The Experts below are selected from a list of 4311 Experts worldwide ranked by ideXlab platform
Alan R Tall - One of the best experts on this subject based on the ideXlab platform.
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Abstract 523: Regulation of Pancreatic β-cell Gene Expression and Function by ABCA1 and ABCG1
Arteriosclerosis Thrombosis and Vascular Biology, 2015Co-Authors: Liming Hou, Alan R Tall, Marit Westerterp, Fatiha Tabet, Blake J. Cochran, Philip J. Barter, Kerry-anne RyeAbstract:Background: Loss-of-function mutations in the ABCA1 gene cause beta cell dysfunction in humans. Insulin secretion is impaired and glucose metabolism is adversely affected in mice with conditional deletion of ABCA1 in beta cells and in ABCG1 knockout mice. These effects are exacerbated in mice with conditional beta cell ABCA1 deletion plus global ABCG1 deficiency. To identify key beta cell pathways regulated by ABCA1 and ABCG1, we generated mice with beta cell-specific deletion of ABCA1 and ABCG1 (ABCA1β-cell-/-/ABCG1βcell-/- DKO mice). Aim: Identification of genes in key beta cell metabolic and signal transduction pathways that are regulated by ABCA1 and ABCG1. Methods: Islets were isolated from 16 week old chow fed ABCA1β-cell-/-/ABCG1β-cell-/- DKO mice. mRNA was extracted and subjected to Affymetrix GeneChip Mouse Gene ST 2.0 analysis, followed by Partek Genomics Suite and Ingeunity Pathway analysis. Islet cholesterol levels were determined by HPLC. Plasma and HDL cholesterol levels were measured enzyma...
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deletion of abca1 and ABCG1 impairs macrophage migration because of increased rac1 signaling
Circulation Research, 2011Co-Authors: Tamara A Pagler, Mousumi Mondal, Kathryn J Moore, Marit Westerterp, Andrew J. Murphy, Frederick R Maxfield, Mi Wang, 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, Edward B Thorp, Ira Tabas, Joseph L Witztum, Tracie A Seimon, 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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The Role ABCG1 in Cellular Cholesterol Efflux: Relevance to Atherosclerosis and Endothelial Function
High Density Lipoproteins Dyslipidemia and Coronary Heart Disease, 2010Co-Authors: Alan R TallAbstract:The ability of HDL to promote the efflux of cholesterol from macrophage foam cells is thought to be central to its antiatherogenic properties. The active transport of cholesterol from macrophage foam cells to plasma HDL or apoA-1 is mediated by ABCG1 or ABCA1, respectively. In most reports, transplantation of ABCG1−/− bone marrow in atherosclerosis-susceptible recipient mice results in unchanged or reduced atherosclerosis, reflecting compensatory upregulation of ABCA1 or increased apoptosis of ABCG1 deficient macrophages. Transplantation of ABCA1−/−ABCG1−/− bone marrow in LDL receptor deficient mice results in dramatic leukocytosis, infiltration of multiple organs with foam cells, and neutrophils and accelerated atherosclerosis. ABCG1 is also highly expressed in endothelial cells and has a major role in efflux of cholesterol and 7-oxysterols. ABCG1−/− mice display markedly impaired endothelium-dependent relaxation, reflecting reduced formation of the active, dimeric form of eNOS. The combined activities of ABCA1 and ABCG1 have important antiatherogenic and anti-inflammatory roles, acting in both macrophage foam cells and endothelium.
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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, Minako Ishibashi, Mohamed Lamkanfi, Rong Li, Nan Wang, 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...
Peter A. Edwards - One of the best experts on this subject based on the ideXlab platform.
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dancing with the sterols critical roles for ABCG1 abca1 mirnas and nuclear and cell surface receptors in controlling cellular sterol homeostasis
Biochimica et Biophysica Acta, 2012Co-Authors: Elizabeth J Tarling, Peter A. EdwardsAbstract:Abstract ATP binding cassette (ABC) transporters represent a large and diverse family of proteins that transport specific substrates across a membrane. The importance of these transporters is illustrated by the finding that inactivating mutations within 17 different family members are known to lead to specific human diseases. Clinical data from humans and/or studies with mice lacking functional transporters indicate that ABCA1, ABCG1, ABCG4, ABCG5 and ABCG8 are involved in cholesterol and/or phospholipid transport. This review discusses the multiple mechanisms that control cellular sterol homeostasis, including the roles of microRNAs, nuclear and cell surface receptors and ABC transporters, with particular emphasis on recent findings that have provided insights into the role(s) of ABCG1. This article is part of a Special Issue entitled Advances in High Density Lipoprotein Formation and Metabolism: A Tribute to John F. Oram (1945–2010).
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ATP binding cassette transporter G1 (ABCG1) is an intracellular sterol transporter
Proceedings of the National Academy of Sciences of the United States of America, 2011Co-Authors: Elizabeth J Tarling, Peter A. EdwardsAbstract:Four members of the mammalian ATP binding cassette (ABC) transporter G subfamily are thought to be involved in transmembrane (TM) transport of sterols. The residues responsible for this transport are unknown. The mechanism of action of ABCG1 is controversial and it has been proposed to act at the plasma membrane to facilitate the efflux of cellular sterols to exogenous high-density lipoprotein (HDL). Here we show that ABCG1 function is dependent on localization to intracellular endosomes. Importantly, localization to the endosome pathway distinguishes ABCG1 and/or ABCG4 from all other mammalian members of this superfamily, including other sterol transporters. We have identified critical residues within the TM domains of ABCG1 that are both essential for sterol transport and conserved in some other members of the ABCG subfamily and/or the insulin-induced gene 2 (INSIG-2). Our conclusions are based on studies in which (i) biotinylation of peritoneal macrophages showed that endogenous ABCG1 is intracellular and undetectable at the cell surface, (ii) a chimeric protein containing the TM of ABCG1 and the cytoplasmic domains of the nonsterol transporter ABCG2 is both targeted to endosomes and functional, and (iii) ABCG1 colocalizes with multiple proteins that mark late endosomes and recycling endosomes. Mutagenesis studies identify critical residues in the TM domains that are important for ABCG1 to alter sterol efflux, induce sterol regulatory element binding protein-2 (SREBP-2) processing, and selectively attenuate the oxysterol-mediated repression of SREBP-2 processing. Our data demonstrate that ABCG1 is an intracellular sterol transporter that localizes to endocytic vesicles to facilitate the redistribution of specific intracellular sterols away from the endoplasmic reticulum (ER).
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Differential expression and function of ABCG1 and ABCG4 during development and aging
Journal of lipid research, 2009Co-Authors: Dragana D. Bojanic, Paul T. Tarr, Greg D. Gale, Desmond J. Smith, Dean Bok, Bryan Chen, Steven Nusinowitz, Anita Lövgren-sandblom, Ingemar Björkhem, Peter A. EdwardsAbstract:ABCG1 and ABCG4 are highly homologous members of the ATP binding cassette (ABC) transporter family that regulate cellular cholesterol homeostasis. In adult mice, ABCG1 is known to be expressed in numerous cell types and tissues, whereas ABCG4 expression is limited to the central nervous system (CNS). Here, we show significant differences in expression of these two transporters during development. Examination of beta-galactosidase-stained tissue sections from ABCG1(-/-)LacZ and Abcg4(-/-)LacZ knockin mice shows that ABCG4 is highly but transiently expressed both in hematopoietic cells and in enterocytes during development. In contrast, ABCG1 is expressed in macrophages and in endothelial cells of both embryonic and adult liver. We also show that ABCG1 and ABCG4 are both expressed as early as E12.5 in the embryonic eye and developing CNS. Loss of both ABCG1 and ABCG4 results in accumulation in the retina and/or brain of oxysterols, in altered expression of liver X receptor and sterol-regulatory element binding protein-2 target genes, and in a stress response gene. Finally, behavioral tests show that Abcg4(-/-) mice have a general deficit in associative fear memory. Together, these data indicate that loss of ABCG1 and/or ABCG4 from the CNS results in changes in metabolic pathways and in behavior.
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ABCG1 and abcg4 are coexpressed in neurons and astrocytes of the cns and regulate cholesterol homeostasis through srebp 2
Journal of Lipid Research, 2008Co-Authors: Paul T. Tarr, Peter A. EdwardsAbstract:Here, we describe the initial characterization of Abcg4 -/- mice and identify overlapping functions of ABCG4 and ABCG1 in the brain. Histological examination of tissues from Abcg4 +/- /nlsLacZ and Abegl +/- /nlsLacZ mice demonstrates that coexpression of Abcg4 and Abcgl is restricted to neurons and astrocytes of the central nervous system (CNS). Interestingly, Abcg4 mRNA is undetectable outside the CNS, in contrast with the broad tissue and cellular expression of Abcgl. We also used primary astrocytes, microglia, neurons, and macrophages to demonstrate that the expression of Abcgl, but not Abcg4, is induced after the activation of liver X receptor. Cellular localization studies demonstrated that both proteins reside in RhoB-positive endocytic vesicle membranes. Furthermore, overexpression of either ABCG1 or ABCG4 increased the processing of sterol-regulatory element binding protein 2 (SREBP-2) to the transcriptionally active protein, thus accounting for the observed increase in the expression of SREBP-2 target genes and cholesterol synthesis. Consistent with these latter results, we show that the expression levels of the same SREBP-2 target genes are repressed in the brains of Abcgl -/- and, to a lesser extent, Abcg4 -/- mice.jlr Based on the results of the current study, we propose that ABCG1 and ABCG4 mediate the intracellular vesicular transport of cholesterol/ sterols within both neurons and astrocytes to regulate cholesterol transport in the brain.
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ATP-binding cassette transporter G1 and lipid homeostasis.
Current Opinion in Lipidology, 2006Co-Authors: Ángel Baldán, Paul T. Tarr, Peter A. EdwardsAbstract:PURPOSE OF REVIEW: This review briefly discusses the ATP-binding cassette transporter G (ABCG) family members and emphasizes recent studies that identify ABCG1 as a key regulator of cellular lipid homeostasis. RECENT FINDINGS: The in-vivo importance of ABCG1 has recently been demonstrated with both loss-of-function and gain-of-function studies in mice. Administration of a diet high in both fat and cholesterol to ABCG1 mice results in massive cholesterol accumulation in both the liver and lungs. In contrast, lipid accumulation is greatly attenuated in transgenic mice that express both the murine and human ABCG1 genes. Despite the observed tissue lipid accumulation, plasma lipid levels and lipoprotein cholesterol distribution are not significantly different between wild-type, ABCG1, and hABCG1 transgenic mice. Other studies show that ABCG1 expression is induced following activation of the nuclear receptor LXR and that over expression of ABCG1 results in increased efflux of cellular cholesterol to HDL or phospholipid vesicles. SUMMARY: The ABCG1 transporter plays a key role in regulating cellular cholesterol and lipid homeostasis. Elucidation of the molecular mechanism by which ABCG1 controls sterol flux should provide critical information that may link ABCG1 to the reverse cholesterol transport pathway or diseases such as atherosclerosis.
Lucia Rohrer - One of the best experts on this subject based on the ideXlab platform.
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lipidation of apolipoprotein a i by atp binding cassette transporter abc a1 generates an interaction partner for ABCG1 but not for scavenger receptor bi
Biochimica et Biophysica Acta, 2008Co-Authors: Iris Lorenzi, Silvija Radosavljevic, Arnold Von Eckardstein, Lucia RohrerAbstract:Abstract The ATP-binding cassette transporters ABCA1 and ABCG1 as well as scavenger receptor BI (SR-BI) mediate the efflux of lipids from macrophages to apolipoprotein A-I (apoA-I) and high density lipoproteins (HDL). We used RNA interference in RAW264.7 macrophages to study the interactions of ABCA1, ABCG1, and SR-BI with lipid-free apoA-I, native and reconstituted HDL with apoA-I:phosphatidylcholine ratios of either 1:40 (rHDL1:40) or 1:100 (rHDL1:100). Knock-down of ABCA1 inhibits the cellular binding at 4 °C of lipid-free apoA-I but not of HDL whereas suppression of ABCG1 or SR-BI reduces the binding of HDL but not lipid-free apoA-I. The degree of lipidation influences the interactions of rHDL with ABCG1 and SR-BI. Knock-down of ABCG1 inhibits more effectively the binding and cholesterol efflux capacities of lipid-poorer rHDL1:40 whereas knock-down of SR-BI has a more profound effect on the binding and cholesterol efflux capacities of lipid-richer rHDL1:100. Moreover, knock-down of ABCG1 but not SR-BI interferes with the association of lipid-free apoA-I during prolonged incubation at 37 °C. Finally, knock-down of ABCG1 inhibits the binding of initially lipid-free apoA-I which has been preconditioned by cells with high ABCA1 activity. The gained ability of initially lipid-free apoA-I to interact with ABCG1 is accompanied by its shift from electrophoretic pre-β- to α-mobility. Taken together, these data suggest that the interaction of lipid-free apoA-I with ABCA1 generates a particle that immediately interacts with ABCG1 but not with SR-BI. Furthermore, the degree of lipidation influences the interaction of HDL with ABCG1 or SR-BI.
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Lipidation of apolipoprotein A-I by ATP-binding cassette transporter (ABC) A1 generates an interaction partner for ABCG1 but not for scavenger receptor BI
Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids, 2008Co-Authors: Iris Lorenzi, Silvija Radosavljevic, Arnold Von Eckardstein, Lucia RohrerAbstract:The ATP-binding cassette transporters ABCA1 and ABCG1 as well as scavenger receptor BI (SR-BI) mediate the efflux of lipids from macrophages to apolipoprotein A-I (apoA-I) and high density lipoproteins (HDL). We used RNA interference in RAW264.7 macrophages to study the interactions of ABCA1, ABCG1, and SR-BI with lipid-free apoA-I, native and reconstituted HDL with apoA-I:phosphatidylcholine ratios of either 1:40 (rHDL(1:40)) or 1:100 (rHDL(1:100)). Knock-down of ABCA1 inhibits the cellular binding at 4 degrees C of lipid-free apoA-I but not of HDL whereas suppression of ABCG1 or SR-BI reduces the binding of HDL but not lipid-free apoA-I. The degree of lipidation influences the interactions of rHDL with ABCG1 and SR-BI. Knock-down of ABCG1 inhibits more effectively the binding and cholesterol efflux capacities of lipid-poorer rHDL(1:40) whereas knock-down of SR-BI has a more profound effect on the binding and cholesterol efflux capacities of lipid-richer rHDL(1:100). Moreover, knock-down of ABCG1 but not SR-BI interferes with the association of lipid-free apoA-I during prolonged incubation at 37 degrees C. Finally, knock-down of ABCG1 inhibits the binding of initially lipid-free apoA-I which has been preconditioned by cells with high ABCA1 activity. The gained ability of initially lipid-free apoA-I to interact with ABCG1 is accompanied by its shift from electrophoretic pre-beta- to alpha-mobility. Taken together, these data suggest that the interaction of lipid-free apoA-I with ABCA1 generates a particle that immediately interacts with ABCG1 but not with SR-BI. Furthermore, the degree of lipidation influences the interaction of HDL with ABCG1 or SR-BI
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lipid efflux by the atp binding cassette transporters abca1 and ABCG1
Biochimica et Biophysica Acta, 2006Co-Authors: Clara Cavelier, Iris Lorenzi, Lucia Rohrer, Arnold Von EckardsteinAbstract:Plasma levels of high-density lipoproteins (HDL) and apolipoprotein A-I (apoA-I) are inversely correlated with the risk of cardiovascular disease. One major atheroprotective mechanism of HDL and apoA-I is their role in reverse cholesterol transport, i.e., the transport of excess cholesterol from foam cells to the liver for secretion. The ATP-binding cassette transporters ABCA1 and ABCG1 play a pivotal role in this process by effluxing lipids from foam cells to apoA-I and HDL, respectively. In the liver, ABCA1 activity is one rate-limiting step in the formation of HDL. In macrophages, ABCA1 and ABCG1 prevent the excessive accumulation of lipids and thereby protect the arteries from developing atherosclerotic lesions. However, the mechanisms by which ABCA1 and ABCG1 mediate lipid removal are still unclear. Particularly, three questions remain controversial and are discussed in this review: (1) Do apoA-I and HDL directly interact with ABCA1 and ABCG1, respectively? (2) Does cholesterol efflux involve retroendocytosis of apoA-I or HDL? (3) Which lipids are directly transported by ABCA1 and ABCG1?
Iris Lorenzi - One of the best experts on this subject based on the ideXlab platform.
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lipidation of apolipoprotein a i by atp binding cassette transporter abc a1 generates an interaction partner for ABCG1 but not for scavenger receptor bi
Biochimica et Biophysica Acta, 2008Co-Authors: Iris Lorenzi, Silvija Radosavljevic, Arnold Von Eckardstein, Lucia RohrerAbstract:Abstract The ATP-binding cassette transporters ABCA1 and ABCG1 as well as scavenger receptor BI (SR-BI) mediate the efflux of lipids from macrophages to apolipoprotein A-I (apoA-I) and high density lipoproteins (HDL). We used RNA interference in RAW264.7 macrophages to study the interactions of ABCA1, ABCG1, and SR-BI with lipid-free apoA-I, native and reconstituted HDL with apoA-I:phosphatidylcholine ratios of either 1:40 (rHDL1:40) or 1:100 (rHDL1:100). Knock-down of ABCA1 inhibits the cellular binding at 4 °C of lipid-free apoA-I but not of HDL whereas suppression of ABCG1 or SR-BI reduces the binding of HDL but not lipid-free apoA-I. The degree of lipidation influences the interactions of rHDL with ABCG1 and SR-BI. Knock-down of ABCG1 inhibits more effectively the binding and cholesterol efflux capacities of lipid-poorer rHDL1:40 whereas knock-down of SR-BI has a more profound effect on the binding and cholesterol efflux capacities of lipid-richer rHDL1:100. Moreover, knock-down of ABCG1 but not SR-BI interferes with the association of lipid-free apoA-I during prolonged incubation at 37 °C. Finally, knock-down of ABCG1 inhibits the binding of initially lipid-free apoA-I which has been preconditioned by cells with high ABCA1 activity. The gained ability of initially lipid-free apoA-I to interact with ABCG1 is accompanied by its shift from electrophoretic pre-β- to α-mobility. Taken together, these data suggest that the interaction of lipid-free apoA-I with ABCA1 generates a particle that immediately interacts with ABCG1 but not with SR-BI. Furthermore, the degree of lipidation influences the interaction of HDL with ABCG1 or SR-BI.
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Lipidation of apolipoprotein A-I by ATP-binding cassette transporter (ABC) A1 generates an interaction partner for ABCG1 but not for scavenger receptor BI
Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids, 2008Co-Authors: Iris Lorenzi, Silvija Radosavljevic, Arnold Von Eckardstein, Lucia RohrerAbstract:The ATP-binding cassette transporters ABCA1 and ABCG1 as well as scavenger receptor BI (SR-BI) mediate the efflux of lipids from macrophages to apolipoprotein A-I (apoA-I) and high density lipoproteins (HDL). We used RNA interference in RAW264.7 macrophages to study the interactions of ABCA1, ABCG1, and SR-BI with lipid-free apoA-I, native and reconstituted HDL with apoA-I:phosphatidylcholine ratios of either 1:40 (rHDL(1:40)) or 1:100 (rHDL(1:100)). Knock-down of ABCA1 inhibits the cellular binding at 4 degrees C of lipid-free apoA-I but not of HDL whereas suppression of ABCG1 or SR-BI reduces the binding of HDL but not lipid-free apoA-I. The degree of lipidation influences the interactions of rHDL with ABCG1 and SR-BI. Knock-down of ABCG1 inhibits more effectively the binding and cholesterol efflux capacities of lipid-poorer rHDL(1:40) whereas knock-down of SR-BI has a more profound effect on the binding and cholesterol efflux capacities of lipid-richer rHDL(1:100). Moreover, knock-down of ABCG1 but not SR-BI interferes with the association of lipid-free apoA-I during prolonged incubation at 37 degrees C. Finally, knock-down of ABCG1 inhibits the binding of initially lipid-free apoA-I which has been preconditioned by cells with high ABCA1 activity. The gained ability of initially lipid-free apoA-I to interact with ABCG1 is accompanied by its shift from electrophoretic pre-beta- to alpha-mobility. Taken together, these data suggest that the interaction of lipid-free apoA-I with ABCA1 generates a particle that immediately interacts with ABCG1 but not with SR-BI. Furthermore, the degree of lipidation influences the interaction of HDL with ABCG1 or SR-BI
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lipid efflux by the atp binding cassette transporters abca1 and ABCG1
Biochimica et Biophysica Acta, 2006Co-Authors: Clara Cavelier, Iris Lorenzi, Lucia Rohrer, Arnold Von EckardsteinAbstract:Plasma levels of high-density lipoproteins (HDL) and apolipoprotein A-I (apoA-I) are inversely correlated with the risk of cardiovascular disease. One major atheroprotective mechanism of HDL and apoA-I is their role in reverse cholesterol transport, i.e., the transport of excess cholesterol from foam cells to the liver for secretion. The ATP-binding cassette transporters ABCA1 and ABCG1 play a pivotal role in this process by effluxing lipids from foam cells to apoA-I and HDL, respectively. In the liver, ABCA1 activity is one rate-limiting step in the formation of HDL. In macrophages, ABCA1 and ABCG1 prevent the excessive accumulation of lipids and thereby protect the arteries from developing atherosclerotic lesions. However, the mechanisms by which ABCA1 and ABCG1 mediate lipid removal are still unclear. Particularly, three questions remain controversial and are discussed in this review: (1) Do apoA-I and HDL directly interact with ABCA1 and ABCG1, respectively? (2) Does cholesterol efflux involve retroendocytosis of apoA-I or HDL? (3) Which lipids are directly transported by ABCA1 and ABCG1?
Nan Wang - One of the best experts on this subject based on the ideXlab platform.
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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, Minako Ishibashi, Mohamed Lamkanfi, Rong Li, Nan Wang, 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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ABCG1 and HDL protect against endothelial dysfunction in mice fed a high-cholesterol diet
The Journal of clinical investigation, 2008Co-Authors: Naoki Terasaka, Carrie L Welch, Tamara A Pagler, Nan Wang, Laurent Yvan-charvet, Nino Mzhavia, Read Langlois, Ira J. GoldbergAbstract:Plasma HDL levels are inversely related to the incidence of atherosclerotic disease. Some of the atheroprotective effects of HDL are likely mediated via preservation of EC function. Whether the beneficial effects of HDL on ECs depend on its involvement in cholesterol efflux via the ATP-binding cassette transporters ABCA1 and ABCG1, which promote efflux of cholesterol and oxysterols from macrophages, has not been investigated. To address this, we assessed endothelial function in Abca1–/–, ABCG1–/–, and Abca1–/–ABCG1–/– mice fed either a high-cholesterol diet (HCD) or a Western diet (WTD). Non-atherosclerotic arteries from WTD-fed ABCG1–/– and Abca1–/–ABCG1–/– mice exhibited a marked decrease in endothelium-dependent vasorelaxation, while Abca1–/– mice had a milder defect. In addition, eNOS activity was reduced in aortic homogenates generated from ABCG1–/– mice fed either a HCD or a WTD, and this correlated with decreased levels of the active dimeric form of eNOS. More detailed analysis indicated that ABCG1 was expressed primarily in ECs, and that these cells accumulated the oxysterol 7-ketocholesterol (7-KC) when ABCG1–/– mice were fed a WTD. Consistent with these data, ABCG1 had a major role in promoting efflux of cholesterol and 7-KC in cultured human aortic ECs (HAECs). Furthermore, HDL treatment of HAECs prevented 7-KC–induced ROS production and active eNOS dimer disruption in an ABCG1-dependent manner. Our data suggest that ABCG1 and HDL maintain EC function in HCD-fed mice by promoting efflux of cholesterol and 7-oxysterols and preserving active eNOS dimer levels.
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atp binding cassette transporters g1 and g4 mediate cholesterol and desmosterol efflux to hdl and regulate sterol accumulation in the brain
The FASEB Journal, 2008Co-Authors: Nan Wang, Laurent Yvancharvet, Tim Vanmierlo, Dieter Lutjohann, Monique Mulder, Taewan Kim, Alan R TallAbstract:Transporters in the ABCG family appear to be involved in the cellular excretion of cholesterol and other sterols in a cell- and tissue-specific fashion. Overexpression of ATP-binding cassette transporters G1 (ABCG1) and G4 (Abcg4) can promote cellular cholesterol efflux to high-density lipoprotein (HDL), but the in vivo functions of Abcg4 are poorly understood. We used mice with knockouts of ABCG1 or Abcg4 singly or together to further elucidate the function of these transporters. ABCG1 and Abcg4 are highly expressed in the brain and are found in both astrocytes and neurons. Whereas ABCG1−/− or Abcg4−/− mice showed essentially normal levels of brain sterols, in ABCG1−/−/Abcg4−/− mice, levels of several sterol intermediates in the cholesterol biosynthetic pathway, namely desmosterol, lathosterol, and lanosterol, as well as 27-OH cholesterol, were increased 2- to 3-fold. Overexpression of ABCG1 or Abcg4 promoted efflux of desmosterol and cholesterol from cells to HDL, and combined deficiency of these transp...
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sr bi inhibits ABCG1 stimulated net cholesterol efflux from cells to plasma hdl
Journal of Lipid Research, 2008Co-Authors: Laurent Yvancharvet, Tamara A Pagler, Nan Wang, Takafumi Senokuchi, May Brundert, Franz Rinninger, Alan R TallAbstract:This study compares the roles of ABCG1 and scavenger receptor class B type I (SR-BI) singly or together in promoting net cellular cholesterol efflux to plasma HDL containing active LCAT. In transfected cells, SR-BI promoted free cholesterol efflux to HDL, but this was offset by an increased uptake of HDL cholesteryl ester (CE) into cells, resulting in no net efflux. Coexpression of SR-BI with ABCG1 inhibited the ABCG1-mediated net cholesterol efflux to HDL, apparently by promoting the reuptake of CE from medium. However, ABCGl-mediated cholesterol efflux was not altered in cholesterol-loaded, SR-BI-deficient (SR-BI -/- ) macrophages. Briefly cultured macrophages collected from SR-BI -/- mice loaded with acetylated LDL in the peritoneal cavity did exhibit reduced efflux to HDL. However, this was attributable to reduced expression of ABCG1 and ABCA1, likely reflecting increased macrophage cholesterol efflux to apolipoprotein E-enriched HDL during loading in SR-BI -/ mice.jlr In conclusion, cellular SR-BI does not promote net cholesterol efflux from cells to plasma HDL containing active LCAT as a result of the reuptake of HDL-CE into cells. Previous findings of increased atherosclerosis in mice transplanted with SR-BI -/- bone marrow probably cannot be explained by a defect in macrophage cholesterol efflux.
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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, Naoki Terasaka, Mollie Ranalletta, Rong Li, Nan Wang, 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.
