Published online before print March 7, 2002, doi: 10.1161/01.ATV.0000014804.35824.DA
© 2002 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Increased Atherosclerosis in Hyperlipidemic Mice With Inactivation of ABCA1 in Macrophages
From Pfizer Global Research and Development, Groton, Conn
Correspondence to Robert J. Aiello or Omar L. Francone, Pfizer Global Research and Development, Department of Cardiovascular and Metabolic Diseases, Eastern Point Rd, Groton, CT 06340. E-mail Robert_J_Aiello{at}groton.pfizer.com or Omar_L_Francone@groton.pfizer.com
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
The ATP-binding cassette transporter A1 (ABCA1) encodes a membrane protein that promotes cholesterol and phospholipid efflux from cells. Mutations in ABCA1 lead to HDL deficiency and tissue accumulation of macrophages in patients with homozygous Tangier disease. In this study, we examined whether the complete absence of ABCA1 or selected inactivation in macrophages is accompanied by an increase in atherosclerotic lesion progression in hypercholesterolemic apolipoprotein E–deficient (apoE-/-) mice and LDLR receptor–deficient (LDLr-/-) mice. The absence of ABCA1 led to reduced plasma cholesterol levels in both the apoE-/- and LDLr-/- mice, along with severe skin xanthomatosis characterized by marked foamy macrophages and cholesterol ester accumulation. However, the complete absence of ABCA1 did not affect the development, progression, or composition of atherosclerotic lesions in either the LDLr-/- or the apoE-/- mice fed a chow or atherogenic diet. In contrast, bone marrow transplantation studies demonstrated that the selective inactivation of ABCA1 in macrophages markedly increased atherosclerosis and foam cell accumulation in apoE-/-. Taken together, these findings demonstrate that the complete absence of ABCA1 has a major impact on plasma lipoprotein homeostasis, and the proposed antiatherogenic effect resulting from ABCA1 deficiency is compensated by a less atherogenic profile. ABCA1 deficiency in macrophages, however, demonstrates the antiatherogenic properties of ABCA1 independent of plasma lipids and HDL levels.
Key Words: ABCA1 • atherosclerosis • xanthomatosis • HDL
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The ATP-binding cassette (ABC) transporter superfamily contains membrane proteins that use ATP as a source of energy to translocate a variety of substrates across extra- and intra-cellular membranes.1 ABCs are defined by the presence of nucleotide-binding domains containing two conserved peptide motifs known as walker A and walker B, with a unique signature between the two walker motifs. Genetic variation in these genes is the cause of, or contributor to, a wide variety of human disorders with Mendelian and complex inheritance, including cystic fibrosis, neurological disease, retinal degeneration, cholesterol, and bile transport defects, anemia, and drug response.2
ABCA1, a member of the ABCA subfamily, has near-ubiquitous expression in different mammalian tissues and cell types.3,4 This transporter is particularly abundant in macrophages, where its expression is tightly controlled by intracellular cholesterol levels.3 In addition, its activity is increased by protein kinases and is modulated at the transcriptional level by several metabolites including cAMP,4,5 cis-retinoic acid,6 peroxisomal proliferator-activated receptor, 7,8 interferon 
, 9 and oxysterol ligands for LXR.10,11
Several functions have been attributed to ABCA1 since its discovery. It has been implicated in the engulfment of apoptotic cells and12 secretion of leaderless proteins such as interleukin-1ß13 and as an electroneutral anion exchanger.14 More recently, ABCA1 has been shown to be mutated in patients with Tangier disease.15–17 In vivo models with either natural mutations18 or targeted inactivation of ABCA119 have confirmed these findings and demonstrated the pivotal role of ABCA1 in the trafficking of lipids, biogenesis of HDL, and overall cholesterol homeostasis as demonstrated by the deposition of cholesterol in tissue macrophages.
Since the discovery of the inverse relationship between HDL levels and coronary artery disease, modification of HDL metabolism and ABCA1 expression in particular have been considered potential targets for therapeutic interventions to prevent atherosclerosis. Tangier disease patients have an increased risk of coronary artery disease20,21 but not as dramatic as one would expect in individuals with an almost complete absence of HDL. It is possible that Tangier patients are partially protected from the development of atherosclerosis because of low levels of circulating LDL.22
The aim of this study was to examine the pathophysiological consequences of ABCA1 deletion in two mouse models of atherosclerosis in the setting of severe hypercholesterolemia. The ABCA1-deficient mice on a DBA1/J background were crossbred to apolipoprotein E–deficient (apoE-/-) mice and LDLR receptor–deficient (LDLr-/-) mice. The findings from these studies revealed that the complete absence of ABCA1 led to plasma lipid reductions and severe foam cell accumulation in the skin and uterus without affecting the development of atherosclerosis. In contrast, specific inactivation of ABCA1 in monocytes markedly increased the development of atherosclerosis in apoE-/- mice without altering plasma cholesterol homeostasis.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Animals and Diets
ApoE-/- mice, backcrossed to C57BL6 for 10 generations, and ABCA1-/- mice in a DBA1/J inbred background, were mated, and the double heterozygous offspring were intercrossed. The resulting apoE+/-/ABCA1+/- offspring were mated to produce apoE-/- and apoE-/-/ABCA1-/- mice. LDLr-/- mice backcrossed to C57BL6 for 9 generations were mated to ABCA1-/- mice, and double heterozygous were mated to produce LDLr-/- and LDLr-/-/ABCA1-/- mice. Genotypes were determined by using polymerase chain reaction analysis. Mice were maintained on a 12-hour light/dark cycle and fed a rodent chow diet (Purine Prolab RMH 3000 rodent diet) or Western-type diet (HFHC) containing 0.15% cholesterol and 20% saturated fat (Harlan Teklab). Atherosclerosis was studied in offspring from the same mating at ages indicated in text. The study protocol was approved by the Institutional Animal Care and Use Committee and all animals received humane treatment according to the criteria stated by the National Academy of Sciences National Research Council (NRC) publication 86-23, 1985.
Tissue Preparation and Lipid Staining
Mice were anesthetized with ketamine:xylazine:PBS (1:1:2) and perfusion-fixed with 4% paraformaldehyde. Mice were euthanized by exsanguination under anesthesia. After removal and fixation in 10% neutral-buffered formalin, tissues were infiltrated with 30% gum sucrose for 24 hours at 4°C, embedded in Tissue-Tek OCT compound (Sakura Finetek), cross-sectioned (10 µm) at -30°C, stained for lipids with Oil red O (Polyscientific), and counterstained with Gill III hematoxylin (Sigma). Additional samples of these tissues were post-perfusion–fixed in formalin and embedded in paraffin for immunohistochemical analysis. Cholesterol and cholesteryl ester content of skin was determined in 1-cm2 samples taken from the back of the neck. Skin samples from the apoE-/-/ABCA1-/- mice were mostly macroscopically involved, as shown in Figure 1A, compared with skin samples from littermates. Samples were homogenized in PBS and extracted by using chloroform:methanol (2:1) as described by Folch et al.23 Cholesterol and cholesteryl esters were quantified on a gas chromatograph (Hewlett-Packard) and expressed as µg/g of tissue.
|
Immunohistochemistry
Rat IgG1 (Serotec) anti-F4/80 and rabbit IgG (Dako) anti-lysozyme antibodies were used as macrophage markers while a mouse IgG2a anti–smooth muscle actin (Dako) antibody was used as a specific marker for actin in formalin-fixed, paraffin-embedded sections. For F4/80, sections were blocked with 10% normal rabbit serum, incubated with the anti-F4/80 antibody followed by incubation with a peroxidase-labeled rabbit anti-rat IgG antibody (Vector). Sections were then incubated with the Elite ABC kit (Vector) for 30 minutes, stained with the Dako Liquid DAB for 5 minutes, and counterstained with hematoxylin. For smooth muscle actin, sections were deparaffinized, rehydrated, and steamed for 20 minutes in Citra pH 6 buffer (Biogenex). Mouse IgG2a anti–smooth muscle actin (Dako) was mixed with the biotinylated anti-mouse IgG2a antibody and mouse serum per the ARK kit instructions (Dako). Sections were incubated with the mixture for 1 hour at room temperature followed by a 45-minute incubation with Dako streptavidin-horseradish peroxidase, stained with DAB, and counterstained with hematoxylin. For lysozymes, sections were incubated with proteinase K (Dako), blocked with 10% normal goat serum, and incubated with a rabbit IgG (Dako) anti-lysozyme antibody diluted 1:200 in PBS mixed with 1% normal goat serum, followed by incubation with peroxidase-labeled goat anti-rabbit IgG antibody (Vector) diluted 1:150 in PBS mixed with 1% normal goat serum at room temperature. The sections were visualized with the Vector Elite ABC kit DAB substrate stained with Dako Liquid DAB+ counterstained with hematoxylin. Tissue sections incubated without primary antibody and the appropriate IgG isotypes were used as negative control.
Aortic Tree Analysis
Mice were anesthetized with ketamine:xylazine:PBS (1:1:2) and perfusion-fixed with 4% paraformaldehyde. The entire aortic tree was removed, cleaned of adventitia, and laid out on a piece of polystyrene, and a digital image was obtained with a digital camera (Sony). The percent aortic surface covered by lesions was determined by using an en face preparation as previously described.24
Atherosclerotic Lesion Analysis
To determine cross-sectional lesion area, hearts were perfusion-fixed in 4% paraformaldehyde, infiltrated with 30% gum sucrose for 24 hours at 4°C, and embedded in OCT compound. Tissues were sectioned (10 µm, -18°C) as previously described,24 stained with Oil red O, and counterstained with hematoxylin. Results are expressed as the average lesion size per section or as the percent of the total cross sectional vessel wall stained with Oil red O as previously described.24 For each animal, the average lesion area of 12 to 16 sections was determined, and data are expressed as lesion size or mean percent lesion area±SD.
Bone Marrow Transplantation
Recipient female apoE-/- mice were divided into two groups of mice at 12 weeks of age. Bone marrow was harvested from male apoE-/- mice and apoE-/-/ABCA1-/- littermates and transplanted into lethally irradiated recipient mice as previously described.25 Twelve weeks after transplantation, animals were sacrificed, and tissues were collected. Repopulation with donor bone marrow was confirmed by the presence of the ABCA1-/- allele and chromosome quantitation in the DNA harvested from bone marrow and peritoneal macrophages by using polymerase chain reaction analysis as previously described.25
Plasma Lipids and Lipoprotein Analysis
Plasma samples were isolated from blood collected either retro-orbitally or by terminal bleeds. Cholesterol, triglyceride, and phospholipid levels were determined by using enzymatic colorimetric assays (Wako Biochemicals). Apolipoprotein A-I (apoA-I) and apolipoprotein B (apoB) were determined by using ELISA as previously described.19 Lipoproteins were isolated from pooled plasma from six apoE-/-, apoE-/-/ABCA1-/-, LDLr-/-, and LDLr-/-/ABCA1-/- mice fed either a chow or a HFHC diet by fast protein liquid chromatography (FPLC) as previously described.19
Statistical Analysis
Results are expressed as mean±SD. Significant differences between means were determined by using the Student’s two-tailed t test.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Morphological Analysis
A complete necropsy was performed to determine morphological changes related to the absence of ABCA1 in apoE-/- mice. The main necropsy finding in hypercholesterolemic mice possessing the null allele for ABCA1 was the accumulation of foam cells with identical characteristics in several tissues, most notably the skin and uterus, without changes in atherosclerotic lesion size. Accumulation of macrophage-derived foam cells was also observed, although to a lesser extent, in the lamina propria of the squamous mucosa at the squamous-glandular gastric junction, lung, liver, the upper one third of the kidney medulla, adrenal, and cortico-medullary junction of lymph nodes (Figure 1). In addition, pancreas, mesentery, ovary, large and small intestine, urinary bladder, lymphatic vessels, spleen, and periodontal tissue showed occasional presence of foam cells which progressed with age (data not shown). Several tissues, including blood vessels and brain, did not show accumulation of macrophages, suggesting that the absence of ABCA1 in a setting of hyperlipidemia leads to a selective and targeted trafficking and/or retention of macrophages.
In apoE-/-/ABCA1-/- mice, cutaneous abnormalities became macroscopically visible at an early age and were characterized by the presence of ulcerations and excoriations leading to pruritus (Figure 2b). Microscopically, extensive intercytoplasmic staining with Oil red O was consistently observed in apoE-/-/ABCA1-/- mice (Figure 2d) when compared with apoE-/- control littermates (Figure 2c). The lipid accumulation and the severity of the cell infiltrates correlated with age and were independent of sex. A similar accumulation of foamy cells in the skin and uterus was observed in the LDLr-/-/ABCA1-/- mice fed a HFHC diet (data not shown).
|
To quantify the accumulation of lipids in skin, 1-cm2 tissue samples were taken from the back of the necks of age- and sex-matched apoE-/-/ABCA1-/- and apoE-/- mice. After homogenization, tissue lipids were extracted and cholesterol and cholesteryl esters determined by gas chromatography. Free cholesterol was increased by 2.5-fold in apoE-/-/ABCA1-/- mice compared with apoE-/- control littermates (217.8±80 µg/mg tissue vs 88.7±45 µg/mg tissue, n= 6, P<0.01). Cholesteryl esters were elevated by 7.5-fold in apoE-/-/ABCA1-/- mice when compared with apoE-/- control mice (121.6±48 µg/mg tissue vs 16.3±6.4 µg/mg, n= 6, P<0.0001).
To identify the cell type of the foam cells, paraffin sections of skin, uterus, stomach, and lymph nodes were stained with smooth muscle actin and two macrophage markers, F4/80 and lysozyme. A representative paraffin section from the uterus from an apoE-/-/ABCA1-/- mouse is shown in Figure 3. The lipid-filled foam cells (Figure 3a) did not stain for smooth muscle actin (Figure 3b) but were positive for both macrophage markers (Figure 3c and d, respectively). The F4/80 staining was strong and mostly located at the periphery of the cells while the lysozyme staining was weaker and intracytoplasmic. These findings were identical in all tissues in which foam cell accumulation was observed and indicate the presence of macrophage-derived foam cells.
|
Development and Progression of Atherosclerotic Lesions in Mice Lacking ABCA1
Because the original strain of ABCA1-/- mice on a normal cholesterolemic DBA1J background do not develop atherosclerosis, ABCA1-/- mice were mated to two atheroscerosis-susceptible strains of mouse: apoE-/- and LDLr-/- mice. Offspring from the same mating fed either a chow or a HFHC diet were used to determine the extent of atherosclerosis by cross sections at the aortic valve, the brachiochephalic region, or the entire aorta from aortic arch to the renal branch after en face preparations (Figure 4). In general, lesions in the apoE-/- strains on the mixed DBA/BL6 background were smaller and less complex than lesions previously reported for apoE-/- mice on a pure C57/BL6 background.24 Lesions from 16-week-old apoE-/-/ABCA1-/- and the apoE-/- mice consisted mainly of fatty streaks ranging from superficial foam cells to layers of foam cells within the lesions. Lesions in both groups were mainly confined to the proximal aorta and aortic arch. Unexpectedly, no greater foam cell accumulation was observed in apoE-/-/ABCA1-/- mice when compared with control apoE-/- littermates. Consistent with this finding, the atherosclerotic lesion area was not different between genotypes in 20-week-old mice fed a chow diet (Figure 1e and 1f and Table 1). An additional experiment was carried out to explore lesion development at a younger age.
|
|
As with animals studied at 20 weeks of age, there was no difference in the extent of atherosclerosis in 12-week-old mice lacking ABCA1 compared with their control littermates in the aortic valve sinus or throughout the entire aortic tree (Table 1). In addition, a dietary challenge consisting of feeding mice for 8 weeks with a HFHC diet did not significantly affect the development of atherosclerosis (Table 1) but there was a trend toward increased lesion area in the en face preparations (Table 1). In all animals, paraffin sections of the brachiochephalic region were stained with Movats Pentachrome and evaluated for compositional differences. At all ages studied, lesions in this region in both the apoE-/-/ABCA1-/- and their littermate controls (apoE-/-) were small, consisting mainly of fatty streaks, and no difference in lesion composition was observed between genotypes (data not shown). In contrast to the simple lesion found in the brachiochephalic region of the apoE-/- strain, much more distinct atherosclerotic lesions were produced in the LDLr-/- strains fed a HFHC diet. The complex lesions consisting of multilayered foam cells with areas of calcification necrosis and cholesterol clefts were found in both the LDLr-/- and the LDLr-/-/ABCA1-/- fed a HFHC diet. Lesion size in the aortic valve and throughout the entire aortic tree was also identical between age-matched littermates of LDLr-/- mice with and without the null alleles for ABCA1, fed either a chow or HFHC diet for 8 and 16 weeks (Table 1). Taken together, these findings suggest no measurable consequences of the complete absence of ABCA1 in the progression and extent of atherosclerosis development.
Plasma Lipids and Lipoproteins Analysis
In the absence of ABCA1, apoE-/- mice have a marked reduction on plasma apoAI levels. On a chow diet, plasma levels of apoAI were reduced to 87% of controls in apoE-/-/ABCA1-/- mice (Table 2). Identical results were observed when mice were fed a HFHC diet (Table 2), consistent with previous studies19 indicating a near complete absence of HDL in mice lacking ABCA1 even in the setting of hypercholesterolemia. Plasma triglyceride and phospholipid concentrations were not significantly different between genotypes. The disparity in cholesterol levels is more prominent in mice fed a HFHC diet on the LDLr-/- background (Table 2). As observed in the apoE-/-/ABCA1-/- mice, LDLr-/-/ABCA1-/- mice had significantly lower cholesterol levels than control mice when fed the HFHC diet. The relatively lower plasma cholesterol levels in apoE-/-/ABCA1-/- mice and in the LDLr-/-/ABCA1-/- mice could be largely accounted for by reductions in the VLDL and LDL fractions in mice fed either a chow or a HFHC diet as demonstrated by FPLC (Figure 4).
|
Macrophage Inactivation of ABCA1-Effects on Plasma Lipids and Atherosclerosis
To determine whether ABCA1 deficiency in macrophages contributed to the development of atherosclerosis a bone marrow transplantation study was performed in which bone marrow from apoE-/-/ABCA1-/- or apoE-/- control mice was transplanted into recipient mice. After transplantation, mice were fed a chow diet for 12 weeks. By then, apoE-/- mice which received bone marrow from apoE-/-/ABCA1-/- had no changes in plasma cholesterol, triglycerides or HDL when compared with control recipient mice (Figure 5). In contrast, histological analysis of aortic valve, sinus and entire aorta following en face preparations revealed a significant increase in atherosclerosis in these mice lacking ABCA1 in macrophages compared with controls (Figure 5). These findings demonstrate the antiatherogenic function of ABCA1 in macrophages independently of changes in plasma lipids.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Analysis of ABCA1 in several in vitro and in vivo studies has provided compelling evidence that ABCA1 is intimately involved in the synthesis of HDL and lipoprotein homeostasis. Lack of function, as a consequence of natural mutations, leads to Tangier Disease, a rare autosomal recessive genetic disorder characterized by virtually no HDL, 40% reductions in LDL levels and abnormal deposition of cholesteryl esters in the reticuloendothelial system. Clinically, the majority of patients with severe HDL and apoAI deficiencies suffer from premature atherosclerosis.26 Since its discovery, ABCA1 has been considered a potential candidate for therapeutic intervention to prevent atherosclerosis. Interestingly, individuals homozygous and heterozogous for mutations in the ABCA1 gene have an increased risk of coronary artery disease, but not to the degree expected with complete absence of HDL. Similarly, chickens with a mutation in ABCA1 are no more susceptible to diet-induced or spontaneous atherosclerosis than normal animals.27 Preliminary studies in our laboratory indicate that DBA mice with a targeted inactivation of ABCA119 do not develop atherosclerotic lesions on either a chow or HFHC diet (data not shown). The lack of ABCA1 did not increase the susceptibility or progression of atherosclerosis in hyperlipidemic mice fed either a chow or HFHC diet despite the complete absence of apoAI and HDL. This finding may reflect changes in plasma cholesterol homeostasis as demonstrated by the decrease in plasma cholesterol and VLDL fractions from mice lacking ABCA1. Similar changes in plasma lipid profiles are observed in chickens,27 ABCA1 knockout mice19 and patients with Tangier Disease.22 Thus, we hypothesize that the proposed atherogenic effect resulting from ABCA1 deficiency was compensated for by a less atherogenic lipid profile, resulting in similar lesion areas between the groups. Consistent with this hypothesis, the selective inactivation of ABCA1 in macrophages significantly increased atherosclerosis development in the absence of changes in plasma lipid profiles. Since the contribution of macrophages to the overall plasma HDL levels is minimal25 these studies suggest that the antiatherogenic properties of ABCA1 are independent of plasma levels of HDL.
The mechanism by which ABCA1 affects plasma levels of apoB remains unclear. The lipid effects are seen in both the apoE-/- and the LDLr-/- strains, mouse models with severely compromised clearance of apoB containing lipoproteins. It is unlikely that the decrease in plasma cholesterol levels resulted from altered receptor clearance rates. Previous transcript imaging of ABCA1 deficient mice have shown that cholesterol biosynthetic enzymes are decreased compared with wild-type littermates,19 suggesting a decrease in cholesterol synthesis. In addition, studies in transgenic mice demonstrated that the increased levels of plasma apoB-containing lipoproteins observed in mice expressing human ABCA1 was not due to increased secretion of apoB.28 More recently, Joyce et al29 demonstrated that the overexpression of ABCA1 in apoE-/- mice led to increased atherosclerosis despite minimal changes in plasma lipids. In contrast, overexpression of ABCA1 in C57BL/6 mice fed a HFHC diet significantly changed plasma lipid profiles. Clearly, additional studies are required to understand the mechanisms underlying these lipid modulating effects of ABCA1.
The most outstanding phenotype observed in this study is the massive foam cell accumulation in tissues other than atherosclerosis-prone vessels in mice lacking ABCA1. Marked macrophage and foam cell accumulation was observed in skin and uterus and to a lesser extent in stomach, lymph nodes, kidneys and lungs. Several genetic mouse models develop xanthomas and show a marked accumulation of cholesterol and cholesteryl esters characteristic of typical xanthomatosis observed in patients with genetic disorders of lipoprotein metabolism.30
The mechanism(s) leading to foam cell accumulation in certain tissues but not in others, particularly the vessel wall remains unclear. Severe hypercholesterolemia was necessary to exacerbate the xanthomatosis in the ABCA1-deficent mice, whereas normal cholesterolemic ABCA1-deficient mice do not form similar foam cell lesions.19 Because monocyte infiltration and the accumulation of cholesterol in lesional macrophages are the hallmark of atherosclerosis, it was surprising that there was massive foam cell formation in certain tissues without affecting atherosclerosis. One possible explanation is that tissues like skin and uterus, which undergo rapid cell division and proliferation, not only require an influx of lipoprotein-derived cholesterol as suggested by Accad et al,31 but also require the efficient removal of apoptotic bodies and cell membranes. Oram32 proposed that sterol accumulation in macrophages plays different functional roles in different tissues. In some tissues, macrophages infiltrate to clear apoptotic and necrotic cells, and thus, a major source of cholesterol is likely derived from cell membranes. Conversely, lipoproteins are considered the major source of cholesterol in arterial macrophages, and reduction in these atherogenic lipoproteins as observed in mice with complete inactivation of ABCA1 may explain why foam cell accumulation was greater in proliferating tissues than the arterial wall. This is consistent with the findings from the bone marrow transplantation study in which selective inactivation of ABCA1 in macrophages does not alter plasma cholesterol homeostasis and yet lead to increased foam cell accumulation at the vessel wall. Our finding of accumulation of foam cells in specific tissues may also suggest a targeted infiltration or retention of macrophages lacking functional ABCA1. The trafficking of monocytes to various tissues is known to be regulated by a complex multistep process involving specific cell-cell adhesion interactions between monocytes and endothelial cells, chemoattractant factors, and their receptors.33 The recruitment of monocytes to any given tissue appears to require a specific pattern of adhesion factors and chemokines.34 The ability of lipoprotein cholesterol to alter the expression of specific adhesion factors and chemokines receptors on circulating macrophages is well-documented in vivo and in vitro.35,36 It is therefore conceivable that changes in intracellular sterol levels resulting from the absence of ABCA1 causes a pleiotropic phenotype in which macrophages are selectively targeted to certain tissues and not others. This hypothesis was first suggested by Schmitz et al37 to explain the differences in phenotypes observed among patients with Tangier disease. Our studies in hypercholesterolemic mice deficient in ABCA1 show massive tissue-specific accumulation of macrophages and may provide a valuable animal model to unravel the mechanisms and physiology of macrophage trafficking.
In conclusion, our findings demonstrate that the complete absence of ABCA1 has a major impact in plasma lipoprotein homeostasis, and the proposed antiatherogenic effect resulting from ABCA1 deficiency is likely compensated by a less atherogenic lipid profile. ABCA1 deficiency in macrophages, however, demonstrates the antiatherogenic properties of ABCA1 independent of plasma lipids and HDL levels. Our results also highlight ABCA1’s potential role in monocyte targeting and trafficking, and provide the basis for additional experiments to elucidate its function and relationship to the development of atherosclerosis.
|
Acknowledgments |
|---|
We thank Roy Jarvis and Brenda Yanak for their assistance with the animal breeding and husbandry. We also thank Edwin Berryman for his help with the animal photography, Gail Cameron for help with the bone marrow transplant, Ann Freeman and Eliot Sugarman for their technical assistance, and Dr Patricia Uelmen-Huey for her help and insightful comments during the preparation of this manuscript.
Received February 6, 2002; accepted February 26, 2002.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Dean M, Hamon Y, Chimini G. The human ATP-binding cassette (ABC) transporter superfamily. J Lipid Res. 2001; 42: 1007–1017.
2.
Dean M, Rzhetsky A, Allikmets R. The human ATP-binding cassette (ABC) transporter superfamily. Genome Res. 2001; 11: 1156–1166.
3. Langmann T, Klucken J, Reil M, Liebisch G, Luciani M-F, Chimini G, Kaminski WE, Schmitz G. Molecular cloning of the human ATP binding cassette transporter 1 (hABC1): evidence for sterol-dependent regulation in macrophages. Biochem Biophys Res Commun. 1999; 257: 29–33.[CrossRef][Medline] [Order article via Infotrieve]
4.
Bortnick AE, Rothblat GH, Stoudt G, Hoppe KL, Royer LJ, McNeish J, Francone OL. The correlation of ATP-binding cassette 1 mRNA levels with cholesterol efflux from various cell lines. J Biol Chem. 2000; 275: 28634–28640.
5.
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.
6. Schwartz K, Lawn RM, Wade DP. ABC1 gene expression and ApoA-I-mediated cholesterol efflux are regulated by LXR. Biochem Biophys Res Commun. 2000; 274: 794–802.[CrossRef][Medline] [Order article via Infotrieve]
7. Chinetti G, Lestavel S, Bocher V, Remaley AT, Neve B, Torra IP, Teissier E, Minnich A, Jaye M, Duverger N, Brewer HB, Fruchart JC, Clavey V, Staels B. PPAR-alpha and PPAR-gamma activators induce cholesterol removal from human macrophage foam cells through stimulation of the ABCA1 pathway. Nat Med. 2001; 7: 53–58.[CrossRef][Medline] [Order article via Infotrieve]
8. 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]
9.
Panousis CG, Zuckerman SH. Interferon-gamma induces downregulation of Tangier disease gene (ATP-binding-cassette transporter 1) in macrophage-derived foam cells. Arterioscler Thromb Vasc Biol. 2000; 20: 1565–1571.
10.
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.
11.
Venkateswaran A, Laffitte BA, Joseph SB, Mak PA, Wilpitz DC, Edwards PA, Tontonoz P. Control of cellular cholesterol efflux by the nuclear oxysterol receptor LXR alpha. Proc Natl Acad Sci U S A. 2000; 97: 12097–12102.
12. Luciani M-F, Chimini G. The ATP binding cassette transporter ABC1 is required for the engulfment of corpses generated by apoptotic cell death. EMBO. 1996; 15: 226–235.[Medline] [Order article via Infotrieve]
13.
Hamon Y, Luciani M-F, Becq F, Verrier B, Rubartelli A, Chimini G. Interleukin-1ß secretion is impaired by inhibitors of the ATP binding cassette transporter, ABC1. Blood. 1997; 90: 2911–2915.
14.
Becq F, Hamon Y, Bajetto A, Gola M, Verrier B, Chimini G. ABC1, an ATP binding cassette transporter is required for phagocytosis of apoptotic cells, generates a regulated anion flux after expression in Xenopus laevis oocytes. J Biol Chem. 1997; 272: 2695–2699.
15. 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, 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]
16. Bodzioch M, Orso E, Klucken J, Langmann T, Böttcher A, Diedrich W, Drobnik W, Barlage S, Büchler C, Porsch-Özcürümez 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]
17. 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]
18.
Schreyer SA, Hart LK, Attie AD. Hypercatabolism of lipoprotein-free apolipoprotein A-I in HDL-deficient mutant chickens. Arterioscler Thromb. 1994; 14: 2053–2059.
19.
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 O. 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.
20.
Schaefer EJ. Clinical, biochemical, and genetic features in familial disorders of high density lipoprotein deficiency. Arteriosclerosis. 1984; 4: 303–322.
21. Clee SM, Zwinderman AH, Engert JC, Zwarts KY, Molhuizen HOF, Roomp K, Jukema JW, van Wijland M, van Dam M, Hudson TJ, Brooks-Wilson A, Genest J Jr, Hayden MR. Common genetic variation in ABCA1 is associated with altered lipoprotein levels and a modified risk for coronary artery disease. Circulation. 2001; 103: r13–r20.
22. Schaefer EJ, Blum CB, Levy RI, Jenkins LL, Alaupovic P, Foster DM, Brewer B Jr. Metabolism of high-density lipoprotein apolipoproteins in Tangier disease. N Engl J Med. 1978; 299: 905–910.[Abstract]
23.
Folch J, Lees M, Sloane-Stanley GH. A simple method for the isolation and purification of total lipids form animal tissues. J Biol Chem. 1957; 226: 497–509.
24.
Bourassa P-AK, Milos PM, Gaynor BJ, Breslow JL, Aiello RJ. Estrogen reduces atherosclerosis lesion development in apolipoprotein E-deficient mice. Proc Natl Acad Sci U S A. 1996; 93: 10022–10027.
25. Haghpassand M, Bourassa P-AK, 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]
26.
Gordon DJ, Probstfeld JL, Garrison RJ, Neaton JD, Castelli WP, Knoke JD, Jacobs DR, Bangdiwala S, Tyroler HA. High-density lipoprotein cholesterol and cardiovascular disease: four prospective American studies. Circulation. 1989; 79: 8–15.
27.
Poernama F, Subramanian R, Cook ME, Attie AD. High density lipoprotein deficiency syndrome in chickens is not associated with an increased susceptibility to atherosclerosis. Arterioscler Thromb. 1992; 12: 601–607.
28. Vaisman BL, Lambert G, Amar M, Joyce C, Ito T, Shamburek RD, Cain WJ, Fruchart-Najib J, Neufeld ED, Remaley AT, Brewer HB, Santamarina-Fojo S. ABCA1 overexpression leads to hyperalphalipoproteinemia and increased biliary cholesterol excretion in transgenic mice. J Clin Invest. 2001; 108: 303–309.[CrossRef][Medline] [Order article via Infotrieve]
29.
Joyce CW, Amar MJA, Lambert G, Vaisman BL, Paigen B, Najib-Fruchart J, Hoyt-Jr RF, Neufeld ED, Remaley AT, Fredrickson DS, Brewer-Jr HB, Santamarina-Fojo S. The ATP binding cassette transporter A1 (ABCA1) modulates the development of aortic atherosclerosis in C57BL/6 and apoE-knockout mice. Proc Natl Acad Sci U S A. 2002; 99: 407–412.
30. Bhattacharyya AK, Connor WE. ß-Sitosterolemia and xanthomatosis. J Clin Invest. 197; 53: 1033–1043.
31. Accad M, Smith SJ, Newland DL, Sanan DA, King LE Jr, Linton MF, Fazio S, Farese RV Jr. Massive xanthomatosis and altered composition of atherosclerotic lesions and hyperlipidemic mice lacking acyl CoA:cholesterol acyltransferase 1. J Clin Invest. 2000; 105: 711–719.[Medline] [Order article via Infotrieve]
32. Oram JF. Novel approaches to treating cardiovascular disease: lessons from Tangier disease. Exp Opin Invest Drugs. 2001; 10: 427–438.
33. Springer TA. Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm. Cell. 1994; 76: 301–314.[CrossRef][Medline] [Order article via Infotrieve]
34.
Manka D, Collins RG, Ley K, Beaudet AL, Sarembock IJ. Absence of P-selectin, but not intercellular adhesion molecule-1, attenuates neointimal growth after arterial injury in apolipoprotein E-deficient mice. Circ. 2001; 103: 1000–1005.
35.
Bell FP, Gerrity RG. Evidence for an altered lipid metabolic state in circulating blood monocytes under conditions of hyperlipidemia in swine and its implications in arterial lipid metabolism. Arterioscler Thromb. 1992; 12: 155–162.
36.
Han KH, Tangirala RK, Green SR, Quehenberger O. Chemokine receptor CCR2 expression and monocyte chemoattractant protein-1-mediated chemotaxis in human monocytes. Arterioscler Thromb Vasc Biol. 1998; 18: 1983–1991.
37. Schmitz G, Kaminski WE, Porsch-Ozcurumez M, Klucken J, Orso E, Bodzioch M, Buchler C, Drobnik W, ATP-binding cassette transporter A1 (ABCA1) in macrophages: a dual function in inflammation and lipid metabolism? Patholbiol. 1999; 67: 236–240.
This article has been cited by other articles:
 |
|
 |
|
  H. Tanigawa, J. T. Billheimer, J.-i. Tohyama, I. V. Fuki, D. S. Ng, G. H. Rothblat, and D. J. Rader Lecithin: Cholesterol Acyltransferase Expression Has Minimal Effects on Macrophage Reverse Cholesterol Transport In Vivo Circulation, July 14, 2009; 120(2): 160 - 169. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. J. Wilhelm, M. Zabalawi, J. M. Grayson, A. E. Weant, A. S. Major, J. Owen, M. Bharadwaj, R. Walzem, L. Chan, K. Oka, et al. Apolipoprotein A-I and Its Role in Lymphocyte Cholesterol Homeostasis and Autoimmunity Arterioscler Thromb Vasc Biol, June 1, 2009; 29(6): 843 - 849. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. R. Brunham, R. R. Singaraja, M. Duong, J. M. Timmins, C. Fievet, N. Bissada, M. H. Kang, A. Samra, J.-C. Fruchart, B. McManus, et al. Tissue-Specific Roles of ABCA1 Influence Susceptibility to Atherosclerosis Arterioscler Thromb Vasc Biol, April 1, 2009; 29(4): 548 - 554. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Baldan, D. D. Bojanic, and P. A. Edwards The ABCs of sterol transport J. Lipid Res., April 1, 2009; 50(Supplement): S80 - S85. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. M. Vaughan, C. Tang, and J. F. Oram ABCA1 mutants reveal an interdependency between lipid export function, apoA-I binding activity, and Janus kinase 2 activation J. Lipid Res., February 1, 2009; 50(2): 285 - 292. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Kralova Lesna, P. Suchanek, J. Kovar, P. Stavek, and R. Poledne Replacement of dietary saturated FAs by PUFAs in diet and reverse cholesterol transport J. Lipid Res., November 1, 2008; 49(11): 2414 - 2418. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Mukhamedova, G. Escher, W. D'Souza, U. Tchoua, A. Grant, Z. Krozowski, M. Bukrinsky, and D. Sviridov Enhancing apolipoprotein A-I-dependent cholesterol efflux elevates cholesterol export from macrophages in vivo J. Lipid Res., November 1, 2008; 49(11): 2312 - 2322. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Burgess, K. Naus, J. Chan, V. Hirsch-Reinshagen, G. Tansley, L. Matzke, B. Chan, A. Wilkinson, J. Fan, J. Donkin, et al. Overexpression of Human ABCG1 Does Not Affect Atherosclerosis in Fat-Fed ApoE-Deficient Mice Arterioscler Thromb Vasc Biol, October 1, 2008; 28(10): 1731 - 1737. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Zhu, J.-Y. Lee, J. M. Timmins, J. M. Brown, E. Boudyguina, A. Mulya, A. K. Gebre, M. C. Willingham, E. M. Hiltbold, N. Mishra, et al. Increased Cellular Free Cholesterol in Macrophage-specific Abca1 Knock-out Mice Enhances Pro-inflammatory Response of Macrophages J. Biol. Chem., August 22, 2008; 283(34): 22930 - 22941. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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]
|
|
|
|
|
|
M.-S. Kuo, J. M. Kalbfleisch, P. Rutherford, D. Gifford-Moore, X.-d. Huang, R. Christie, K. Hui, K. Gould, and M. Rekhter Chemical analysis of atherosclerotic plaque cholesterol combined with histology of the same tissue J. Lipid Res., June 1, 2008; 49(6): 1353 - 1363. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Out, M. Hoekstra, K. Habets, I. Meurs, V. de Waard, R. B. Hildebrand, Y. Wang, G. Chimini, J. Kuiper, T. J.C. Van Berkel, et al. Combined Deletion of Macrophage ABCA1 and ABCG1 Leads to Massive Lipid Accumulation in Tissue Macrophages and Distinct Atherosclerosis at Relatively Low Plasma Cholesterol Levels Arterioscler Thromb Vasc Biol, February 1, 2008; 28(2): 258 - 264. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Yan, M. I. Mayranpaa, J. Wong, J. Perttila, M. Lehto, M. Jauhiainen, P. T. Kovanen, C. Ehnholm, A. J. Brown, and V. M. Olkkonen OSBP-related Protein 8 (ORP8) Suppresses ABCA1 Expression and Cholesterol Efflux from Macrophages J. Biol. Chem., January 4, 2008; 283(1): 332 - 340. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Frikke-Schmidt, B. G. Nordestgaard, G. B. Jensen, R. Steffensen, and A. Tybjaerg-Hansen Genetic Variation in ABCA1 Predicts Ischemic Heart Disease in the General Population Arterioscler Thromb Vasc Biol, January 1, 2008; 28(1): 180 - 186. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M.-D. Wang, V. Franklin, and Y. L. Marcel In Vivo Reverse Cholesterol Transport From Macrophages Lacking ABCA1 Expression Is Impaired Arterioscler Thromb Vasc Biol, August 1, 2007; 27(8): 1837 - 1842. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. G. Yancey, H. Yu, M. F. Linton, and S. Fazio A Pathway-Dependent on ApoE, ApoAI, and ABCA1 Determines Formation of Buoyant High-Density Lipoprotein by Macrophage Foam Cells Arterioscler Thromb Vasc Biol, May 1, 2007; 27(5): 1123 - 1131. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Out, M. Hoekstra, I. Meurs, P. de Vos, J. Kuiper, M. Van Eck, and T. J.C. Van Berkel Total Body ABCG1 Expression Protects Against Early Atherosclerotic Lesion Development in Mice Arterioscler Thromb Vasc Biol, March 1, 2007; 27(3): 594 - 599. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Zabalawi, M. Bharadwaj, H. Horton, M. Cline, M. Willingham, M. J. Thomas, and M. G. Sorci-Thomas Inflammation and skin cholesterol in LDLr-/-, apoA-I-/- mice: link between cholesterol homeostasis and self-tolerance? J. Lipid Res., January 1, 2007; 48(1): 52 - 65. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. D. Linder, R.-L. Uronen, M. Holtta-Vuori, P. van der Sluijs, J. Peranen, and E. Ikonen Rab8-dependent Recycling Promotes Endosomal Cholesterol Removal in Normal and Sphingolipidosis Cells Mol. Biol. Cell, January 1, 2007; 18(1): 47 - 56. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. F. Oram and A. M. Vaughan ATP-Binding Cassette Cholesterol Transporters and Cardiovascular Disease Circ. Res., November 10, 2006; 99(10): 1031 - 1043. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. W. Joyce, E. M. Wagner, F. Basso, M. J. Amar, L. A. Freeman, R. D. Shamburek, C. L. Knapper, J. Syed, J. Wu, B. L. Vaisman, et al. ABCA1 Overexpression in the Liver of LDLr-KO Mice Leads to Accumulation of Pro-atherogenic Lipoproteins and Enhanced Atherosclerosis J. Biol. Chem., November 3, 2006; 281(44): 33053 - 33065. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Bukrinsky and D. Sviridov Human immunodeficiency virus infection and macrophage cholesterol metabolism. J. Leukoc. Biol., November 1, 2006; 80(5): 1044 - 1051. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. M. Vaughan and J. F. Oram ABCA1 and ABCG1 or ABCG4 act sequentially to remove cellular cholesterol and generate cholesterol-rich HDL J. Lipid Res., November 1, 2006; 47(11): 2433 - 2443. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Out, M. Hoekstra, R. B. Hildebrand, J. K. Kruit, I. Meurs, Z. Li, F. Kuipers, T. J.C. Van Berkel, and M. Van Eck Macrophage ABCG1 Deletion Disrupts Lipid Homeostasis in Alveolar Macrophages and Moderately Influences Atherosclerotic Lesion Development in LDL Receptor-Deficient Mice Arterioscler Thromb Vasc Biol, October 1, 2006; 26(10): 2295 - 2300. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Baldan, L. Pei, R. Lee, P. Tarr, R. K. Tangirala, M. M. Weinstein, J. Frank, A. C. Li, P. Tontonoz, and P. A. Edwards Impaired Development of Atherosclerosis in Hyperlipidemic Ldlr-/- and ApoE-/- Mice Transplanted With Abcg1-/- Bone Marrow Arterioscler Thromb Vasc Biol, October 1, 2006; 26(10): 2301 - 2307. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Lee-Rueckert, R. Vikstedt, J. Metso, C. Ehnholm, P. T. Kovanen, and M. Jauhiainen Absence of endogenous phospholipid transfer protein impairs ABCA1-dependent efflux of cholesterol from macrophage foam cells J. Lipid Res., August 1, 2006; 47(8): 1725 - 1732. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Cuchel and D. J. Rader Macrophage Reverse Cholesterol Transport: Key to the Regression of Atherosclerosis? Circulation, May 30, 2006; 113(21): 2548 - 2555. [Full Text] [PDF]
|
|
|
|
|
|
H. Mezdour, G. Larigauderie, G. Castro, G. Torpier, J. Fruchart, M. Nowak, J.-C. Fruchart, M. Rouis, and N. Maeda Characterization of a new mouse model for human apolipoprotein A-I/C-III/A-IV deficiency J. Lipid Res., May 1, 2006; 47(5): 912 - 920. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Van Eck, R. R. Singaraja, D. Ye, R. B. Hildebrand, E. R. James, M. R. Hayden, and T. J.C. Van Berkel Macrophage ATP-Binding Cassette Transporter A1 Overexpression Inhibits Atherosclerotic Lesion Progression in Low-Density Lipoprotein Receptor Knockout Mice Arterioscler Thromb Vasc Biol, April 1, 2006; 26(4): 929 - 934. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Y. Lee, A. Lesimple, M. Denis, J. Vincent, A. Larsen, O. Mamer, L. Krimbou, J. Genest, and M. Marcil Increased sphingomyelin content impairs HDL biogenesis and maturation in human Niemann-Pick disease type B J. Lipid Res., March 1, 2006; 47(3): 622 - 632. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Le Goff, P. Zheng, G. Brubaker, and J. D. Smith Identification of the cAMP-Responsive Enhancer of the Murine ABCA1 Gene: Requirement for CREB1 and STAT3/4 Elements Arterioscler Thromb Vasc Biol, March 1, 2006; 26(3): 527 - 533. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. H. Huang, M. L. Fitzgerald, and T. Mazzone Distinct Cellular Loci for the ABCA1-Dependent and ABCA1-Independent Lipid Efflux Mediated by Endogenous Apolipoprotein E Expression Arterioscler Thromb Vasc Biol, January 1, 2006; 26(1): 157 - 162. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. W. S. Ko, A. Paul, K. Ma, L. Li, and L. Chan Endothelial lipase modulates HDL but has no effect on atherosclerosis development in apoE-/- and LDLR-/- mice J. Lipid Res., December 1, 2005; 46(12): 2586 - 2594. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Ohashi, H. Mu, X. Wang, Q. Yao, and C. Chen Reverse cholesterol transport and cholesterol efflux in atherosclerosis QJM, December 1, 2005; 98(12): 845 - 856. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. R. Bates, J.-Q. Tao, H. L. Collins, O. L. Francone, and G. H. Rothblat Pulmonary abnormalities due to ABCA1 deficiency in mice Am J Physiol Lung Cell Mol Physiol, December 1, 2005; 289(6): L980 - L989. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K.-i. Okuhira, M. L. Fitzgerald, D. A. Sarracino, J. J. Manning, S. A. Bell, J. L. Goss, and M. W. Freeman Purification of ATP-binding Cassette Transporter A1 and Associated Binding Proteins Reveals the Importance of {beta}1-Syntrophin in Cholesterol Efflux J. Biol. Chem., November 25, 2005; 280(47): 39653 - 39664. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Takata, V. Chu, A. R. Collins, C. J. Lyon, W. Wang, F. Blaschke, D. Bruemmer, E. Caglayan, W. Daley, J. Higaki, et al. Transcriptional Repression of ATP-Binding Cassette Transporter A1 Gene in Macrophages: A Novel Atherosclerotic Effect of Angiotensin II Circ. Res., October 28, 2005; 97(9): e88 - e96. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. F. Oram and J. W. Heinecke ATP-Binding Cassette Transporter A1: A Cell Cholesterol Exporter That Protects Against Cardiovascular Disease Physiol Rev, October 1, 2005; 85(4): 1343 - 1372. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Albrecht, J. H. McVey, J. I. Elliott, A. Sardini, I. Kasza, A. D. Mumford, R. P. Naoumova, E. G. D. Tuddenham, K. Szabo, and C. F. Higgins A novel missense mutation in ABCA1 results in altered protein trafficking and reduced phosphatidylserine translocation in a patient with Scott syndrome Blood, July 15, 2005; 106(2): 542 - 549. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Ragozin, A. Niemeier, A. Laatsch, B. Loeffler, M. Merkel, U. Beisiegel, and J. Heeren Knockdown of Hepatic ABCA1 by RNA Interference Decreases Plasma HDL Cholesterol Levels and Influences Postprandial Lipemia in Mice Arterioscler Thromb Vasc Biol, July 1, 2005; 25(7): 1433 - 1438. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. J. Harvey and D. P. Ramji Interferon-{gamma} and atherosclerosis: Pro- or anti-atherogenic? Cardiovasc Res, July 1, 2005; 67(1): 11 - 20. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. F. Lewis and D. J. Rader New Insights Into the Regulation of HDL Metabolism and Reverse Cholesterol Transport Circ. Res., June 24, 2005; 96(12): 1221 - 1232. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Coutinho, R. R. Singaraja, M. Kang, D. J. Arenillas, L. N. Bertram, N. Bissada, B. Staels, J.-C. Fruchart, C. Fievet, A. M. Joseph-George, et al. Complete functional rescue of the ABCA1-/- mouse by human BAC transgenesis J. Lipid Res., June 1, 2005; 46(6): 1113 - 1123. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P.J. Barter Antiatherogenic Properties of Fibrates Arterioscler Thromb Vasc Biol, June 1, 2005; 25(6): 1095 - 1096. [Full Text] [PDF]
|
|
|
|
|
|
O. L. Francone, L. Royer, G. Boucher, M. Haghpassand, A. Freeman, D. Brees, and R. J. Aiello Increased Cholesterol Deposition, Expression of Scavenger Receptors, and Response to Chemotactic Factors in Abca1-Deficient Macrophages Arterioscler Thromb Vasc Biol, June 1, 2005; 25(6): 1198 - 1205. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S Soumian, C Albrecht, A. Davies, and R. Gibbs ABCA1 and atherosclerosis Vascular Medicine, May 1, 2005; 10(2): 109 - 119. [Abstract] [PDF]
|
|
|
|
|
|
D. E. Dove, Y. R. Su, W. Zhang, W. G. Jerome, L. L. Swift, M. F. Linton, and S. Fazio ACAT1 Deficiency Disrupts Cholesterol Efflux and Alters Cellular Morphology in Macrophages Arterioscler Thromb Vasc Biol, January 1, 2005; 25(1): 128 - 134. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Albrecht, S. Soumian, J.S. Amey, A. Sardini, C.F. Higgins, A.H. Davies, and R.G.J. Gibbs ABCA1 Expression in Carotid Atherosclerotic Plaques Stroke, December 1, 2004; 35(12): 2801 - 2806. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Le Goff, D.-Q. Peng, M. Settle, G. Brubaker, R. E. Morton, and J. D. Smith Cyclosporin A Traps ABCA1 at the Plasma Membrane and Inhibits ABCA1-Mediated Lipid Efflux to Apolipoprotein A-I Arterioscler Thromb Vasc Biol, November 1, 2004; 24(11): 2155 - 2161. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. M. Quinet, D. A. Savio, A. R. Halpern, L. Chen, C. P. Miller, and P. Nambi Gene-selective modulation by a synthetic oxysterol ligand of the liver X receptor J. Lipid Res., October 1, 2004; 45(10): 1929 - 1942. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Ando, S. Tsuruoka, H. Yamamoto, T. Takamura, S. Kaneko, and A. Fujimura Effects of Pravastatin on the Expression of ATP-Binding Cassette Transporter A1 J. Pharmacol. Exp. Ther., October 1, 2004; 311(1): 420 - 425. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Assmann and A. M. Gotto Jr HDL Cholesterol and Protective Factors in Atherosclerosis Circulation, June 15, 2004; 109(23_suppl_1): III-8 - III-14. [Abstract] [Full Text]
|
|
|
|
|
|
D. M. Selva, V. Hirsch-Reinshagen, B. Burgess, S. Zhou, J. Chan, S. McIsaac, M. R. Hayden, G. L. Hammond, A. W. Vogl, and C. L. Wellington The ATP-binding cassette transporter 1 mediates lipid efflux from Sertoli cells and influences male fertility J. Lipid Res., June 1, 2004; 45(6): 1040 - 1050. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. W. Chisholm, J. Hong, S. A. Mills, and R. M. Lawn The LXR ligand T0901317 induces severe lipogenesis in the db/db diabetic mouse J. Lipid Res., November 1, 2003; 44(11): 2039 - 2048. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. E. Sobel, D. J. Taatjes, and D. J. Schneider Intramural Plasminogen Activator Inhibitor Type-1 and Coronary Atherosclerosis Arterioscler Thromb Vasc Biol, November 1, 2003; 23(11): 1979 - 1989. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. O. Martinez, B. Agerholm-Larsen, N. Wang, W. Chen, and A. R. Tall Phosphorylation of a Pest Sequence in ABCA1 Promotes Calpain Degradation and Is Reversed by ApoA-I J. Biol. Chem., September 26, 2003; 278(39): 37368 - 37374. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Zabalawi, S. Bhat, T. Loughlin, M. J. Thomas, E. Alexander, M. Cline, B. Bullock, M. Willingham, and M. G. Sorci-Thomas Induction of Fatal Inflammation in LDL Receptor and ApoA-I Double-Knockout Mice Fed Dietary Fat and Cholesterol Am. J. Pathol., September 1, 2003; 163(3): 1201 - 1213. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. D. Covey, M. Krieger, W. Wang, M. Penman, and B. L. Trigatti Scavenger Receptor Class B Type I-Mediated Protection Against Atherosclerosis in LDL Receptor-Negative Mice Involves Its Expression in Bone Marrow-Derived Cells Arterioscler Thromb Vasc Biol, September 1, 2003; 23(9): 1589 - 1594. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. R. Singaraja, L. R. Brunham, H. Visscher, J. J.P. Kastelein, and M. R. Hayden Efflux and Atherosclerosis: The Clinical and Biochemical Impact of Variations in the ABCA1 Gene Arterioscler Thromb Vasc Biol, August 1, 2003; 23(8): 1322 - 1332. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. M. Vaughan and J. F. Oram ABCA1 redistributes membrane cholesterol independent of apolipoprotein interactions J. Lipid Res., July 1, 2003; 44(7): 1373 - 1380. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Wang and A. R. Tall Regulation and Mechanisms of ATP-Binding Cassette Transporter A1-Mediated Cellular Cholesterol Efflux Arterioscler Thromb Vasc Biol, July 1, 2003; 23(7): 1178 - 1184. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Tontonoz and D. J. Mangelsdorf Liver X Receptor Signaling Pathways in Cardiovascular Disease Mol. Endocrinol., June 1, 2003; 17(6): 985 - 993. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. K. Hovingh, M. J. A. van Wijland, A. Brownlie, R. J. Bisoendial, M. R. Hayden, J. J. P. Kastelein, and A. K. Groen The role of the ABCA1 transporter and cholesterol efflux in familial hypoalphalipoproteinemia J. Lipid Res., June 1, 2003; 44(6): 1251 - 1255. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. J. Aiello, D. Brees, and O. L. Francone ABCA1-Deficient Mice: Insights Into the Role of Monocyte Lipid Efflux in HDL Formation and Inflammation Arterioscler Thromb Vasc Biol, June 1, 2003; 23(6): 972 - 980. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Joyce, L. Freeman, H. B. Brewer Jr, and S. Santamarina-Fojo Study of ABCA1 Function in Transgenic Mice Arterioscler Thromb Vasc Biol, June 1, 2003; 23(6): 965 - 971. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A. Lyons, H. Wittenburg, R. Li, K. A. Walsh, G. A. Churchill, M. C. Carey, and B. Paigen Quantitative trait loci that determine lipoprotein cholesterol levels in DBA/2J and CAST/Ei inbred mice, J. Lipid Res., May 1, 2003; 44(5): 953 - 967. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. G. Yancey, A. E. Bortnick, G. Kellner-Weibel, M. de la Llera-Moya, M. C. Phillips, and G. H. Rothblat Importance of Different Pathways of Cellular Cholesterol Efflux Arterioscler Thromb Vasc Biol, May 1, 2003; 23(5): 712 - 719. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. D. Mulligan, M. T. Flowers, A. Tebon, J. J. Bitgood, C. Wellington, M. R. Hayden, and A. D. Attie ABCA1 Is Essential for Efficient Basolateral Cholesterol Efflux during the Absorption of Dietary Cholesterol in Chickens J. Biol. Chem., April 4, 2003; 278(15): 13356 - 13366. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Sun, M. Hao, Y. Luo, C.-p. Liang, D. L. Silver, C. Cheng, F. R. Maxfield, and A. R. Tall Stearoyl-CoA Desaturase Inhibits ATP-binding Cassette Transporter A1-mediated Cholesterol Efflux and Modulates Membrane Domain Structure J. Biol. Chem., February 14, 2003; 278(8): 5813 - 5820. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Feng and I. Tabas ABCA1-mediated Cholesterol Efflux Is Defective in Free Cholesterol-loaded Macrophages. MECHANISM INVOLVES ENHANCED ABCA1 DEGRADATION IN A PROCESS REQUIRING FULL NPC1 ACTIVITY J. Biol. Chem., November 1, 2002; 277(45): 43271 - 43280. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. T. Reddy, S. Hama, C. Ng, V. Grijalva, M. Navab, and A. M. Fogelman ATP-Binding Cassette Transporter 1 Participates in LDL Oxidation by Artery Wall Cells Arterioscler Thromb Vasc Biol, November 1, 2002; 22(11): 1877 - 1883. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. K. Tangirala, E. D. Bischoff, S. B. Joseph, B. L. Wagner, R. Walczak, B. A. Laffitte, C. L. Daige, D. Thomas, R. A. Heyman, D. J. Mangelsdorf, et al. Identification of macrophage liver X receptors as inhibitors of atherosclerosis PNAS, September 3, 2002; 99(18): 11896 - 11901. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||