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• W2109320834 abstract "Mammalian cells have developed various responses to minimize accumulation of unesterified cholesterol, as the latter can result in cell toxicity and death [reviewed in this edition by Bjo¨rkhem (Bjo¨rkhem, I. 2009. Are side-chain oxidized oxysterols regulators also in vivo? J. Lipid Res. In press)]. These responses include esterification to sequester excess sterol in intracellular lipid droplets, repression of both cholesterol synthesis and LDL receptor expression (thus reducing endocytosis of LDL), and induction of a panoply of genes that promote sterol efflux and affect lipid metabolism. The nuclear receptor liver-X-receptor (LXR) functions as a cellular “sterol sensor” and plays a critical role in these latter transcriptional changes [reviewed in this edition by Glass (Shibata, N., and Glass C, K. 2009. Regulation of macrophage function in inflammation and atherosclerosis. J. Lipid Res. In press)]. Activation of LXR by either endogenous oxysterols or synthetic agonists induces the expression of many genes, including those encoding ATP-binding cassette (ABC) transporters ABCA1, ABCG1, ABCG5, and ABCG8. As discussed below, these four proteins function to promote sterol efflux from cells. Mammalian cells have developed various responses to minimize accumulation of unesterified cholesterol, as the latter can result in cell toxicity and death [reviewed in this edition by Bjo¨rkhem (Bjo¨rkhem, I. 2009. Are side-chain oxidized oxysterols regulators also in vivo? J. Lipid Res. In press)]. These responses include esterification to sequester excess sterol in intracellular lipid droplets, repression of both cholesterol synthesis and LDL receptor expression (thus reducing endocytosis of LDL), and induction of a panoply of genes that promote sterol efflux and affect lipid metabolism. The nuclear receptor liver-X-receptor (LXR) functions as a cellular “sterol sensor” and plays a critical role in these latter transcriptional changes [reviewed in this edition by Glass (Shibata, N., and Glass C, K. 2009. Regulation of macrophage function in inflammation and atherosclerosis. J. Lipid Res. In press)]. Activation of LXR by either endogenous oxysterols or synthetic agonists induces the expression of many genes, including those encoding ATP-binding cassette (ABC) transporters ABCA1, ABCG1, ABCG5, and ABCG8. As discussed below, these four proteins function to promote sterol efflux from cells. The ABC transporters comprise a large (>250) family of transmembrane proteins that are present across all phyla (as reviewed in Ref. 1Dean M. Hamon Y. Chimini G. The human ATP-binding cassette (ABC) transporter superfamily.J. Lipid Res. 2001; 42: 1007-1017Abstract Full Text Full Text PDF PubMed Google Scholar). The ABC motif spans ∼120 amino acids, which contain three small noncontiguous conserved domains termed Walker A, C-loop or signature motif, and Walker B. The C-loop distinguishes ABC transporters from other ATP-binding proteins. The members of this family have been categorized into seven groups (ABC-A through ABC-G), but traditionally they were referred to as “half transporters” or “full transporters;” the former contain six transmembrane domains and one ABC motif, and the latter are a tandem repetition of the 6 + 1 structure. These proteins facilitate the transport of a wide array of substrates, including phospholipids, sterols, bile acids, peptides, and various drugs, across membrane bilayers by a process requiring the binding and hydrolysis of ATP. The importance of ABCA1 was realized in 1999, 5 years after its original cloning, when it was shown that patients with Tangier disease have mutations in both copies of the gene (as reviewed in Ref. 2Attie A.D. ABCA1: at the nexus of cholesterol, HDL and atherosclerosis.Trends Biochem. Sci. 2007; 32: 172-179Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar). These patients have little or no plasma HDL and accumulate cholesterol esters and lipids in reticuloendothelial cells. Patients with familial hypoalphalipoproteinemia are heterozygotes with one ABCA1 mutant allele and also exhibit abnormally low HDL levels (2Attie A.D. ABCA1: at the nexus of cholesterol, HDL and atherosclerosis.Trends Biochem. Sci. 2007; 32: 172-179Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar). Intriguingly, in spite of the reduced HDL levels, these latter patients do not have an increased risk for cardiovascular disease (3Frikke-Schmidt R. Nordestgaard B.G. Stene M.C. Sethi A.A. Remaley A.T. Schnohr P. Grande P. Tybjaerg-Hansen A. Association of loss-of-function mutations in the ABCA1 gene with high-density lipoprotein cholesterol levels and risk of ischemic heart disease.JAMA. 2008; 299: 2524-2532Crossref PubMed Scopus (393) Google Scholar). It is now well accepted that: i) ABCA1 is expressed in multiple cells and tissues (Fig. 1); ii) the gene is highly induced following activation of LXR; iii) ABCA1 protein localizes to both the plasma membrane and intracellular vesicles; and iv) ABCA1 promotes the efflux of phospholipids and cholesterol to lipid-poor apoproteins, such as apoA1, so as to generate preβ HDL (2Attie A.D. ABCA1: at the nexus of cholesterol, HDL and atherosclerosis.Trends Biochem. Sci. 2007; 32: 172-179Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar). Besides being controlled by intracellular oxysterol levels through LXR, ABCA1 expression has also been reported to be modulated by intracellular cAMP levels, PKC-dependent phosphorylation, hormone-sensitive lipase activity, peroxisome proliferator-activated receptors, and certain fatty acids (4Cavelier C. Lorenzi I. Rohrer L. Eckardstein A.von Lipid efflux by the ATP-binding cassette transporters ABCA1 and ABCG1.Biochim. Biophys. Acta. 2006; 1761: 655-666Crossref PubMed Scopus (186) Google Scholar). The exact molecular mechanism involved in the ABCA1-dependent lipid mobilization has yet to be established. Although apoA1 has been shown to bind to ABCA1 in the plasma membrane, it is unclear whether this is necessary for ABCA1-mediated lipid efflux (2Attie A.D. ABCA1: at the nexus of cholesterol, HDL and atherosclerosis.Trends Biochem. Sci. 2007; 32: 172-179Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar). Indeed, there is considerable disagreement as to the physiological substrate of ABCA1: it is still not clear if ABCA1 directly transports both phospholipids and cholesterol to lipid-poor apoA1, or whether it effluxes phospholipids to apoA1, with cholesterol being transferred subsequently via an ABCA1-independent pathway (5Vaughan A.M. Oram J.F. ABCA1 redistributes membrane cholesterol independent of apolipoprotein interactions.J. Lipid Res. 2003; 44: 1373-1380Abstract Full Text Full Text PDF PubMed Scopus (177) Google Scholar). It has been proposed that ABCG1 may be important in the “secondary” cholesterol efflux process and thus function synergistically with ABCA1 (see section on ABCG1) (4Cavelier C. Lorenzi I. Rohrer L. Eckardstein A.von Lipid efflux by the ATP-binding cassette transporters ABCA1 and ABCG1.Biochim. Biophys. Acta. 2006; 1761: 655-666Crossref PubMed Scopus (186) Google Scholar). Evidence has also been presented to support a model in which ABCA1 increases cholesterol levels in the outer leaflet of the plasma membrane, thus promoting the formation of membrane buds or protrusions to which apoA1 binds before dissociating with bound lipid (6Vedhachalam C. Duong P.T. Nickel M. Nguyen D. Dhanasekaran P. Saito H. Rothblat G.H. Phillips S.Lund-Katz, and M.C. Mechanism of ATP-binding cassette transporter A1-mediated cellular lipid efflux to apolipoprotein A-I and formation of high density lipoprotein particles.J. Biol. Chem. 2007; 282: 25123-25130Abstract Full Text Full Text PDF PubMed Scopus (285) Google Scholar). Yet another model involves retroendocytosis of apoA1, intracellular lipidation via ABCA1, and then resecretion (4Cavelier C. Lorenzi I. Rohrer L. Eckardstein A.von Lipid efflux by the ATP-binding cassette transporters ABCA1 and ABCG1.Biochim. Biophys. Acta. 2006; 1761: 655-666Crossref PubMed Scopus (186) Google Scholar). However, a recent study raised doubts about the importance of the latter pathway (7Faulkner L.E. Panagotopulos S.E. Johnson J.D. Woollett L.A. Hui D.Y. Witting S.R. Maiorano J.N. Davidson W.S. An analysis of the role of a retroendocytosis pathway in ABCA1-mediated cholesterol efflux from macrophages.J. Lipid Res. 2008; 49: 1322-1332Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar). Regardless of the exact mechanism, the net result is that hepatic and intestinal ABCA1 contribute ∼80% and ∼20%, respectively, to HDL biogenesis (8Singaraja R.R. Stahmer B. Brundert M. Merkel M. Heeren J. Bissada N. Kang M. Timmins J.M. Ramakrishnan R. Parks J.S. al et Hepatic ATP-binding cassette transporter A1 is a key molecule in high-density lipoprotein cholesteryl ester metabolism in mice.Arterioscler. Thromb. Vasc. Biol. 2006; 26: 1821-1827Crossref PubMed Scopus (29) Google Scholar, 9Brunham L.R. Kruit J.K. Iqbal J. Fievet C. Timmins J.M. Pape T.D. Coburn B.A. Bissada N. Staels B. Groen A.K. al et Intestinal ABCA1 directly contributes to HDL biogenesis in vivo.J. Clin. Invest. 2006; 116: 1052-1062Crossref PubMed Scopus (419) Google Scholar). Accordingly, HDL levels of Abca1−/− mice are decreased >90% (10McNeish J. Aiello R.J. Guyot D. Turi T. Gabel C. Aldinger C. Hoppe K.L. Roach M.L. Royer L.J. Wet J.de al et High density lipoprotein deficiency and foam cell accumulation in mice with targeted disruption of ATP-binding cassette transporter-1.Proc. Natl. Acad. Sci. USA. 2000; 97: 4245-4250Crossref PubMed Scopus (481) Google Scholar, 11Christiansen-Weber T.A. Voland J.R. Wu Y. Ngo K. Roland B.L. Nguyen S. Peterson P.A. Fung-Leung W.P. Functional loss of ABCA1 in mice causes severe placental malformation, aberrant lipid distribution, and kidney glomerulonephritis as well as high-density lipoprotein cholesterol deficiency.Am. J. Pathol. 2000; 157: 1017-1029Abstract Full Text Full Text PDF PubMed Scopus (204) Google Scholar). Consistent with a role for ABCA1 in effluxing intracellular sterols, Abca1−/− mice show evidence of cholesterol accumulation in a variety of macrophage-rich tissues including the lung, spleen, lymph nodes, thymus, and skin (10McNeish J. Aiello R.J. Guyot D. Turi T. Gabel C. Aldinger C. Hoppe K.L. Roach M.L. Royer L.J. Wet J.de al et High density lipoprotein deficiency and foam cell accumulation in mice with targeted disruption of ATP-binding cassette transporter-1.Proc. Natl. Acad. Sci. USA. 2000; 97: 4245-4250Crossref PubMed Scopus (481) Google Scholar, 11Christiansen-Weber T.A. Voland J.R. Wu Y. Ngo K. Roland B.L. Nguyen S. Peterson P.A. Fung-Leung W.P. Functional loss of ABCA1 in mice causes severe placental malformation, aberrant lipid distribution, and kidney glomerulonephritis as well as high-density lipoprotein cholesterol deficiency.Am. J. Pathol. 2000; 157: 1017-1029Abstract Full Text Full Text PDF PubMed Scopus (204) Google Scholar). These data suggest that ABCA1 is important for macrophages to regulate sterol homeostasis. Indeed, Abca1−/− macrophages show increased free and esterified cholesterol, and enhanced inflammatory responses (12Zhu X. Lee J.Y. Timmins J.M. Brown J.M. Boudyguina E. Mulya A. Gebre A.K. Willingham M.C. Hiltbold E.M. Mishra N. al et Increased cellular free cholesterol in macrophage-specific Abca1 knock-out mice enhances pro-inflammatory response of macrophages.J. Biol. Chem. 2008; 283: 22930-22941Abstract Full Text Full Text PDF PubMed Scopus (285) Google Scholar). Despite the increase in “foamy” macrophages in several tissues, there is no corresponding increase in atherosclerosis in Abca1−/− (10McNeish J. Aiello R.J. Guyot D. Turi T. Gabel C. Aldinger C. Hoppe K.L. Roach M.L. Royer L.J. Wet J.de al et High density lipoprotein deficiency and foam cell accumulation in mice with targeted disruption of ATP-binding cassette transporter-1.Proc. Natl. Acad. Sci. USA. 2000; 97: 4245-4250Crossref PubMed Scopus (481) Google Scholar, 11Christiansen-Weber T.A. Voland J.R. Wu Y. Ngo K. Roland B.L. Nguyen S. Peterson P.A. Fung-Leung W.P. Functional loss of ABCA1 in mice causes severe placental malformation, aberrant lipid distribution, and kidney glomerulonephritis as well as high-density lipoprotein cholesterol deficiency.Am. J. Pathol. 2000; 157: 1017-1029Abstract Full Text Full Text PDF PubMed Scopus (204) Google Scholar), Abca1−/−Ldlr−/−, or Abca1−/−ApoE−/− (13Aiello R.J. Brees D. Bourassa P.A. Royer L. Lindsey S. Coskran T. Haghpassand M. Francone O.L. Increased atherosclerosis in hyperlipidemic mice with inactivation of ABCA1 in macrophages.Arterioscler. Thromb. Vasc. Biol. 2002; 22: 630-637Crossref PubMed Scopus (344) Google Scholar) mice. To explore the specific role of macrophage ABCA1 in atherosclerosis, investigators utilized bone marrow transplant studies using atherosclerotic-susceptible hyperlipidemic recipient mice; these studies showed that atherosclerotic lesions were increased ∼60% or reduced ∼30% when donor cells were derived from either Abca1−/− mice or transgenic ABCA1 mice, respectively (13Aiello R.J. Brees D. Bourassa P.A. Royer L. Lindsey S. Coskran T. Haghpassand M. Francone O.L. Increased atherosclerosis in hyperlipidemic mice with inactivation of ABCA1 in macrophages.Arterioscler. Thromb. Vasc. Biol. 2002; 22: 630-637Crossref PubMed Scopus (344) Google Scholar, 14Van Eck M. Singaraja R.R. Ye D. Hildebrand R.B. James E.R. Hayden M.R. Berkel T.J. Van Macrophage ATP-binding cassette transporter A1 overexpression inhibits atherosclerotic lesion progression in low-density lipoprotein receptor knockout mice.Arterioscler. Thromb. Vasc. Biol. 2006; 26: 929-934Crossref PubMed Scopus (150) Google Scholar). These studies demonstrate that loss of ABCA1 from macrophages results in sterol accumulation within these cells, while plasma lipoprotein levels are unchanged. In addition to its role in controlling plasma HDL and macrophage sterol levels, ABCA1 also affects lipoprotein levels in the central nervous system (CNS). The cerebrospinal fluid of Abca1−/− mice contains very low levels of an abnormally poorly lipidated ApoE (see Ref. (15Wahrle S.E. Jiang H. Parsadanian M. Kim J. Li A. Knoten A. Jain S. Wellington V.Hirsch-Reinshagen, C.L. Bales K.R. al et Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease.J. Clin. Invest. 2008; 118: 671-682PubMed Google Scholar) and references therein). Given the association between apoE and Alzheimer’s disease (AD), it was proposed that ABCA1 might impact amyloid protein deposition by modulating the lipidation and clearance of apoE. In agreement with this proposal, deposition of brain amyloid protein in amyloid precursor protein transgenic mice was increased or decreased following either deletion or overexpression of ABCA1, respectively (15Wahrle S.E. Jiang H. Parsadanian M. Kim J. Li A. Knoten A. Jain S. Wellington V.Hirsch-Reinshagen, C.L. Bales K.R. al et Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease.J. Clin. Invest. 2008; 118: 671-682PubMed Google Scholar). These results suggest that ABCA1 plays a critical role in amyloidogenesis, and, consequently, it has been proposed that pharmacological intervention in the ABCA1/apoE/amyloid protein axis might prove useful in the control of AD (15Wahrle S.E. Jiang H. Parsadanian M. Kim J. Li A. Knoten A. Jain S. Wellington V.Hirsch-Reinshagen, C.L. Bales K.R. al et Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease.J. Clin. Invest. 2008; 118: 671-682PubMed Google Scholar). Mammalian ABCG1 was identified in the mid 1990s, and shown to encode a protein of 74 kDa that has 33% amino acid identity with the Drosophila transporter White (16Savary S. Denizot F. Luciani M. Mattei M. Chimini G. Molecular cloning of a mammalian ABC transporter homologous to Drosophila white gene.Mamm. Genome. 1996; 7: 673-676Crossref PubMed Scopus (52) Google Scholar). Subsequent studies demonstrated that ABCG1 mRNA levels were highly induced following sterol loading of cells and/or activation of the nuclear receptor LXR (as reviewed in Ref. 17Baldan A. Tarr P. Lee R. Edwards P.A. ATP-binding cassette transporter G1 and lipid homeostasis.Curr. Opin. Lipidol. 2006; 17: 227-232Crossref PubMed Scopus (70) Google Scholar) in multiple tissues (Fig. 1). The cellular localization of ABCG1 remains to be clearly established, as it has been reported to reside in either intracellular compartments or the plasma membrane (18Vaughan A.M. Oram J.F. ABCG1 redistributes cell cholesterol to domains removable by high density lipoprotein but not by lipid-depleted apolipoproteins.J. Biol. Chem. 2005; 280: 30150-30157Abstract Full Text Full Text PDF PubMed Scopus (224) Google Scholar, 19Tarr P.T. Edwards P.A. ABCG1 and ABCG4 are coexpressed in neurons and astrocytes of the CNS and regulate cholesterol homeostasis through SREBP-2.J. Lipid Res. 2008; 49: 169-182Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar, 20Wang N. Ranalletta M. Matsuura F. Peng F. Tall A.R. LXR-Induced Redistribution of ABCG1 to Plasma Membrane in Macrophages Enhances Cholesterol Mass Efflux to HDL.Arterioscler Thromb Vasc Biol. 2006; 26: 310-316Crossref Scopus (185) Google Scholar). The initial studies demonstrated that ABCG1 could mediate the efflux of intracellular cholesterol to different exogenous lipid acceptors such as HDL, LDL, small phospholipid vesicles, apoA1-phospholipid complexes and even cyclodextrin, but not to lipid-poor apoproteins (as reviewed in Ref. 17Baldan A. Tarr P. Lee R. Edwards P.A. ATP-binding cassette transporter G1 and lipid homeostasis.Curr. Opin. Lipidol. 2006; 17: 227-232Crossref PubMed Scopus (70) Google Scholar). In contrast to ABCA1, ABCG1 does not affect phospholipid efflux. A two-step process has been proposed in which ABCA1 initially promotes lipidation of lipid-poor apo-proteins, and ABCG1 subsequently facilitates a further enrichment with cholesterol (as reviewed in Ref. 4Cavelier C. Lorenzi I. Rohrer L. Eckardstein A.von Lipid efflux by the ATP-binding cassette transporters ABCA1 and ABCG1.Biochim. Biophys. Acta. 2006; 1761: 655-666Crossref PubMed Scopus (186) Google Scholar). However, the physiological relevance of this model is unclear as, in contrast to Abca1−/− mice (10McNeish J. Aiello R.J. Guyot D. Turi T. Gabel C. Aldinger C. Hoppe K.L. Roach M.L. Royer L.J. Wet J.de al et High density lipoprotein deficiency and foam cell accumulation in mice with targeted disruption of ATP-binding cassette transporter-1.Proc. Natl. Acad. Sci. USA. 2000; 97: 4245-4250Crossref PubMed Scopus (481) Google Scholar, 11Christiansen-Weber T.A. Voland J.R. Wu Y. Ngo K. Roland B.L. Nguyen S. Peterson P.A. Fung-Leung W.P. Functional loss of ABCA1 in mice causes severe placental malformation, aberrant lipid distribution, and kidney glomerulonephritis as well as high-density lipoprotein cholesterol deficiency.Am. J. Pathol. 2000; 157: 1017-1029Abstract Full Text Full Text PDF PubMed Scopus (204) Google Scholar), plasma lipoprotein levels are unchanged in Abcg1−/− mice (21Kennedy M.A. Barrera G.C. Nakamura K. Baldan A. Tarr P.T. Fishbein M.C. Frank J.S. Francone O. Edwards P.A. ABCG1 has a critical role in mediating cholesterol efflux to HDL and preventing cellular lipid accumulation.Cell Metab. 2005; 1: 121-131Abstract Full Text Full Text PDF PubMed Scopus (680) Google Scholar). Although ABCG1 is expressed at high levels in many cell types and tissues, the major phenotype of Abcg1−/− mice is an age-dependent pulmonary lipidosis that involves deposition of free and esterified cholesterol in alveolar macrophages, increased surfactant levels, and enlarged type 2 cells containing abnormal lamellar bodies (21Kennedy M.A. Barrera G.C. Nakamura K. Baldan A. Tarr P.T. Fishbein M.C. Frank J.S. Francone O. Edwards P.A. ABCG1 has a critical role in mediating cholesterol efflux to HDL and preventing cellular lipid accumulation.Cell Metab. 2005; 1: 121-131Abstract Full Text Full Text PDF PubMed Scopus (680) Google Scholar, 22Baldan A. Tarr P. Vales C.S. Frank J. Shimotake T.K. Hawgood S. Edwards P.A. Deletion of the transmembrane transporter ABCG1 results in progressive pulmonary lipidosis.J. Biol. Chem. 2006; 281: 29401-29410Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar). This lipidosis is accelerated when Abcg1−/− mice are fed a high-fat, high-cholesterol diet (21Kennedy M.A. Barrera G.C. Nakamura K. Baldan A. Tarr P.T. Fishbein M.C. Frank J.S. Francone O. Edwards P.A. ABCG1 has a critical role in mediating cholesterol efflux to HDL and preventing cellular lipid accumulation.Cell Metab. 2005; 1: 121-131Abstract Full Text Full Text PDF PubMed Scopus (680) Google Scholar, 22Baldan A. Tarr P. Vales C.S. Frank J. Shimotake T.K. Hawgood S. Edwards P.A. Deletion of the transmembrane transporter ABCG1 results in progressive pulmonary lipidosis.J. Biol. Chem. 2006; 281: 29401-29410Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar, 23Out R. Hoekstra M. Meurs I. Vos P.de Kuiper J. Eck M.Van Berkel T.J. Van Total body ABCG1 expression protects against early atherosclerotic lesion development in mice.Arterioscler. Thromb. Vasc. Biol. 2007; 27: 594-599Crossref PubMed Scopus (68) Google Scholar), suggesting that dietary lipids contribute to the sterol imbalance in the lungs. We have suggested that the lung phenotype noted in Abcg1−/− mice may result from the continual cellular uptake of cholesterol-containing surfactant coupled with a defect in ABCG1-dependent sterol efflux (22Baldan A. Tarr P. Vales C.S. Frank J. Shimotake T.K. Hawgood S. Edwards P.A. Deletion of the transmembrane transporter ABCG1 results in progressive pulmonary lipidosis.J. Biol. Chem. 2006; 281: 29401-29410Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar). Clearly the increased expression of Abca1 in the lungs of these mice (22Baldan A. Tarr P. Vales C.S. Frank J. Shimotake T.K. Hawgood S. Edwards P.A. Deletion of the transmembrane transporter ABCG1 results in progressive pulmonary lipidosis.J. Biol. Chem. 2006; 281: 29401-29410Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar) is insufficient to compensate for the loss of ABCG1. Besides the overt lipid phenotype in the lungs, gene expression was also altered in the brains of Abcg1−/− mice: Abca1 was increased while Srebp-2 and Srebp-2 target genes involved in cholesterol biosynthesis were decreased (19Tarr P.T. Edwards P.A. ABCG1 and ABCG4 are coexpressed in neurons and astrocytes of the CNS and regulate cholesterol homeostasis through SREBP-2.J. Lipid Res. 2008; 49: 169-182Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar, 24Burgess B.L. Parkinson P.F. Racke M.M. Fan V.Hirsch-Reinshagen, J. Wong C. Stukas S. Theroux L. Chan J.Y. Donkin J. al et ABCG1 influences the brain cholesterol biosynthetic pathway but does not affect amyloid precursor protein or apolipoprotein E metabolism in vivo.J. Lipid Res. 2008; 49: 1254-1267Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar). Conversely, overexpression of ABCG1 led to increased expression of Srebp-2 and its targets (19Tarr P.T. Edwards P.A. ABCG1 and ABCG4 are coexpressed in neurons and astrocytes of the CNS and regulate cholesterol homeostasis through SREBP-2.J. Lipid Res. 2008; 49: 169-182Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar, 24Burgess B.L. Parkinson P.F. Racke M.M. Fan V.Hirsch-Reinshagen, J. Wong C. Stukas S. Theroux L. Chan J.Y. Donkin J. al et ABCG1 influences the brain cholesterol biosynthetic pathway but does not affect amyloid precursor protein or apolipoprotein E metabolism in vivo.J. Lipid Res. 2008; 49: 1254-1267Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar). These changes suggest that the brains of Abcg1−/− mice contain increased levels of oxysterols that activate LXR and repress SREBP-2 maturation and activity. Together, these results support the proposal that the function of ABCG1 is to regulate the intracellular mobilization of sterols. The observation that cholesterol ester droplets accumulate in pulmonary Abcg1−/− macrophages (21Kennedy M.A. Barrera G.C. Nakamura K. Baldan A. Tarr P.T. Fishbein M.C. Frank J.S. Francone O. Edwards P.A. ABCG1 has a critical role in mediating cholesterol efflux to HDL and preventing cellular lipid accumulation.Cell Metab. 2005; 1: 121-131Abstract Full Text Full Text PDF PubMed Scopus (680) Google Scholar, 22Baldan A. Tarr P. Vales C.S. Frank J. Shimotake T.K. Hawgood S. Edwards P.A. Deletion of the transmembrane transporter ABCG1 results in progressive pulmonary lipidosis.J. Biol. Chem. 2006; 281: 29401-29410Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar, 23Out R. Hoekstra M. Meurs I. Vos P.de Kuiper J. Eck M.Van Berkel T.J. Van Total body ABCG1 expression protects against early atherosclerotic lesion development in mice.Arterioscler. Thromb. Vasc. Biol. 2007; 27: 594-599Crossref PubMed Scopus (68) Google Scholar) suggested that loss of ABCG1 might be associated with an increased atherosclerotic burden due to increased numbers of lipid-loaded macrophages in the artery wall. However, Abcg1−/− mice are not hyperlipidemic, and thus do not develop atherosclerosis even on a Western diet (21Kennedy M.A. Barrera G.C. Nakamura K. Baldan A. Tarr P.T. Fishbein M.C. Frank J.S. Francone O. Edwards P.A. ABCG1 has a critical role in mediating cholesterol efflux to HDL and preventing cellular lipid accumulation.Cell Metab. 2005; 1: 121-131Abstract Full Text Full Text PDF PubMed Scopus (680) Google Scholar). To circumvent this problem bone-marrow-transplant studies were performed using donor cells from Abcg1−/− or wild-type mice and recipient hyperlipidemic Ldlr−/− mice (25Out R. Hoekstra M. Hildebrand R.B. Kruit J.K. Meurs I. Li Z. Kuipers F. Berkel T.J. Van Eck M.Van Macrophage ABCG1 deletion disrupts lipid homeostasis in alveolar macrophages and moderately influences atherosclerotic lesion development in LDL receptor-deficient mice.Arterioscler. Thromb. Vasc. Biol. 2006; 26: 2295-2300Crossref PubMed Scopus (173) Google Scholar, 26Baldan A. Pei L. Lee R. Tarr P. Tangirala R.K. Weinstein M.M. Frank J. Li A.C. Tontonoz P. Edwards P.A. Impaired development of atherosclerosis in hyperlipidemic Ldlr−/− and ApoE−/− mice transplanted with Abcg1−/− bone marrow.Arterioscler. Thromb. Vasc. Biol. 2006; 26: 2301-2307Crossref PubMed Scopus (151) Google Scholar, 27Ranalletta M. Wang N. Han S. Welch L.Yvan-Charvet, C. Tall A.R. Decreased atherosclerosis in low-density lipoprotein receptor knockout mice transplanted with Abcg1−/− bone marrow.Arterioscler. Thromb. Vasc. Biol. 2006; 26: 2308-2315Crossref PubMed Scopus (149) Google Scholar). Two studies reported a significant decrease (20–50%) in lesion size in mice transplanted with Abcg1−/− cells (26Baldan A. Pei L. Lee R. Tarr P. Tangirala R.K. Weinstein M.M. Frank J. Li A.C. Tontonoz P. Edwards P.A. Impaired development of atherosclerosis in hyperlipidemic Ldlr−/− and ApoE−/− mice transplanted with Abcg1−/− bone marrow.Arterioscler. Thromb. Vasc. Biol. 2006; 26: 2301-2307Crossref PubMed Scopus (151) Google Scholar, 27Ranalletta M. Wang N. Han S. Welch L.Yvan-Charvet, C. Tall A.R. Decreased atherosclerosis in low-density lipoprotein receptor knockout mice transplanted with Abcg1−/− bone marrow.Arterioscler. Thromb. Vasc. Biol. 2006; 26: 2308-2315Crossref PubMed Scopus (149) Google Scholar) that was attributed to either accelerated apoptosis of Abcg1−/− macrophages (26Baldan A. Pei L. Lee R. Tarr P. Tangirala R.K. Weinstein M.M. Frank J. Li A.C. Tontonoz P. Edwards P.A. Impaired development of atherosclerosis in hyperlipidemic Ldlr−/− and ApoE−/− mice transplanted with Abcg1−/− bone marrow.Arterioscler. Thromb. Vasc. Biol. 2006; 26: 2301-2307Crossref PubMed Scopus (151) Google Scholar), or to increased secretion of athero-protective apoE by the Abcg1−/− macrophages (27Ranalletta M. Wang N. Han S. Welch L.Yvan-Charvet, C. Tall A.R. Decreased atherosclerosis in low-density lipoprotein receptor knockout mice transplanted with Abcg1−/− bone marrow.Arterioscler. Thromb. Vasc. Biol. 2006; 26: 2308-2315Crossref PubMed Scopus (149) Google Scholar). The relative importance of apoptosis versus apoE secretion in providing lesion protection in this model remains to be determined. In contrast, a third paper reported a “moderately significant” increase in lesion size in the Ldlr−/− mice receiving bone marrow from Abcg1−/− mice (25Out R. Hoekstra M. Hildebrand R.B. Kruit J.K. Meurs I. Li Z. Kuipers F. Berkel T.J. Van Eck M.Van Macrophage ABCG1 deletion disrupts lipid homeostasis in alveolar macrophages and moderately influences atherosclerotic lesion development in LDL receptor-deficient mice.Arterioscler. Thromb. Vasc. Biol. 2006; 26: 2295-2300Crossref PubMed Scopus (173) Google Scholar). The reasons for these variable results remain obscure. Based on the proposed role of ABCG1 in facilitating cholesterol efflux from macrophages, it seemed likely that transgenic ABCG1 mice would be protected from diet-induced atherosclerosis. Thus, the finding that overexpression of ABCG1 in Ldlr−/− (28Basso F. Amar M.J. Wagner E.M. Vaisman B. Paigen B. Remaley S.Santamarina-Fojo, and A.T. Enhanced ABCG1 expression increases atherosclerosis in LDLr-KO mice on a western diet.Biochem. Biophys. Res. Commun. 2006; 351: 398-404Crossref PubMed Scopus (44) Google Scholar) or ApoE−/− (29Burgess B. Naus K. Chan J. Tansley V.Hirsch-Reinshagen, G. Matzke L. Chan B. Wilkinson A. Fan J. Donkin J. al et Overexpression of human ABCG1 does not affect atherosclerosis in fat-fed apoE-deficient mice.Arterioscler Thromb Vasc Biol. 2008; 17: 1731-1737Crossref Scopus (46) Google Scholar) mice either moderately increased or had no effect on lesion size, respectively, is perplexing. Additional" @default.
• W2109320834 created "2016-06-24" @default.
• W2109320834 creator A5006326416 @default.
• W2109320834 creator A5011059025 @default.
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