This Article Full Text Full Text (PDF) All Versions of this Article: 26/10/2295    most recent 01.ATV.0000237629.29842.4cv1 Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Out, R. Articles by Van Eck, M. Search for Related Content PubMed PubMed Citation Articles by Out, R. Articles by Van Eck, M. Related Collections Pathophysiology Genetically altered mice Lipid and lipoprotein metabolism Related Article

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:2295.)
© 2006 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Macrophage ABCG1 Deletion Disrupts Lipid Homeostasis in Alveolar Macrophages and Moderately Influences Atherosclerotic Lesion Development in LDL Receptor-Deficient Mice

Ruud Out; Menno Hoekstra; Reeni B. Hildebrand; Janine K. Kruit; Illiana Meurs; Zhaosha Li; Folkert Kuipers; Theo J.C. Van Berkel; Miranda Van Eck

From the Division of Biopharmaceutics (R.O., M.H., R.B.H., I.M., Z.L., T.J.C.V.B., M.V.E.), Leiden/Amsterdam Center for Drug Research, Gorlaeus Laboratories, Leiden University, Leiden, The Netherlands; From the Center for Liver, Digestive and Metabolic Diseases (J.K., F.K.), Laboratory of Pediatrics, University Medical Center Groningen, Groningen, The Netherlands.

Correspondence to R. Out, Division of Biopharmaceutics, Gorlaeus Laboratories, Einsteinweg 55, 2333CC Leiden, The Netherlands. E-mail r.out{at}lacdr.leidenuniv.nl

Objective— ABCG1 has recently been identified as a facilitator of cellular cholesterol and phospholipid efflux to high-density lipoprotein (HDL). Its expression in macrophages is induced during cholesterol uptake in macrophages and by liver X receptor (LXR). The role of macrophage ABCG1 in atherosclerotic lesion development is, however, still unknown.

Methods and Results— To assess the role of macrophage ABCG1 in atherosclerosis, we generated low-density lipoprotein (LDL) receptor knockout (LDLr^–/–) mice that are selectively deficient in macrophage ABCG1 by using bone marrow transfer (ABCG1^–/– LDLr^–/–). Peritoneal macrophages isolated from donor ABCG1^–/– mice exhibited a 22% (P=0.0007) decrease in cholesterol efflux to HDL. To induce atherosclerosis, transplanted mice were fed a high-cholesterol diet containing 0.25% cholesterol and 15% fat for 6 and 12 weeks. Serum lipid levels and lipoprotein profiles did not differ significantly between ABCG1^–/– LDLr^–/– mice and controls. In lungs of ABCG1^–/– LDLr^–/– mice a striking accumulation of lipids was observed in macrophages localized to the subpleural region. After 6 weeks of high-cholesterol diet feeding the atherosclerotic lesion size was 49±12x10³ µm² for ABCG1^+/+ LDLr^–/– mice versus 65±15x10³ µm² for ABCG1^–/– LDLr^–/– mice and after 12 weeks of high-cholesterol diet feeding 124±17x10³ µm² for ABCG1^+/+ LDLr^–/– mice versus 168±17x10³ µm² for ABCG1^–/– LDLr^–/– mice. Atherosclerotic lesion size depended on both time and the macrophage ABCG1 genotype (P=0.038 by 2-way ANOVA, n8), indicating a moderately 33% to 36% increase in lesion formation in the absence of macrophage ABCG1.

Conclusions— Macrophage ABCG1 deficiency does lead to heavy lipid accumulation in macrophages of the lung, and also a moderately significant effect on atherosclerotic lesion development was observed.

To assess the role of macrophage ABCG1 in atherosclerosis, we generated LDL receptor knockout mice that are selectively deficient in macrophage ABCG1 by using bone marrow transfer. Feeding the mice a high-cholesterol diet led to heavy lipid accumulation in macrophages of the lung, and moderately influenced atherosclerotic lesion development.

Key Words: ABCG1 • atherosclerosis • cholesterol • macrophage • transplantation

Related Article:

Is Two out of Three Enough for ABCG1?

Linda K. Curtiss
Arterioscler Thromb Vasc Biol 2006 26: 2175-2177. [Extract] [Full Text] [PDF]

This article has been cited by other articles:

				A. Baldan, D. D. Bojanic, and P. A. Edwards The ABCs of sterol transport J. Lipid Res., April 1, 2009; 50(Supplement): S80 - S85. [Abstract] [Full Text] [PDF]

				N. Mukhamedova, G. Escher, W. D'Souza, U. Tchoua, A. Grant, Z. Krozowski, M. Bukrinsky, and D. Sviridov Enhancing apolipoprotein A-I-dependent cholesterol efflux elevates cholesterol export from macrophages in vivo J. Lipid Res., November 1, 2008; 49(11): 2312 - 2322. [Abstract] [Full Text] [PDF]

				C. J. Delvecchio, P. Bilan, P. Nair, and J. P. Capone LXR-induced reverse cholesterol transport in human airway smooth muscle is mediated exclusively by ABCA1 Am J Physiol Lung Cell Mol Physiol, November 1, 2008; 295(5): L949 - L957. [Abstract] [Full Text] [PDF]

				B. Burgess, K. Naus, J. Chan, V. Hirsch-Reinshagen, G. Tansley, L. Matzke, B. Chan, A. Wilkinson, J. Fan, J. Donkin, et al. Overexpression of Human ABCG1 Does Not Affect Atherosclerosis in Fat-Fed ApoE-Deficient Mice Arterioscler Thromb Vasc Biol, October 1, 2008; 28(10): 1731 - 1737. [Abstract] [Full Text] [PDF]

				B. L. Burgess, P. F. Parkinson, M. M. Racke, V. Hirsch-Reinshagen, J. Fan, C. Wong, S. Stukas, L. Theroux, J. Y. Chan, J. Donkin, et al. ABCG1 influences the brain cholesterol biosynthetic pathway but does not affect amyloid precursor protein or apolipoprotein E metabolism in vivo J. Lipid Res., June 1, 2008; 49(6): 1254 - 1267. [Abstract] [Full Text] [PDF]

				J. P. Mauldin, M. H. Nagelin, A. J. Wojcik, S. Srinivasan, M. D. Skaflen, C. R. Ayers, C. A. McNamara, and C. C. Hedrick Reduced Expression of ATP-Binding Cassette Transporter G1 Increases Cholesterol Accumulation in Macrophages of Patients With Type 2 Diabetes Mellitus Circulation, May 27, 2008; 117(21): 2785 - 2792. [Abstract] [Full Text] [PDF]

				A. J. Wojcik, M. D. Skaflen, S. Srinivasan, and C. C. Hedrick A Critical Role for ABCG1 in Macrophage Inflammation and Lung Homeostasis J. Immunol., March 15, 2008; 180(6): 4273 - 4282. [Abstract] [Full Text] [PDF]

				R. Out, M. Hoekstra, K. Habets, I. Meurs, V. de Waard, R. B. Hildebrand, Y. Wang, G. Chimini, J. Kuiper, T. J.C. Van Berkel, et al. Combined Deletion of Macrophage ABCA1 and ABCG1 Leads to Massive Lipid Accumulation in Tissue Macrophages and Distinct Atherosclerosis at Relatively Low Plasma Cholesterol Levels Arterioscler Thromb Vasc Biol, February 1, 2008; 28(2): 258 - 264. [Abstract] [Full Text] [PDF]

				D. Yan, M. I. Mayranpaa, J. Wong, J. Perttila, M. Lehto, M. Jauhiainen, P. T. Kovanen, C. Ehnholm, A. J. Brown, and V. M. Olkkonen OSBP-related Protein 8 (ORP8) Suppresses ABCA1 Expression and Cholesterol Efflux from Macrophages J. Biol. Chem., January 4, 2008; 283(1): 332 - 340. [Abstract] [Full Text] [PDF]

				R. Out, W. Jessup, W. Le Goff, M. Hoekstra, I. C. Gelissen, Y. Zhao, L. Kritharides, G. Chimini, J. Kuiper, M. J. Chapman, et al. Coexistence of Foam Cells and Hypocholesterolemia in Mice Lacking the ABC Transporters A1 and G1 Circ. Res., January 4, 2008; 102(1): 113 - 120. [Abstract] [Full Text] [PDF]

				M. J. Thomassen, B. P. Barna, A. G. Malur, T. L. Bonfield, C. F. Farver, A. Malur, H. Dalrymple, M. S. Kavuru, and M. Febbraio ABCG1 is deficient in alveolar macrophages of GM-CSF knockout mice and patients with pulmonary alveolar proteinosis J. Lipid Res., December 1, 2007; 48(12): 2762 - 2768. [Abstract] [Full Text] [PDF]

				A. J. Lusis, J. Yu, and S. S. Wang The Problem of Passenger Genes in Transgenic Mice Arterioscler Thromb Vasc Biol, October 1, 2007; 27(10): 2100 - 2103. [Abstract] [Full Text] [PDF]

				N. Terasaka, N. Wang, L. Yvan-Charvet, and A. R. Tall High-density lipoprotein protects macrophages from oxidized low-density lipoprotein-induced apoptosis by promoting efflux of 7-ketocholesterol via ABCG1 PNAS, September 18, 2007; 104(38): 15093 - 15098. [Abstract] [Full Text] [PDF]

				D. Yan, M. Jauhiainen, R. B. Hildebrand, K. Willems van Dijk, T. J.C. Van Berkel, C. Ehnholm, M. Van Eck, and V. M. Olkkonen Expression of Human OSBP-Related Protein 1L in Macrophages Enhances Atherosclerotic Lesion Development in LDL Receptor-Deficient Mice Arterioscler Thromb Vasc Biol, July 1, 2007; 27(7): 1618 - 1624. [Abstract] [Full Text] [PDF]

				L. Yvan-Charvet, F. Matsuura, N. Wang, M. J. Bamberger, T. Nguyen, F. Rinninger, X.-C. Jiang, C. L. Shear, and A. R. Tall Inhibition of Cholesteryl Ester Transfer Protein by Torcetrapib Modestly Increases Macrophage Cholesterol Efflux to HDL Arterioscler Thromb Vasc Biol, May 1, 2007; 27(5): 1132 - 1138. [Abstract] [Full Text] [PDF]

				R. Out, M. Hoekstra, I. Meurs, P. de Vos, J. Kuiper, M. Van Eck, and T. J.C. Van Berkel Total Body ABCG1 Expression Protects Against Early Atherosclerotic Lesion Development in Mice Arterioscler Thromb Vasc Biol, March 1, 2007; 27(3): 594 - 599. [Abstract] [Full Text] [PDF]

				J. F. Oram and A. M. Vaughan ATP-Binding Cassette Cholesterol Transporters and Cardiovascular Disease Circ. Res., November 10, 2006; 99(10): 1031 - 1043. [Abstract] [Full Text] [PDF]

				L. K. Curtiss Is Two out of Three Enough for ABCG1? Arterioscler Thromb Vasc Biol, October 1, 2006; 26(10): 2175 - 2177. [Full Text] [PDF]