This Article Full Text Full Text (PDF) All Versions of this Article: 26/1/157    most recent 01.ATV.0000193627.12516.1dv1 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 Huang, Z. H. Articles by Mazzone, T. Search for Related Content PubMed PubMed Citation Articles by Huang, Z. H. Articles by Mazzone, T. Related Collections Pathophysiology Cell biology/structural biology Lipid and lipoprotein metabolism Other Vascular biology

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:157.)
© 2006 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Distinct Cellular Loci for the ABCA1-Dependent and ABCA1-Independent Lipid Efflux Mediated by Endogenous Apolipoprotein E Expression

Zhi H. Huang; Michael L. Fitzgerald; Theodore Mazzone

From the Departments of Medicine (Z.H.H., T.M.) and Pharmacology (T.M.), University of Illinois at Chicago; and the Department of Medicine (M.L.F.), Massachusetts General Hospital, Harvard Medical School, Boston, Mass.

Correspondence to Theodore Mazzone, Section of Diabetes and Metabolism (MC 797), University of Illinois at Chicago, 1819 W Polk St, Chicago, IL 60612. E-mail tmazzone{at}uic.edu

Objective— Macrophage expression of both apolipoprotein E (apoE) and ABCA1 have been shown to modulate lipid efflux from these cells and to play an important atheroprotective role in vivo. We evaluated the relationship between apoE and ABCA1 for regulating cellular sterol efflux.

Methods and Results— ApoE-mediated, but ABCA1-independent, lipid efflux was demonstrated in 3 model systems. First, adenoviral-mediated expression of apoE in dermal fibroblasts isolated from ABCA1^–/– mice significantly increased both sterol and phospholipid efflux. Second, expression of human apoE in a macrophage cell line increased sterol efflux, and this increment in efflux was not reduced by suppressing ABCA1 expression. Third, reduction of apoE expression using an apoE small interfering RNA significantly reduced sterol efflux from ABCA1^–/– mouse peritoneal macrophages. ApoE-mediated, but ABCA1-independent, lipid efflux could be differentiated from lipid efflux that was dependent on the extracellular accumulation of secreted apoE, because exogenous cell-derived apoE stimulated efflux only from cells expressing ABCA1. Sterol efflux was usually highest in cells expressing both ABCA1 and apoE, likely representing a summation of the ABCA1-dependent and -independent pathways for apoE-mediated sterol efflux.

Conclusions— ABCA1 expression is required for apoE-mediated efflux when endogenously synthesized apoE accumulates extracellularly. Our results, however, establish the existence of an ABCA1-independent pathway for lipid efflux that requires the intracellular synthesis and/or transport of apoE.

These studies establish 2 separate pathways for lipid efflux mediated by the endogenous expression of cellular apoE. One is mediated by the extracellular accumulation of endogenous apolipoprotein E and depends on the expression of ABCA1. The second requires the intracellular synthesis and transport of apolipoprotein E and is independent of ABCA1.

Key Words: apoE • ABCA1 • macrophage • lipid efflux • atherosclerosis

This article has been cited by other articles:

				J. Barlic, W. Zhu, and P. M. Murphy Atherogenic Lipids Induce High-Density Lipoprotein Uptake and Cholesterol Efflux in Human Macrophages by Up-Regulating Transmembrane Chemokine CXCL16 without Engaging CXCL16-Dependent Cell Adhesion J. Immunol., June 15, 2009; 182(12): 7928 - 7936. [Abstract] [Full Text] [PDF]

				G. S. Getz and C. A. Reardon Apoprotein E as a lipid transport and signaling protein in the blood, liver, and artery wall J. Lipid Res., April 1, 2009; 50(Supplement): S156 - S161. [Abstract] [Full Text] [PDF]

				M. Kockx, W. Jessup, and L. Kritharides Regulation of Endogenous Apolipoprotein E Secretion by Macrophages Arterioscler Thromb Vasc Biol, June 1, 2008; 28(6): 1060 - 1067. [Abstract] [Full Text] [PDF]

				Z. H. Huang, R. M. Luque, R. D. Kineman, and T. Mazzone Nutritional regulation of adipose tissue apolipoprotein E expression Am J Physiol Endocrinol Metab, July 1, 2007; 293(1): E203 - E209. [Abstract] [Full Text] [PDF]

				P. G. Yancey, H. Yu, M. F. Linton, and S. Fazio A Pathway-Dependent on ApoE, ApoAI, and ABCA1 Determines Formation of Buoyant High-Density Lipoprotein by Macrophage Foam Cells Arterioscler Thromb Vasc Biol, May 1, 2007; 27(5): 1123 - 1131. [Abstract] [Full Text] [PDF]

				D. Lucic, Z. H. Huang, D. S. Gu, M. K. Altenburg, N. Maeda, and T. Mazzone Regulation of macrophage apoE secretion and sterol efflux by the LDL receptor J. Lipid Res., February 1, 2007; 48(2): 366 - 372. [Abstract] [Full Text] [PDF]

				M. Ranalletta, N. Wang, S. Han, L. Yvan-Charvet, C. Welch, and A. R. Tall Decreased Atherosclerosis in Low-Density Lipoprotein Receptor Knockout Mice Transplanted With Abcg1-/- Bone Marrow Arterioscler Thromb Vasc Biol, October 1, 2006; 26(10): 2308 - 2315. [Abstract] [Full Text] [PDF]