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Alan R Tall - One of the best experts on this subject based on the ideXlab platform.
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deletion of ABCA1 and abcg1 impairs macrophage migration because of increased rac1 signaling
Circulation Research, 2011Co-Authors: Tamara A Pagler, Kathryn J Moore, Mi Wang, Mousumi Mondal, Andrew J Murphy, Marit Westerterp, Frederick R Maxfield, Alan R TallAbstract:RATIONALE: Reduced plasma cholesterol and increased high-density lipoprotein (HDL) levels promote regression of atherosclerosis, in a process characterized by lipid unloading and emigration of macrophages from lesions. In contrast free cholesterol loading of macrophages leads to imbalanced Rac1/Rho activities and impaired chemotaxis. OBJECTIVE: To study the role of HDL and the ATP-binding cassette transporters ABCA1 and ABCG1 in modulating the chemotaxis of macrophages. METHODS AND RESULTS: ABCA1(-/-)Abcg1(-/-) mouse macrophages displayed profoundly impaired chemotaxis both in a Transwell chamber assay and in the peritoneal cavity of wild-type (WT) mice. HDL reversed impaired chemotaxis in free cholesterol-loaded WT macrophages but was without effect in ABCA1(-/-)Abcg1(-/-) cells, whereas cyclodextrin was effective in both. ABCA1(-/-)Abcg1(-/-) macrophages had markedly increased Rac1 activity and increased association of Rac1 with the plasma membrane (PM). Their defective chemotaxis was reversed by a Rac1 inhibitor. To gain a better understanding of the role of transporters in PM cholesterol movement, we measured transbilayer PM sterol distribution. In WT macrophages, the majority of cholesterol was located on the inner leaflet, whereas on upregulation of transporters by liver X receptor activation, PM sterol was shifted to the outer leaflet, where it could be removed by HDL. ABCA1(-/-)Abcg1(-/-) macrophages showed increased PM sterol content and defective redistribution of sterol to the outer leaflet. CONCLUSIONS: Deletion of ABCA1 and ABCG1 causes an increased cholesterol content on the inner leaflet of the PM, associated with increased Rac1 PM localization, activation, and impairment of migration. ABCA1 and ABCG1 facilitate macrophage chemotaxis by promoting PM transbilayer cholesterol movement and may contribute to the ability of HDL to promote regression of atherosclerosis.
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ABCA1 and abcg1 protect against oxidative stress induced macrophage apoptosis during efferocytosis
Circulation Research, 2010Co-Authors: Laurent Yvancharvet, Carrie L Welch, Tamara A Pagler, Tracie A Seimon, Edward B Thorp, Joseph L Witztum, Ira Tabas, Alan R TallAbstract:Rationale: Antiatherogenic effects of plasma high-density lipoprotein (HDL) include the ability to inhibit apoptosis of macrophage foam cells. The ATP-binding cassette transporters ABCA1 and ABCG1 have a major role in promoting cholesterol efflux from macrophages to apolipoprotein A-1 and HDL and are upregulated during the phagocytosis of apoptotic cells (efferocytosis). Objective: The goal of this study was to determine the roles of ABCA1 and ABCG1 in preserving the viability of macrophages during efferocytosis. Methods and Results: We show that despite similar clearance of apoptotic cells, peritoneal macrophages from ABCA1 −/− Abcg1 −/−, Abcg1 −/−, and, to a lesser extent, ABCA1 −/− mice are much more prone to apoptosis during efferocytosis compared to wild-type cells. Similar findings were observed following incubations with oxidized phospholipids, and the ability of HDL to protect against oxidized phospholipid-induced apoptosis was markedly reduced in ABCA1 −/− Abcg1 −/− and Abcg1 −/− cells. These effects were independent of any role of ABCA1 and ABCG1 in mediating oxidized phospholipid efflux but were reversed by cyclodextrin-mediated cholesterol efflux. The apoptotic response observed in ABCA1 −/− Abcg1 −/− macrophages after oxidized phospholipid exposure or engulfment of apoptotic cells was dependent on an excessive oxidative burst secondary to enhanced assembly of NADPH oxidase (NOX)2 complexes, leading to sustained Jnk activation which turned on the apoptotic cell death program. Increased NOX2 assembly required Toll-like receptors 2/4 and MyD88 signaling, which are known to be enhanced in transporter deficient cells in a lipid raft–dependent fashion. Conclusions: We identified a new beneficial role of ABCA1, ABCG1 and HDL in dampening the oxidative burst and preserving viability of macrophages following exposure to oxidized phospholipids and/or apoptotic cells.
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role of hdl ABCA1 and abcg1 transporters in cholesterol efflux and immune responses
Arteriosclerosis Thrombosis and Vascular Biology, 2010Co-Authors: Laurent Yvancharvet, Nan Wang, Alan R TallAbstract:Atherosclerosis has been characterized as a chronic inflammatory response to cholesterol deposition in arteries, but the mechanisms linking cholesterol accumulation in macrophage foam cells to inflammation are poorly understood. Macrophage cholesterol efflux occurs at all stages of atherosclerosis and protects cells from free cholesterol and oxysterol-induced toxicity. The ATP-binding cassette transporters ABCA1 and ABCG1 are responsible for the major part of macrophage cholesterol efflux to serum or HDL in macrophage foam cells, but other less efficient pathways such as passive efflux are also involved. Recent studies have shown that the sterol efflux activities of ABCA1 and ABCG1 modulate macrophage expression of inflammatory cytokines and chemokines as well as lymphocyte proliferative responses. In macrophages, transporter deficiency causes increased signaling via various Toll-like receptors including TLR4. These studies have shown that the traditional roles of HDL and ABC transporters in cholesterol efflux and reverse cholesterol transport are mechanistically linked to antiinflammatory and immunosuppressive functions of HDL. The underlying mechanisms may involve modulation of sterol levels and lipid organization in cell membranes.
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increased inflammatory gene expression in abc transporter deficient macrophages free cholesterol accumulation increased signaling via toll like receptors and neutrophil infiltration of atherosclerotic lesions
Circulation, 2008Co-Authors: Laurent Yvancharvet, Carrie L Welch, Tamara A Pagler, Mollie Ranalletta, Mohamed Lamkanfi, Minako Ishibashi, Nan Wang, Rong Li, Alan R TallAbstract:Background— Two macrophage ABC transporters, ABCA1 and ABCG1, have a major role in promoting cholesterol efflux from macrophages. Peritoneal macrophages deficient in ABCA1, ABCG1, or both show enhanced expression of inflammatory and chemokine genes. This study was undertaken to elucidate the mechanisms and consequences of enhanced inflammatory gene expression in ABC transporter–deficient macrophages. Methods and Results— Basal and lipopolysaccharide-stimulated thioglycollate-elicited peritoneal macrophages showed increased inflammatory gene expression in the order ABCA1−/−Abcg1−/−>Abcg1−/−>ABCA1−/−>wild-type. The increased inflammatory gene expression was abolished in macrophages deficient in Toll-like receptor 4 (TLR4) or MyD88/TRIF. TLR4 cell surface concentration was increased in ABCA1−/−Abcg1−/−>Abcg1−/−> ABCA1−/−> wild-type macrophages. Treatment of transporter-deficient cells with cyclodextrin reduced and cholesterol-cyclodextrin loading increased inflammatory gene expression. ABCA1−/−Abcg1− bone ma...
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combined deficiency of ABCA1 and abcg1 promotes foam cell accumulation and accelerates atherosclerosis in mice
Journal of Clinical Investigation, 2007Co-Authors: Laurent Yvancharvet, Carrie L Welch, Mollie Ranalletta, Nan Wang, Rong Li, Naoki Terasaka, Alan R TallAbstract:HDLs protect against the development of atherosclerosis, but the underlying mechanisms are poorly understood. HDL and its apolipoproteins can promote cholesterol efflux from macrophage foam cells via the ATP-binding cassette transporters ABCA1 and ABCG1. Experiments addressing the individual roles of ABCA1 and ABCG1 in the development of atherosclerosis have produced mixed results, perhaps because of compensatory upregulation in the individual KO models. To clarify the role of transporter-mediated sterol efflux in this disease process, we transplanted BM from ABCA1–/–Abcg1–/– mice into LDL receptor–deficient mice and administered a high-cholesterol diet. Compared with control and single-KO BM recipients, ABCA1–/–Abcg1–/– BM recipients showed accelerated atherosclerosis and extensive infiltration of the myocardium and spleen with macrophage foam cells. In experiments with isolated macrophages, combined ABCA1 and ABCG1 deficiency resulted in impaired cholesterol efflux to HDL or apoA-1, profoundly decreased apoE secretion, and increased secretion of inflammatory cytokines and chemokines. In addition, these cells showed increased apoptosis when challenged with free cholesterol or oxidized LDL loading. These results suggest that the combined effects of ABCA1 and ABCG1 in mediating macrophage sterol efflux are central to the antiatherogenic properties of HDL.
Tetsuya Terasaki - One of the best experts on this subject based on the ideXlab platform.
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expression of nuclear receptor mrna and liver x receptor mediated regulation of abc transporter a1 at rat blood brain barrier
Neurochemistry International, 2008Co-Authors: Shin Ichi Akanuma, Sumio Ohtsuki, Masachika Fujiyoshi, Satoko Hori, Tetsuya TerasakiAbstract:Abstract The aim of the present study was to investigate the expression of nuclear receptor mRNA and regulation of the expression of ATP-binding cassette (ABC) transporters by nuclear receptor agonists in rat brain capillary endothelial cells, which form the blood–brain barrier, by using rat brain capillary fraction from 8-week-old rats and a conditionally immortalized brain capillary endothelial cell line (TR-BBB13). RT-PCR analysis revealed that liver X receptor α and β, retinoid X receptor α and β and peroxisome proliferator-activating receptor α and β mRNAs were expressed in the rat brain capillary endothelial cells and TR-BBB cells. In contrast, pregnane X receptor, farnesoid X receptor and constitutive androstane receptor were not detected. Furthermore, treatment with a liver X receptor agonist increased the ABCA1 mRNA level in TR-BBB13 cells, while ABCG2 mRNA expression was not affected. Treatment with a rat pregnane X receptor agonist did not affect the ABCB1 mRNA level in TR-BBB13 cells. These results demonstrate that the rat blood–brain barrier has an expressional regulation mechanism via sterol-related nuclear receptor, and indicate that the blood–brain barrier in 8-week-old rats lacks ABCB1 regulation via pregnane X receptor.
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Expression of nuclear receptor mRNA and liver X receptor-mediated regulation of ABC transporter A1 at rat blood-brain barrier.
Neurochemistry international, 2007Co-Authors: Shin Ichi Akanuma, Sumio Ohtsuki, Masachika Fujiyoshi, Satoko Hori, Tetsuya TerasakiAbstract:The aim of the present study was to investigate the expression of nuclear receptor mRNA and regulation of the expression of ATP-binding cassette (ABC) transporters by nuclear receptor agonists in rat brain capillary endothelial cells, which form the blood-brain barrier, by using rat brain capillary fraction from 8-week-old rats and a conditionally immortalized brain capillary endothelial cell line (TR-BBB13). RT-PCR analysis revealed that liver X receptor alpha and beta, retinoid X receptor alpha and beta and peroxisome proliferator-activating receptor alpha and beta mRNAs were expressed in the rat brain capillary endothelial cells and TR-BBB cells. In contrast, pregnane X receptor, farnesoid X receptor and constitutive androstane receptor were not detected. Furthermore, treatment with a liver X receptor agonist increased the ABCA1 mRNA level in TR-BBB13 cells, while ABCG2 mRNA expression was not affected. Treatment with a rat pregnane X receptor agonist did not affect the ABCB1 mRNA level in TR-BBB13 cells. These results demonstrate that the rat blood-brain barrier has an expressional regulation mechanism via sterol-related nuclear receptor, and indicate that the blood-brain barrier in 8-week-old rats lacks ABCB1 regulation via pregnane X receptor.
Trond Berg - One of the best experts on this subject based on the ideXlab platform.
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ABCA1, ABCG1 and SR-BI: hormonal regulation in primary rat hepatocytes and human cell lines
BMC Molecular Biology, 2007Co-Authors: Marita Sporstøl, Winnie Eskild, Norbert Roos, Seyed Ali Mousavi, Trond BergAbstract:Background Scavenger receptor type B class I (SR-BI), ABC transporter A1 (ABCA1) -and G1 (ABCG1) all play important roles in the reverse cholesterol transport. Reverse cholesterol transport is a mechanism whereby the body can eliminate excess cholesterol. Here, the regulation of SR-BI, ABCA1, and ABCG1 by dexamethasone (a synthetic glucocorticoid) and insulin were studied in order to gain more insight into the role of these two hormones in the cholesterol metabolism.
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ABCA1, ABCG1 and SR-BI: hormonal regulation in primary rat hepatocytes and human cell lines
BMC Molecular Biology, 2007Co-Authors: Marita Sporstøl, Winnie Eskild, Norbert Roos, Seyed Ali Mousavi, Trond BergAbstract:Background Scavenger receptor type B class I (SR-BI), ABC transporter A1 (ABCA1) -and G1 (ABCG1) all play important roles in the reverse cholesterol transport. Reverse cholesterol transport is a mechanism whereby the body can eliminate excess cholesterol. Here, the regulation of SR-BI, ABCA1, and ABCG1 by dexamethasone (a synthetic glucocorticoid) and insulin were studied in order to gain more insight into the role of these two hormones in the cholesterol metabolism. Results By use of real time RT-PCR and Western blotting we examined the expression of our target genes. The results show that SR-BI, ABCA1 and ABCG1 mRNA expression increased in response to dexamethasone while insulin treatment reduced the expression in primary rat hepatocytes. The stimulatory effect of dexamethasone was reduced by the addition of the anti-glucocorticoid mifepristone. In HepG2 cells and THP-1 macrophages, however, the effect of dexamethasone was absent or inhibitory with no significant change in the presence of mifepristone. The latter observation may be a result of the low protein expression of glucocorticoid receptor (GR) in these cell lines. Conclusion Our results illustrates that insulin and glucocorticoids, two hormones crucial in the carbohydrate metabolism, also play an important role in the regulation of genes central in reverse cholesterol transport. We found a marked difference in mRNA expression between the primary cells and the two established cell lines when studying the effect of dexamethasone which may result from the varying expression levels of GR.
Andrew J. Brown - One of the best experts on this subject based on the ideXlab platform.
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the e3 ubiquitin ligases huwe1 and nedd4 1 are involved in the post translational regulation of the abcg1 and abcg4 lipid transporters
Journal of Biological Chemistry, 2015Co-Authors: Shereen M Aleidi, Laura J. Sharpe, Andrew J. Brown, Vicky Howe, Alryel Yang, Ingrid C GelissenAbstract:The ATP-binding cassette transporter ABCG1 has an essential role in cellular cholesterol homeostasis, and dysregulation has been associated with a number of high burden diseases. Previous studies reported that ABCG1 is ubiquitinated and degraded via the ubiquitin proteasome system. However, so far the molecular mechanism, including the identity of any of the rate-limiting ubiquitination enzymes, or E3 ligases, is unknown. Using liquid chromatography mass spectrometry, we identified two HECT domain E3 ligases associated with ABCG1, named HUWE1 (HECT, UBA, and WWE domain containing 1, E3 ubiquitin protein ligase) and NEDD4-1 (Neural precursor cell-expressed developmentally down regulated gene 4), of which the latter is the founding member of the NEDD4 family of ubiquitin ligases. Silencing both HUWE1 and NEDD4-1 in cells overexpressing human ABCG1 significantly increased levels of the ABCG1 monomeric and dimeric protein forms, however ABCA1 protein expression was unaffected. In addition, ligase silencing increased ABCG1-mediated cholesterol export to HDL in cells overexpressing the transporter as well as in THP-1 macrophages. Reciprocally, overexpression of both ligases resulted in a significant reduction in protein levels of both the ABCG1 monomeric and dimeric forms. Like ABCG1, ABCG4 protein levels and cholesterol export activity were significantly increased after silencing both HUWE1 and NEDD4-1 in cells overexpressing this closely related ABC half-transporter. In summary, we have identified for the first time two E3 ligases that are fundamental enzymes in the post-translational regulation of ABCG1 and ABCG4 protein levels and cellular cholesterol export activity.
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cellular cholesterol regulates ubiquitination and degradation of the cholesterol export proteins ABCA1 and abcg1
Journal of Biological Chemistry, 2014Co-Authors: Victar Hsieh, Andrew J. Brown, Ingrid C Gelissen, Wendy Jessup, Cecilia Sandoval, Jeannette C Hallab, Maaike Kockx, Mathew Traini, Leonard KritharidesAbstract:The objective of this study was to examine the influence of cholesterol in post-translational control of ABCA1 and ABCG1 protein expression. Using CHO cell lines stably expressing human ABCA1 or ABCG1, we observed that the abundance of these proteins is increased by cell cholesterol loading. The response to increased cholesterol is rapid, is independent of transcription, and appears to be specific for these membrane proteins. The effect is mediated through cholesterol-dependent inhibition of transporter protein degradation. Cell cholesterol loading similarly regulates degradation of endogenously expressed ABCA1 and ABCG1 in human THP-1 macrophages. Turnover of ABCA1 and ABCG1 is strongly inhibited by proteasomal inhibitors and is unresponsive to inhibitors of lysosomal proteolysis. Furthermore, cell cholesterol loading inhibits ubiquitination of ABCA1 and ABCG1. Our findings provide evidence for a rapid, cholesterol-dependent, post-translational control of ABCA1 and ABCG1 protein levels, mediated through a specific and sterol-sensitive mechanism for suppression of transporter protein ubiquitination, which in turn decreases proteasomal degradation. This provides a mechanism for acute fine-tuning of cholesterol transporter activity in response to fluctuations in cell cholesterol levels, in addition to the longer term cholesterol-dependent transcriptional regulation of these genes.
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The UPS and downs of cholesterol homeostasis
Trends in Biochemical Sciences, 2014Co-Authors: Laura J. Sharpe, Emma C L Cook, Noam Zelcer, Andrew J. BrownAbstract:An emerging theme in the regulation of cholesterol homeostasis is the role of the ubiquitin proteasome system (UPS), through which proteins are ubiquitylated and then degraded in response to specific signals. The UPS controls all aspects of cholesterol metabolism including its synthesis, uptake, and efflux. We review here recent work uncovering the ubiquitylation and degradation of key players in cholesterol homeostasis. This includes the low-density lipoprotein (LDL) receptor, transcription factors (sterol regulatory element binding proteins and liver X receptors), flux-controlling enzymes in cholesterol synthesis (3-hydroxy-3-methylglutaryl-CoA reductase and squalene monooxygenase), and cholesterol exporters (ATP-binding cassette transporters ABCA1 and ABCG1). We explore which E3 ligases are involved, and identify areas deserving of further research.
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osbp related protein 8 orp8 suppresses ABCA1 expression and cholesterol efflux from macrophages
Journal of Biological Chemistry, 2008Co-Authors: Mikko I Mayranpaa, Andrew J. Brown, Jenny Wong, Julia Perttila, Markku Lehto, Matti Jauhiainen, Petri T Kovanen, Christian Ehnholm, Vesa M OlkkonenAbstract:Abstract ORP8 is a previously unexplored member of the family of oxysterol-binding protein-related proteins (ORP). We now report the expression pattern, the subcellular distribution, and data on the ligand binding properties and the physiological function of ORP8. ORP8 is localized in the endoplasmic reticulum (ER) via its C-terminal transmembrane span and binds 25-hydroxycholesterol, identifying it as a new ER oxysterol-binding protein. ORP8 is expressed at highest levels in macrophages, liver, spleen, kidney, and brain. Immunohistochemical analysis revealed ORP8 in the shoulder regions of human coronary atherosclerotic lesions, where it is present in CD68(+) macrophages. In advanced lesions the ORP8 mRNA was up-regulated 2.7-fold as compared with healthy coronary artery wall. Silencing of ORP8 by RNA interference in THP-1 macrophages increased the expression of ATP binding cassette transporter A1 (ABCA1) and concomitantly cholesterol efflux to lipid-free apolipoprotein A-I but had no significant effect on ABCG1 expression or cholesterol efflux to spherical high density lipoprotein HDL2. Experiments employing an ABCA1 promoter-luciferase reporter confirmed that ORP8 silencing enhances ABCA1 transcription. The silencing effect was partially attenuated by mutation of the DR4 element in the ABCA1 promoter and synergized with that of the liver X receptor agonist T0901317. Furthermore, inactivation of the E-box in the promoter synergized with ORP8 silencing, suggesting that the suppressive effect of ORP8 involves both the liver X receptor and the E-box functions. Our data identify ORP8 as a negative regulator of ABCA1 expression and macrophage cholesterol efflux. ORP8 may, thus, modulate the development of atherosclerosis.
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ABCA1 and abcg1 synergize to mediate cholesterol export to apoa i
Arteriosclerosis Thrombosis and Vascular Biology, 2005Co-Authors: Ingrid C Gelissen, Andrew J. Brown, Maaike Kockx, Leonard Kritharides, Matthew J Harris, Carmel M Quinn, Sian Cartland, Mathana Packianathan, Wendy JessupAbstract:Objective— To study the acceptor specificity for human ABCG1 (hABCG1)-mediated cholesterol efflux. Methods and Results— Cells overexpressing hABCG1 were created in Chinese Hamster Ovary (CHO-K1) cells and characterized in terms of lipid composition. hABCG1 expressed in these cells formed homodimers and was mostly present intracellularly. Cholesterol efflux from hABCG1 cells to HDL 2 and HDL 3 was increased but not to lipid-free apolipoproteins. A range of phospholipid containing acceptors apart from high-density lipoprotein (HDL) subclasses were also efficient in mediating ABCG1-dependent export of cholesterol. Importantly, a buoyant phospholipid-containing fraction generated from incubation of lipid-free apoA-I with macrophages was nearly as efficient as HDL 2 . The capacity of acceptors to induce ABCG1-mediated efflux was strongly correlated with their total phospholipid content, suggesting that acceptor phospholipids drive ABCG1-mediated efflux. Most importantly, acceptors for ABCG1-mediated cholesterol export could be generated from incubation of cells with lipid-free apoA-I through the action of ABCA1 alone. Conclusions— These results indicate a synergistic relationship between ABCA1 and ABCG1 in peripheral tissues, where ABCA1 lipidates any lipid-poor/free apoA-I to generate nascent or pre–β-HDL. These particles in turn may serve as substrates for ABCG1-mediated cholesterol export.
Alan T. Remaley - One of the best experts on this subject based on the ideXlab platform.
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increased cholesterol efflux capacity in metabolic syndrome relation with qualitative alterations in hdl and lcat
Atherosclerosis, 2015Co-Authors: Alan T. Remaley, Lita A Freeman, Diego Lucero, Denis Sviridov, Graciela Lopez, Eduardo Fassio, Laura SchreierAbstract:Abstract Background Metabolic syndrome (MetS) is associated with changes in HDL levels, composition and sub-fraction profile. Whether these alterations affect HDL anti-atherogenic function, specifically measured as its capacity to perform cholesterol efflux, is not yet clearly known. Objective To evaluate the relation between serum cholesterol efflux capacity and the changes in HDL composition and sub-fraction profile in MetS. Methods In 35 non-treated MetS patients and 15 healthy controls, HDL mediated cholesterol efflux was measured as the ability of apoB-depleted serum to accept cholesterol from cholesterol-loaded BHK cells expressing either ABCA1 or ABCG1. Additionally we determined: lipid profile, HDL sub-fractions (NMR) and LCAT mass (ELISA). Isolated HDL (δ:1.063–1.210 g/mL) was chemically characterized. Pre-β1-HDL was determined by 2D-electrophoresis in a sub-group of MetS and controls (n = 6 each). Results Surprisingly, MetS patients presented higher ABCA1 mediated cholesterol efflux (10.4 ± 1.8 vs. 8.7 ± 0.3%; p = 0.0001), without differences in ABCG1 efflux. In MetS, HDL showed reduction in particle size and number (p Conclusion This is the first description of ABCA1 mediated cholesterol efflux in MetS. Regardless the reduced HDL-cholesterol, in vitro cholesterol efflux capacity by ABCA1 was enhanced, linked to increased pre-β1-HDL and slightly reduced in LCAT mass that would probably reflect a delay in reverse cholesterol transport occurring in MetS.
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ABCA1 contributes to macrophage deposition of extracellular cholesterol
Journal of Lipid Research, 2015Co-Authors: Sebastian R. Freeman, Boris L. Vaisman, Janet Chang, Neta Varsano, Lia Addadi, Alan T. Remaley, Howard S. KruthAbstract:: We previously reported that cholesterol-enriched macrophages excrete cholesterol into the extracellular matrix. A monoclonal antibody that detects cholesterol microdomains labels the deposited extracellular particles. Macro-phage deposition of extracellular cholesterol depends, in part, on ABCG1, and this cholesterol can be mobilized by HDL components of the reverse cholesterol transport process. The objective of the current study was to determine whether ABCA1 also contributes to macrophage deposition of extracellular cholesterol. ABCA1 functioned in extracellular cholesterol deposition. The liver X receptor agonist, TO901317 (TO9), an ABCA1-inducing factor, restored cholesterol deposition that was absent in cholesterol-enriched ABCG1(-/-) mouse macrophages. In addition, the ABCA1 inhibitor, probucol, blocked the increment in cholesterol deposited by TO9-treated wild-type macrophages, and completely inhibited deposition from TO9-treated ABCG1(-/-) macrophages. Lastly, ABCA1(-/-) macrophages deposited much less extracellular cholesterol than wild-type macrophages. These findings demonstrate a novel function of ABCA1 in contributing to macrophage export of cholesterol into the extracellular matrix.
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high density lipoprotein induces proliferation and migration of human prostate androgen independent cancer cells by an ABCA1 dependent mechanism
Molecular Cancer Research, 2010Co-Authors: Yoshitaka Sekine, John A Stonik, Steve J Demosky, Yosuke Furuya, Hidekazu Koike, Kazuhiro Suzuki, Alan T. RemaleyAbstract:Androgen deprivation therapy for prostate cancer leads to a significant increase of high-density lipoprotein (HDL), which is generally viewed as beneficial, particularly for cardiovascular disease, but the effect of HDL on prostate cancer is unknown. In this study, we investigated the effect of HDL on prostate cancer cell proliferation, migration, intracellular cholesterol levels, and the role of cholesterol transporters, namely ABCA1, ABCG1, and SR-BI in these processes. HDL induced cell proliferation and migration of the androgen-independent PC-3 and DU145 cells by a mechanism involving extracellular signal-regulated kinase (ERK) 1/2 and Akt, but had no effect on the androgen-dependent LNCaP cell, which did not express ABCA1 unlike the other cell lines. Treatment with HDL did not significantly alter the cholesterol content of the cell lines. Knockdown of ABCA1 but not ABCG1 or SR-BI by small interfering RNA (siRNA) inhibited HDL-induced cell proliferation, migration, and ERK1/2 and Akt signal transduction in PC-3 cells. Moreover, after treatment of LNCaP cells with charcoal-stripped fetal bovine serum, ABCA1 was induced ∼10-fold, enabling HDL to induce ERK1/2 activation, whereas small interfering RNA knockdown of ABCA1 inhibited HDL-induced ERK1/2 activation. Simvastatin, which inhibited ABCA1 expression in PC-3 and DU145 cells, attenuated HDL-induced PC-3 and DU145 cell proliferation, migration, and ERK1/2 and Akt phosphorylation. In human prostate biopsy samples, ABCA1 mRNA expression was ∼2-fold higher in the androgen deprivation therapy group than in subjects with benign prostatic hyperplasia or pretreatment prostate cancer groups. In summary, these results suggest that HDL by an ABCA1-dependent mechanism can mediate signal transduction, leading to increased proliferation and migration of prostate cancer cells. Mol Cancer Res; 8(9); 1284–94. ©2010 AACR.
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role of the hepatic ABCA1 transporter in modulating intrahepatic cholesterol and plasma hdl cholesterol concentrations
Journal of Lipid Research, 2003Co-Authors: Federica Basso, Alan T. Remaley, Marcelo Amar, Jamila Fruchartnajib, Lita A Freeman, Catherine L Knapper, John A Stonik, Edward B Neufeld, Terese R Tansey, Nicholas DuvergerAbstract:The current model for reverse cholesterol trans- port proposes that HDL transports excess cholesterol de- rived primarily from peripheral cells to the liver for re- moval. However, recent studies in ABCA1 transgenic mice suggest that the liver itself may be a major source of HDL cholesterol (HDL-C). To directly investigate the hepatic con- tribution to plasma HDL-C levels, we generated an adeno- virus (rABCA1-GFP-AdV) that targets expression of mouse ABCA1-GFP in vivo to the liver. Compared with mice in- jected with control AdV, infusion of rABCA1-GFP-AdV into C57Bl/6 mice resulted in increased expression of mouse ABCA1 mRNA and protein in the liver. ApoA-I-dependent cholesterol efflux was increased 2.6-fold in primary hepato- cytes isolated 1 day after rABCA1-GFP-AdV infusion. He- patic ABCA1 expression in C57Bl/6 mice (n � 15) raised baseline levels of TC, PL, FC, HDL-C, apoE, and apoA-I by 150-300% ( P � 0.05 all). ABCA1 expression led to sig- nificant compensatory changes in expression of genes that increase hepatic cholesterol, including HMG-CoA reduc- tase (3.5-fold), LDLr (2.1-fold), and LRP (5-fold) in the liver. These combined results demonstrate that ABCA1 plays a key role in hepatic cholesterol efflux, inducing path- ways that modulate cholesterol homeostasis in the liver, and establish the liver as a major source of plasma HDL-C. — Basso, F., L. Freeman, C. L. Knapper, A. Remaley, J. Stonik, E. B. Neufeld, T. Tansey, M. J. A. Amar, J. Fruchart-Najib, N. Duverger, S. Santamarina-Fojo, and H. B. Brewer, Jr. Role of the hepatic ABCA1 transporter in modulating intrahepatic cholesterol and plasma HDL cholesterol concentrations. J. Lipid Res. 2003. 44: 296-302.
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the atp binding cassette transporter a1 ABCA1 modulates the development of aortic atherosclerosis in c57bl 6 and apoe knockout mice
Proceedings of the National Academy of Sciences of the United States of America, 2002Co-Authors: Charles Joyce, Alan T. Remaley, Marcelo Amar, Gilles Lambert, Boris Vaisman, Beverly Paigen, Jamila Najibfruchart, Robert F Hoyt, Edward D Neufeld, Donald S FredricksonAbstract:Abstract Identification of mutations in the ABCA1 transporter (ABCA1) as the genetic defect in Tangier disease has generated interest in modulating atherogenic risk by enhancing ABCA1 gene expression. To investigate the role of ABCA1 in atherogenesis, we analyzed diet-induced atherosclerosis in transgenic mice overexpressing human ABCA1 (hABCA1-Tg) and spontaneous lesion formation in hABCA1-Tg × apoE-knockout (KO) mice. Overexpression of hABCA1 in C57BL/6 mice resulted in a unique anti-atherogenic profile characterized by decreased plasma cholesterol (63%), cholesteryl ester (63%), free cholesterol (67%), non-high density lipoprotein (HDL)-cholesterol (53%), and apolipoprotein (apo) B (64%) but markedly increased HDL-cholesterol (2.8-fold), apoA-I (2.2-fold), and apoE (2.8-fold) levels. These beneficial changes in the lipid profile led to significantly lower (65%) aortic atherosclerosis in hABCA1-Tg mice. In marked contrast, ABCA1 overexpression had a minimal effect on the plasma lipid profile of apoE-KO mice and resulted in a 2- to 2.6-fold increase in aortic lesion area. These combined results indicate that overexpression of ABCA1 in C57BL/6 mice on a high cholesterol diet results in an atheroprotective lipoprotein profile and decreased atherosclerosis, and thus provide previously undocumented in vivo evidence of an anti-atherogenic role for the ABCA1 transporter. In contrast, overexpression of ABCA1 in an apoE-KO background led to increased atherosclerosis, further substantiating the important role of apoE in macrophage cholesterol metabolism and atherogenesis. In summary, these results establish that, in the presence of apoE, overexpression of ABCA1 modulates HDL as well as apoB-containing lipoprotein metabolism and reduces atherosclerosis in vivo, and indicate that pharmacological agents that will increase ABCA1 expression may reduce atherogenic risk in humans.
