptors promotes reverse cholesterol transport in vivo. Circulation. 2006; 113: 90–97.
[Abstract/Free Full Text] - Cavelier C, Lorenzi I, Rohrer L, von Eckardstein A. Lipid efflux by the ATP-binding cassette transporters ABCA1 and ABCG1. Biochim Biophys Acta. 2006; 1761: 655–666.[Medline] [Order article via Infotrieve]
- Remaley AT, Stonik JA, Demosky SJ, Neufeld EB, Bocharov AV, Vishnyakova TG, Eggerman TL, Patterson AP, Duverger NJ, Santamarina-Fojo S, Brewer HB Jr Apolipoprotein specificity for lipid efflux by the human ABCAI transporter. Biochem Biophys Res Commun. 2001; 280: 818–823.[CrossRef][Medline] [Order article via Infotrieve]
- Ji Y, Jian B, Wang N, Sun Y, Moya ML, Phillips MC, Rothblat GH, Swaney JB, Tall AR. Scavenger receptor BI promotes high density lipoprotein-mediated cellular cholesterol efflux. J Biol Chem. 1997; 272: 20982–20985.
[Abstract/Free Full Text] - Yancey PG, de la Llera-Moya M, Swarnakar S, Monzo P, Klein SM, Connelly MA, Johnson WJ, Williams DL, Rothblat GH. High density lipoprotein phospholipid composition is a major determinant of the bi-directional flux and net movement of cellular free cholesterol mediated by scavenger receptor BI. J Biol Chem. 2000; 275: 36596–36604.
[Abstract/Free Full Text] - Wang MD, Kiss RS, Franklin V, McBride HM, Whitman SC, Marcel YL. Different cellular traffic of LDL-cholesterol and acetylated LDL-cholesterol leads to distinct reverse cholesterol transport pathways. J Lipid Res. 2007; 48: 633–645.
[Abstract/Free Full Text] - Wang X, Collins HL, Ranalletta M, Fuki IV, Billheimer JT, Rothblat GH, Tall AR, Rader DJ. Macrophage ABCA1 and ABCG1, but not SR-BI, promote macrophage reverse cholesterol transport in vivo. J Clin Invest. 2007; 117: 2216–2224.[CrossRef][Medline] [Order article via Infotrieve]
This article has been cited by other articles:
 |
|
 |
|
  R. Frikke-Schmidt, B. G. Nordestgaard, M. C. A. Stene, A. A. Sethi, A. T. Remaley, P. Schnohr, P. Grande, and A. Tybjaerg-Hansen Association of Loss-of-Function Mutations in the ABCA1 Gene With High-Density Lipoprotein Cholesterol Levels and Risk of Ischemic Heart Disease JAMA, June 4, 2008; 299(21): 2524 - 2532. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||