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ABCG1 influences the brain cholesterol biosynthetic pathway but does not affect amyloid precursor protein or apolipoprotein E metabolism in vivo

2008; Elsevier BV; Volume: 49; Issue: 6 Linguagem: Inglês

10.1194/jlr.m700481-jlr200

ISSN

1539-7262

Autores

Braydon L. Burgess, Pamela F. Parkinson, Margaret M. Racke, Veronica Hirsch‐Reinshagen, Jianjia Fan, Charmaine Wong, Sophie Stukas, Louise Théroux, Jeniffer Chan, James Donkin, Anna Wilkinson, Danielle Balik, Brian R. Christie, Judes Poirier, Dieter Lütjohann, Ronald B. DeMattos, Cheryl L. Wellington,

Tópico(s)

Alzheimer's disease research and treatments

Resumo

Cholesterol homeostasis is of emerging therapeutic importance for Alzheimer's disease (AD). Agonists of liver-X-receptors (LXRs) stimulate several genes that regulate cholesterol homeostasis, and synthetic LXR agonists decrease neuropathological and cognitive phenotypes in AD mouse models. The cholesterol transporter ABCG1 is LXR-responsive and highly expressed in brain. In vitro, conflicting reports exist as to whether ABCG1 promotes or impedes Aβ production. To clarify the in vivo roles of ABCG1 in Aβ metabolism and brain cholesterol homeostasis, we assessed neuropathological and cognitive outcome measures in PDAPP mice expressing excess transgenic ABCG1. A 6-fold increase in ABCG1 levels did not alter Aβ, amyloid, apolipoprotein E levels, cholesterol efflux, or cognitive performance in PDAPP mice. Furthermore, endogenous murine Aβ levels were unchanged in both ABCG1-overexpressing or ABCG1-deficient mice. These data argue against a direct role for ABCG1 in AD. However, excess ABCG1 is associated with decreased levels of sterol precursors and increased levels of SREBP-2 and HMG-CoA-reductase mRNA, whereas deficiency of ABCG1 leads to the opposite effects. Although functions for ABCG1 in cholesterol efflux and Aβ metabolism have been proposed based on results with cellular model systems, the in vivo role of this enigmatic transporter may be largely one of regulating the sterol biosynthetic pathway. Cholesterol homeostasis is of emerging therapeutic importance for Alzheimer's disease (AD). Agonists of liver-X-receptors (LXRs) stimulate several genes that regulate cholesterol homeostasis, and synthetic LXR agonists decrease neuropathological and cognitive phenotypes in AD mouse models. The cholesterol transporter ABCG1 is LXR-responsive and highly expressed in brain. In vitro, conflicting reports exist as to whether ABCG1 promotes or impedes Aβ production. To clarify the in vivo roles of ABCG1 in Aβ metabolism and brain cholesterol homeostasis, we assessed neuropathological and cognitive outcome measures in PDAPP mice expressing excess transgenic ABCG1. A 6-fold increase in ABCG1 levels did not alter Aβ, amyloid, apolipoprotein E levels, cholesterol efflux, or cognitive performance in PDAPP mice. Furthermore, endogenous murine Aβ levels were unchanged in both ABCG1-overexpressing or ABCG1-deficient mice. These data argue against a direct role for ABCG1 in AD. However, excess ABCG1 is associated with decreased levels of sterol precursors and increased levels of SREBP-2 and HMG-CoA-reductase mRNA, whereas deficiency of ABCG1 leads to the opposite effects. Although functions for ABCG1 in cholesterol efflux and Aβ metabolism have been proposed based on results with cellular model systems, the in vivo role of this enigmatic transporter may be largely one of regulating the sterol biosynthetic pathway. Alzheimer's disease apolipoprotein E amyloid precursor protein bacterial artificial chromosome blood-brain barrier Chinese hamster ovary central nervous system cerebrospinal fluid C-terminal fragment human embryonic kidney HMG-CoA-reductase long-term potentiation liver X receptor murine Aβ neuron growth media quantitative reverse transcriptase PCR The central nervous system (CNS) is the richest repository of cholesterol in the body, containing 25% of the body's total cholesterol content but only 2% of its total mass (1.Dietschy J.M. Turley S.D. Cholesterol metabolism in the brain.Curr. Opin. Lipidol. 2001; 12: 105-112Crossref PubMed Scopus (728) Google Scholar). Approximately 70–80% of this cholesterol is stably sequestered in myelin, leaving a relatively small proportion found within highly dynamic neuronal and glial membranes (1.Dietschy J.M. Turley S.D. Cholesterol metabolism in the brain.Curr. Opin. Lipidol. 2001; 12: 105-112Crossref PubMed Scopus (728) Google Scholar). Nearly all brain cholesterol is synthesized in situ; quantitative analyses show that essentially no cholesterol carried on peripheral lipoproteins enters the brain across the blood-brain barrier (BBB) (1.Dietschy J.M. Turley S.D. Cholesterol metabolism in the brain.Curr. Opin. Lipidol. 2001; 12: 105-112Crossref PubMed Scopus (728) Google Scholar). During early development and myelination, the brain has a high demand for cholesterol biosynthesis, and both neurons and glia actively synthesize cholesterol de novo. However, cholesterol biosynthesis is reduced to a low basal rate in adult neurons, which rely largely on cholesterol delivered from glial-derived HDL-like particles enriched in apolipoprotein E (apoE) to meet their lipid requirements. In the CNS, apoE coordinates the mobilization and redistribution of cholesterol and phospholipids during development or in response to injury, and facilitates the membrane remodelling that is associated with synaptic replacement, nerve terminal sprouting, and dendritic remodelling (2.Poirier J. Apolipoprotein E in animal models of CNS injury and Alzheimer's disease.Trends Neurosci. 1994; 17: 525-530Abstract Full Text PDF PubMed Scopus (608) Google Scholar, 3.Mahley R.W. Rall Jr, S.C. Apolipoprotein E: far more than a lipid transport protein.Annu. Rev. Genomics Hum. Genet. 2000; 1: 507-537Crossref PubMed Scopus (1326) Google Scholar). Because cells within the CNS cannot degrade the sterol ring, excess neuronal cholesterol is eliminated from the brain via cyp-46-mediated conversion of cholesterol to 24S-hydroxycholesterol, an oxysterol that can passively diffuse across the BBB into the peripheral circulation (4.Lund E.G. Kerr T.A. Sakai J. Li W.P. Russell D.W. cDNA cloning of mouse and human cholesterol 25-hydroxylases, polytopic membrane proteins that synthesize a potent oxysterol regulator of lipid metabolism.J. Biol. Chem. 1998; 273: 34316-34327Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar, 5.Lund E.G. Guileyardo J.M. Russell D.W. cDNA cloning of cholesterol 24-hydroxylase, a mediator of cholesterol homeostasis in the brain.Proc. Natl. Acad. Sci. USA. 1999; 96: 7238-7243Crossref PubMed Scopus (524) Google Scholar, 6.Lund E.G. Xie C. Kotti T. Turley S.D. Dietschy J.M. Russell D.W. Knockout of the cholesterol 24-hydroxylase gene in mice reveals a brain-specific mechanism of cholesterol turnover.J. Biol. Chem. 2003; 278: 22980-22988Abstract Full Text Full Text PDF PubMed Scopus (310) Google Scholar). Cyp46-deficient mice are impaired in cholesterol turnover and compensate by reducing net sterol synthesis (6.Lund E.G. Xie C. Kotti T. Turley S.D. Dietschy J.M. Russell D.W. Knockout of the cholesterol 24-hydroxylase gene in mice reveals a brain-specific mechanism of cholesterol turnover.J. Biol. Chem. 2003; 278: 22980-22988Abstract Full Text Full Text PDF PubMed Scopus (310) Google Scholar, 7.Kotti T.J. Ramirez D.M.O. Pfeiffer B.E. Huber K.M. Russell D.W. Brain cholesterol turnover required for geranylgeraniol production and learning in mice.Proc. Natl. Acad. Sci. USA. 2006; 103: 3869-3874Crossref PubMed Scopus (193) Google Scholar), demonstrating that the brain, like peripheral tissues, tightly regulates the balance of sterol synthesis and elimination by multiple modes of feedback control that converge upon HMG-CoA-reductase (HMG-CoAR), which catalyses the rate-limiting step in sterol biosynthesis. Intriguingly, a low but continuous flux of sterol synthesis and export is required for normal learning and memory; mice lacking cyp46 have no demonstrable long-term potentiation (LTP) and are profoundly impaired in spatial memory tasks (7.Kotti T.J. Ramirez D.M.O. Pfeiffer B.E. Huber K.M. Russell D.W. Brain cholesterol turnover required for geranylgeraniol production and learning in mice.Proc. Natl. Acad. Sci. USA. 2006; 103: 3869-3874Crossref PubMed Scopus (193) Google Scholar). LTP in brain slices prepared from cyp46-knockout mice is rescued by geranylgeraniol but not by cholesterol, indicating that the isoprenoid branch of the cholesterol biosynthetic pathway plays a crucial role in cognition (7.Kotti T.J. Ramirez D.M.O. Pfeiffer B.E. Huber K.M. Russell D.W. Brain cholesterol turnover required for geranylgeraniol production and learning in mice.Proc. Natl. Acad. Sci. USA. 2006; 103: 3869-3874Crossref PubMed Scopus (193) Google Scholar). Together, these observations suggest that gene products that participate in maintaining sterol homeostasis in the CNS may have important roles for several brain functions, including myelination, neuronal repair, and cognition. Several lines of evidence suggest that impaired brain cholesterol metabolism may also contribute to the pathogenesis of Alzheimer's disease (AD) (8.Wolozin B. Cholesterol and the biology of Alzheimer's disease.Neuron. 2004; 41: 7-10Abstract Full Text Full Text PDF PubMed Scopus (235) Google Scholar). Allelic variation in apoE, the major cholesterol carrier in the CNS, is the best-established genetic risk factor for late-onset sporadic AD (9.Corder E.H. Saunders A.M. Strittmatter W.J. Schmechel D.E. Gaskell P.C. Small G.W. Roses A.D. Haines J.L. Pericak-Vance M.A. Gene dose of apolipoprotein E type 4 and the risk of Alzheimer's disease in late onset families.Science. 1993; 261: 921-923Crossref PubMed Scopus (7262) Google Scholar, 10.Corder E.H. Saunders A.M. Risch N.J. Strittmatter W.J. Schmechel D.E. Gaskell P.C. Rimmler J.B. Locke P.A. Conneally P.M. Schmader K.E. et al.Protective effect of apolipoprotein E type 2 for late onset Alzheimer disease.Nat. Genet. 1994; 7: 180-184Crossref PubMed Scopus (1535) Google Scholar, 11.Poirier J. Davignon J. Bouthillier D. Kogan S. Bertrand P. Gauthier S. Apolipoprotein E polymorphism and Alzheimer's disease.Lancet. 1993; 342: 697-699Abstract PubMed Scopus (1171) Google Scholar). Although the mechanisms by which apoE participates in AD pathogenesis remain a subject of considerable investigation, we and others have recently demonstrated that the lipidation status of apoE participates in the metabolism of Aβ peptides, which are the toxic products that accumulate as amyloid plaques in the brains of AD patients (12.Price D.L. Tanzi R.E. Borchelt D.R. Sisodia S.S. Alzheimer's disease: genetic studies and transgenic models.Annu. Rev. Genet. 1998; 32: 461-493Crossref PubMed Scopus (355) Google Scholar). In the brain, apoE is primarily lipidated by the cholesterol transporter ABCA1; mice deficient in ABCA1 have low levels of poorly lipidated apoE in brain tissues and in cerebrospinal fluid (CSF) (13.Hirsch-Reinshagen V. Zhou S. Burgess B.L. Bernier L. McIsaac S.A. Chan J.Y. Tansley G.H. Cohn J.S. Hayden M.R. Wellington C.L. Deficiency of ABCA1 impairs apolipoprotein E metabolism in brain.J. Biol. Chem. 2004; 279: 41197-41207Abstract Full Text Full Text PDF PubMed Scopus (299) Google Scholar, 14.Wahrle S.E. Jiang H. Parsadanian M. Legleiter J. Han X. Fryer J.D. Kowalewski T. Holtzman D.M. ABCA1 is required for normal CNS apoE levels and for lipidation of astrocyte-secreted apoE.J. Biol. Chem. 2004; 279: 40987-40993Abstract Full Text Full Text PDF PubMed Scopus (337) Google Scholar). Intriguingly, several groups including ours have shown that ABCA1-deficient animals have an increased amyloid load when crossed to mouse models of AD, suggesting that poorly lipidated apoE promotes amyloidogenesis in vivo (15.Hirsch-Reinshagen V. Maia L.F. Burgess B.L. Blain J.F. Naus K.E. McIsaac S.A. Parkinson P.F. Chan J.Y. Tansley G.H. Hayden M.R. et al.The absence of ABCA1 decreases soluble apoE levels but does not diminish amyloid deposition in two murine models of Alzheimer disease.J. Biol. Chem. 2005; 280: 43243-43256Abstract Full Text Full Text PDF PubMed Scopus (193) Google Scholar, 16.Wahrle S. Jiang H. Parsadanian M. Hartman R.E. Bales K.R. Paul S.M. Holtzman D.M. Deletion of Abca1 increases Abeta deposition in the PDAPP transgenic mouse model of Alzheimer disease.J. Biol. Chem. 2005; 280: 43236-43242Abstract Full Text Full Text PDF PubMed Scopus (262) Google Scholar, 17.Koldamova R. Staufenbiel M. Lefterov I. Lack of ABCA1 considerably decreases brain apoE level and increases amyloid deposition in APP23 mice.J. Biol. Chem. 2005; 280: 43224-43235Abstract Full Text Full Text PDF PubMed Scopus (290) Google Scholar). Conversely, increasing ABCA1 levels by 6-fold or greater increases apoE lipidation and virtually eliminates amyloid burden in the PDAPP model of AD (18.Wahrle S.E. Shah A.R. Fagan A.M. Smemo S. Kauwe J.S. Grupe A. Hinrichs A. Mayo K. Jiang H. Thai L.J. et al.Apolipoprotein E levels in cerebrospinal fluid and the effects of ABCA1 polymorphisms.Mol Neurodegener. 2007; 12: 2-7Google Scholar). Although whether the lipidation status of apoE primarily affects Aβ deposition or influences Aβ clearance remains to be fully elucidated, existing studies identify ABCA1-mediated lipidation of apoE as a significant contributing factor to amyloid burden in vivo. A second mechanism whereby cholesterol may contribute to the pathogenesis of AD is the generation of Aβ from amyloid precursor protein (APP), which is influenced by the concentration and distribution of cholesterol in cellular membranes (8.Wolozin B. Cholesterol and the biology of Alzheimer's disease.Neuron. 2004; 41: 7-10Abstract Full Text Full Text PDF PubMed Scopus (235) Google Scholar, 19.Hartmann T. Cholesterol, Aβ and Alzheimer's disease.Trends Neurosci. 2001; 24: 45-48Abstract Full Text Full Text PDF Google Scholar). APP is a type I transmembrane protein that is cleaved along two major proteolytic pathways (20.Haass C. Selkoe D.J. Cellular processing of β-amyloid precursor and the genesis of amyloid β-peptide.Cell. 1993; 75: 154-159Abstract Full Text PDF Scopus (739) Google Scholar). APP can be cleaved by β-secretase (encoded by BACE-1) to release a soluble N-terminal domain of APP into the extracellular space and leave a 99-amino-acid (C99) C-terminal fragment (CTF) attached to the plasma membrane (21.Vassar R. Bennett B.D. Babu-Khan S. Kahn S. Mendiaz E.A. Denis P. Teplow D.B. Ross S. Amarante P. Loeloff R. et al.β-Secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE.Science. 1999; 286: 735-741Crossref PubMed Scopus (3299) Google Scholar). β-secretase activity is thought to occur primarily in lipid rafts, which are detergent-insoluble microdomains rich in cholesterol and sphingomyelin (22.Ehehalt R. Keller P. Haass C. Thiele C. Simons K. Amyloidogenic processing of the Alzheimer β-amyloid precursor protein depends on lipid rafts.J. Cell Biol. 2003; 160: 113-123Crossref PubMed Scopus (920) Google Scholar). C99 is further cleaved by γ-secretase (a complex composed of presenilin, nicastrin, aph1, and pen2) within the membrane to release the APP intracellular domain and liberate Aβ peptides, typically 40 or 42 amino acids in length (23.Kimberley W.T. LaVoie M.J. Ostaszeski B.L. Ye W. Wolfe M.S. Selkoe D.J. γ-Secretase is a membrane protein complex comprised of presenilin, nicastrin, aph-1, and pen-2.Proc. Natl. Acad. Sci. USA. 2003; 100: 6382-6387Crossref PubMed Scopus (676) Google Scholar). The first step in APP cleavage can also be mediated by α-secretase, which cleaves within the Aβ domain and thereby precludes the formation of Aβ species (20.Haass C. Selkoe D.J. Cellular processing of β-amyloid precursor and the genesis of amyloid β-peptide.Cell. 1993; 75: 154-159Abstract Full Text PDF Scopus (739) Google Scholar). Multiple proteins of the ADAM family are reported to possess α-secretase activity, and the activity of ADAM 10 is modulated by the fluidity of the membrane (24.Kojro E. Gimple G. Lammich S. März W. Fahrenholz F. Low cholesterol stimulates the nonamyloidogenic pathway by its effect on the α-secretase ADAM 10.Proc. Natl. Acad. Sci. USA. 2001; 98: 5815-5820Crossref PubMed Scopus (727) Google Scholar, 25.Lammich S. Kojro E. Postina R. Gilbert S. Pfeiffer R. Jasionowski M. Haass C. Fahrenholz F. Constitutive and regulated α-secretase cleavage of Alzheimer's amyloid precursor protein by a disintegrin metalloprotease.Proc. Natl. Acad. Sci. USA. 1999; 96: 3922-3927Crossref PubMed Scopus (984) Google Scholar, 26.Buxbaum J.D. Liu K.N. Luo Y. Slack J.L. Stocking K.L. Peschon J.J. Johnson R.S. Castner B.J. Cerretti D.P. Black R.A. Evidence that tumor necrosis factor α converting enzyme is involved in regulated α-secretase cleavage of the Alzheimer amyloid protein precursor.J. Biol. Chem. 1998; 273: 27765-27767Abstract Full Text Full Text PDF PubMed Scopus (837) Google Scholar). Several studies have shown that conditions of high membrane cholesterol content promote Aβ generation by facilitating the interaction of APP and BACE-1 in lipid rafts (27.Refolo L.M. Pappolla M.A. Malester B. LaFrancois J. Bryant-Thomas T. Wang R. Tint G.S. Sambamurti K. Duff K. Hypercholesterolemia accelerates the Alzheimer's amyloid pathology in a transgenic mouse model.Neurobiol. Dis. 2000; 7: 321-331Crossref PubMed Scopus (884) Google Scholar, 28.Shie F.S. Jin L.W. Cook D.G. Leverenz J.B. LeBoeuf R.C. Diet-induced hypercholesterolemia enhances brain A beta accumulation in transgenic mice.Neuroreport. 2002; 213: 455-459Crossref Scopus (191) Google Scholar, 29.Wahrle S. Das P. Nyborg A.C. McLendon C. Shoji M. Kawarabayashi T. Younkin L.H. Younkin S.G. Golde T.E. Cholesterol-dependent γ-secretase activity in buoyant cholesterol-rich membrane microdomains.Neurobiol. Dis. 2002; 9: 11-23Crossref PubMed Scopus (362) Google Scholar, 30.Burns M. Gaynor K. Olm V. Mercken M. LaFrancois J. Wang L. Matthews P.M. Noble W. Matsuoka Y. Duff K. Presenilin redistribution associated with aberrant cholesterol transport enhances β-amyloid production in vivo.J. Neurosci. 2003; 23: 5645-5649Crossref PubMed Google Scholar). Conversely, depletion of membrane cholesterol by either pharmacological or biochemical means increases α-secretase activity and decreases Aβ production (22.Ehehalt R. Keller P. Haass C. Thiele C. Simons K. Amyloidogenic processing of the Alzheimer β-amyloid precursor protein depends on lipid rafts.J. Cell Biol. 2003; 160: 113-123Crossref PubMed Scopus (920) Google Scholar, 24.Kojro E. Gimple G. Lammich S. März W. Fahrenholz F. Low cholesterol stimulates the nonamyloidogenic pathway by its effect on the α-secretase ADAM 10.Proc. Natl. Acad. Sci. USA. 2001; 98: 5815-5820Crossref PubMed Scopus (727) Google Scholar, 31.Fassbender K. Simons M. Bergmann C. Stroick M. Lütjohann D. Keller P. Runz H. Kühl S. Bertsch T. Bergmann K.von et al.Simvastatin strongly reduces levels of Alzheimer's disease β-amyloid peptides Aβ42 and Aβ40 in vitro and in vivo.Proc. Natl. Acad. Sci. USA. 2001; 98: 5856-5861Crossref PubMed Scopus (1030) Google Scholar, 32.Simons M. Keller P. Strooper B.De Beyreuther K. Dottie C.G. Simons K. Cholesterol depletion inhibits the generation of β-amyloid in hippocampal neurons.Proc. Natl. Acad. Sci. USA. 1998; 95: 6460-6464Crossref PubMed Scopus (1082) Google Scholar, 33.Bodovitz S. Klein W.L. Cholesterol modulates α-secretase cleavage of amyloid precursor protein.J. Biol. Chem. 1996; 271: 4436-4440Abstract Full Text Full Text PDF PubMed Scopus (423) Google Scholar, 34.Buxbaum J.D. Geoghagan N.S. Friedhoff L.T. Cholesterol depletion with physiological concentrations of a statin decreases the formation of the Alzheimer amyloid Abeta peptide.J. Alzheimers Dis. 2001; 3: 221-229Crossref PubMed Scopus (60) Google Scholar). These studies suggest that genes that control the levels or distribution of cellular cholesterol could influence Aβ generation by affecting the accessibility of APP to secretase components, or through direct effects on secretase activity. ABCG1 is a member of the ATP binding cassette superfamily and part of a network of genes that regulate cellular lipid homeostasis (35.Schmitz G. Langmann T. Heimerl S. Role of ABCG1 and other ABCG family members in lipid metabolism.J. Lipid Res. 2001; 42: 1513-1520Abstract Full Text Full Text PDF PubMed Google Scholar). In cultured cells, ABCG1 promotes the efflux of cholesterol, phospholipid, sphingomyelin, and 7-ketocholesterol (36.Cavelier 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, 37.Vaughan A.M. Oram J.F. ABCG1 redistributes cell cholesterol to domains removable by HDL but not by lipid-depleted apolipoproteins.J. Biol. Chem. 2005; 280: 30150-30157Abstract Full Text Full Text PDF PubMed Scopus (224) Google Scholar, 38.Wang N. Ranalletta M. Matsuura F. Peng F. Tall A. LXR-induced redistribution of ABCG1 to plasma membrane in macrophages enhances cholesterol mass efflux to HDL.Arterioscler. Thromb. Vasc. Biol. 2006; 26: 1310-1316Crossref PubMed Scopus (185) Google Scholar, 39.Kobayashi A. Takanezawa Y. Hirata T. Shimizu Y. Misasa K. Kioka N. Arai H. Ueda K. Matsuo M. Efflux of sphingomyelin, cholesterol, and phosphatidylcholine by ABCG1.J. Lipid Res. 2006; 47: 1791-1802Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar, 40.Terasaka N. Wang N. Yvan-Charvet L. Tall A.R. High-density lipoprotein protects macrophages from oxidized low-density lipoprotein-induced apoptosis by promoting efflux of 7-ketocholesterol via ABCG1.Proc. Natl. Acad. Sci. USA. 2007; 104: 15093-15098Crossref PubMed Scopus (214) Google Scholar). These studies have led to a model whereby ABCA1 catalyses the initial transfer of lipids onto lipid-free apolipoproteins, including apoA-I or apoE, to form nascent discoidal particles, which are then fully lipidated in a second phase of efflux mediated by ABCG1 (41.Gelissen I.C. Harris M. Rye K-A. Quinn C. Brown A.J. Kockx M. Cartland S. Packianthan M. Kritharides L. Jessup W. ABCA1 and ABCG1 synergize to mediate cholesterol export to apoA-1.Arterioscler. Thromb. Vasc. Biol. 2006; 26: 534-540Crossref PubMed Scopus (340) Google Scholar, 42.Vaughan A.M. Oram J.F. ABCA1 and ABCG1 or ABCG4 act sequentially to remove cellular cholesterol and generate cholesterol-rich HDL.J. Lipid Res. 2006; 47: 2433-2443Abstract Full Text Full Text PDF PubMed Scopus (231) Google Scholar). In vivo, however, the roles of ABCG1 are less well understood. Several studies have clearly demonstrated that neither overexpression nor deficiency of ABCG1 affects plasma lipid levels, although a recent investigation observed reduced nonesterified fatty acids in ABCG1-deficient mice fed a high-fat diet devoid of cholesterol (43.Kennedy M.A. Barrera G.C. Nakamura K. Baldán A. Tarr P. Fishbein M.C. Frank J. Francone O.L. 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, 44.Baldán 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, 45.Baldán 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, 46.Out R. Hoekstra M. Hildebrand R.B. Kruit J.K. Meurs I. Li Z. Kuipers F. Van Berkel T.J. 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, 47.Out R. Hoekstra M. Meurs I. Vos P.de Kuiper J. Eck M.Van Van Berkel T.J. 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, 48.Ranalletta M. Wang N. Han S. Yvan-Charvet L. Welch 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, 49.Buchmann J. Meyer C. Neschen S. Augustin R. Schmolz K. Kluge R. Al-Hasani H. Jürgens H. Eulenberg K. Wehr R. et al.Ablation of the cholesterol transporter adenosine triphosphate-binding cassette transporter G1 reduces adipose cell size and protects against diet-induced obesity.Endocrinology. 2006; 148: 1561-1573Crossref PubMed Scopus (68) Google Scholar). Several groups have shown that deficiency of ABCG1 leads to accumulation of neutral lipids in several peripheral tissues when animals are challenged with a high-fat diet containing cholesterol, supporting a role for ABCG1 in the regulation of tissue sterol homeostasis (43.Kennedy M.A. Barrera G.C. Nakamura K. Baldán A. Tarr P. Fishbein M.C. Frank J. Francone O.L. 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, 44.Baldán 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, 47.Out R. Hoekstra M. Meurs I. Vos P.de Kuiper J. Eck M.Van Van Berkel T.J. 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). ABCG1 is abundantly expressed in macrophages, yet despite several studies, consensus has not yet been reached as to whether ABCG1 is pro- or anti-atherogenic (45.Baldán 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, 46.Out R. Hoekstra M. Hildebrand R.B. Kruit J.K. Meurs I. Li Z. Kuipers F. Van Berkel T.J. 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, 47.Out R. Hoekstra M. Meurs I. Vos P.de Kuiper J. Eck M.Van Van Berkel T.J. 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, 48.Ranalletta M. Wang N. Han S. Yvan-Charvet L. Welch 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, 50.Curtiss L.K. Is two out of three enough for ABCG1?.Arterioscler. Thromb. Vasc. Biol. 2006; 26: 2175-2177Crossref PubMed Scopus (25) Google Scholar, 51.Basso F. Amar M.J. Wagner E.M. Vaisman B. Paigen B. Santamarina-Fojo S. Remaley 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). ABCG1 is also highly expressed in brain (52.Tansley G.H. Burgess B.L. Bryan M.T. Su Y. Hirsch-Reinshagen V. Pearce J. Chan J.Y. Wilkinson A. Evans J. Naus K.E. et al.The cholesterol transporter ABCG1 modulates the subcellular distribution and proteolytic processing of β-amyloid precursor protein.J. Lipid Res. 2007; 48: 1022-1034Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar, 53.Wang, N., L. Yvan-Charvet, D. Lutjohann, M. Mulder, T. Vanmierlo, T. W. Kim, and A. R. Tall. ATP-binding cassette transporters G1 and G4 mediate cholesterol and desmosterol efflux to HDL and regulate sterol accumulation in the brain. FASEB J. Epub ahead of print. November 26, 2007Google Scholar, 54.Tarr P.T. Edwards P.A. ABCG1 and ABCG4 are co-expressed in neurons and astrocytes of the CNS and regulate cholesterol homeostasis through SREBP-2.J. Lipid Res. 2007; 49: 169-182Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar), and cholesterol efflux from primary cerebellar glia has been reported to correlate better with ABCG1 than ABCA1 (55.Karten B. Campenot R.B. Vance D.E. Vance J.E. Expression of ABCG1, but not ABCA1, correlates with cholesterol release by cerebellar astroglia.J. Biol. Chem. 2006; 281: 4049-4057Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar). Recently, ABCG1 has been shown to mediate intravesicular cholesterol transport of sterols in primary neurons and astrocytes, to influence SREBP-2 processing, and to affect SREBP-2-responsive genes in the CNS (54.Tarr P.T. Edwards P.A. ABCG1 and ABCG4 are co-expressed in neurons and astrocytes of the CNS and regulate cholesterol homeostasis through SREBP-2.J. Lipid Res. 2007; 49: 169-182Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar). Two independent studies have shown that the cholesterol transporter ABCG1 influences APP processing in cultured cells, but reach opposite conclusions about the effect of ABCG1 on Aβ production. Tansley et al. (52.Tansley G.H. Burgess B.L. Bryan M.T. Su Y. Hirsch-Reinshagen V. Pearce J. Chan J.Y. Wilkinson A. Evans J. Naus K.E. et al.The cholesterol transporter ABCG1 modulates the subcellular distribution and proteolytic processing of β-amyloid precursor protein.J. Lipid Res. 2007; 48: 1022-1034Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar) demonstrated that transient transfection of ABCG1 into human embryonic kidney (HEK) 293 cells expressing APP containing the Swedish mutation (APPSwe) increased Aβ40 and Aβ42 levels by approximately 30%. In

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