HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 277, Issue 45, 43271-43280, November 8, 2002

This Article Full Text Full Text (PDF) All Versions of this Article: 277/45/43271    most recent M207532200v1 Alert me when this article is cited 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 Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Feng, B. Articles by Tabas, I. Search for Related Content PubMed PubMed Citation Articles by Feng, B. Articles by Tabas, I. Social Bookmarking                      What's this?

ABCA1-mediated Cholesterol Efflux Is Defective in Free Cholesterol-loaded Macrophages
MECHANISM INVOLVES ENHANCED ABCA1 DEGRADATION IN A PROCESS REQUIRING FULL NPC1 ACTIVITY^*

Bo Feng and Ira Tabas^§¶

From the Departments of  Medicine and ^§ Anatomy and Cell Biology, Columbia University, New York, New York 10032

In advanced atherosclerosis, macrophage foam cells progressively accumulate large amounts of unesterified or "free" cholesterol (FC), a process that is thought to contribute to foam cell death and lesional necrosis. The cellular consequences of early FC accumulation, including those that lead to further FC accumulation, are poorly understood. In this context, we show that cholesterol and phospholipid efflux mediated by ABCA1, which is initially induced in the cholesterol-loaded macrophage, was inhibited by ~80% in pre-toxic FC-loaded macrophages. Cholesterol efflux to HDL₂, which is mediated by a non-ABCA1 pathway, was inhibited by only ~20% in FC-loaded macrophages. FC loading led to decreased levels of ABCA1 protein via increased degradation of ABCA1, and not by decreased transcription or translation of AbcA1 mRNA. The decrease in ABCA1 protein occurred relatively early and was not prevented by caspase inhibitors, indicating that it was not a consequence of FC-induced apoptosis. However, inhibition of proteasomal function by lactacystin largely prevented the degradation of ABCA1. Importantly, the FC-induced decrease in ABCA1 function and protein was almost entirely prevented in macrophages that had partial deficiency of npc1 or were exposed to nanomolar concentrations of U18666A, both of which lead to defective cholesterol trafficking to the endoplasmic reticulum, but leave trafficking to the plasma membrane largely intact. Thus, a relatively early event during FC loading of macrophages is increased degradation of ABCA1, which appears to require trafficking of cholesterol to a peripheral cellular site, but not bulk trafficking of excess cholesterol to the plasma membrane. These findings provide new insight into the post-translational regulation of ABCA1 and the pathobiology of the FC-loaded macrophage.

CiteULike

Complore

Connotea

Del.icio.us

Digg

Reddit

Technorati

This article has been cited by other articles:

				Y. R. Su, J. L. Blakemore, Y. Zhang, M. F. Linton, and S. Fazio Lentiviral Transduction of ApoAI Into Hematopoietic Progenitor Cells and Macrophages: Applications to Cell Therapy of Atherosclerosis Arterioscler. Thromb. Vasc. Biol., August 1, 2008; 28(8): 1439 - 1446. [Abstract] [Full Text] [PDF]

				K. Bowden and N. D. Ridgway OSBP Negatively Regulates ABCA1 Protein Stability J. Biol. Chem., June 27, 2008; 283(26): 18210 - 18217. [Abstract] [Full Text] [PDF]

				D. Cui, E. Thorp, Y. Li, N. Wang, L. Yvan-Charvet, A. R. Tall, and I. Tabas Pivotal Advance: Macrophages become resistant to cholesterol-induced death after phagocytosis of apoptotic cells J. Leukoc. Biol., November 1, 2007; 82(5): 1040 - 1050. [Abstract] [Full Text] [PDF]

				M.-D. Wang, V. Franklin, M. Sundaram, R. S. Kiss, K. Ho, M. Gallant, and Y. L. Marcel Differential Regulation of ATP Binding Cassette Protein A1 Expression and ApoA-I Lipidation by Niemann-Pick Type C1 in Murine Hepatocytes and Macrophages J. Biol. Chem., August 3, 2007; 282(31): 22525 - 22533. [Abstract] [Full Text] [PDF]

				V. Hirsch-Reinshagen, J. Y. Chan, A. Wilkinson, T. Tanaka, J. Fan, G. Ou, L. F. Maia, R. R. Singaraja, M. R. Hayden, and C. L. Wellington Physiologically regulated transgenic ABCA1 does not reduce amyloid burden or amyloid-{beta} peptide levels in vivo J. Lipid Res., April 1, 2007; 48(4): 914 - 923. [Abstract] [Full Text] [PDF]

				A. B. Ghering and W. S. Davidson Ceramide structural features required to stimulate ABCA1-mediated cholesterol efflux to apolipoprotein A-I J. Lipid Res., December 1, 2006; 47(12): 2781 - 2788. [Abstract] [Full Text] [PDF]

				M. Bukrinsky and D. Sviridov Human immunodeficiency virus infection and macrophage cholesterol metabolism. J. Leukoc. Biol., November 1, 2006; 80(5): 1044 - 1051. [Abstract] [Full Text] [PDF]

				I. Zanotti, F. Poti, E. Favari, K. R. Steffensen, J.-A. Gustafsson, and F. Bernini Pitavastatin Effect on ATP Binding Cassette A1-Mediated Lipid Efflux from Macrophages: Evidence for Liver X Receptor (LXR)-Dependent and LXR-Independent Mechanisms of Activation by cAMP J. Pharmacol. Exp. Ther., April 1, 2006; 317(1): 395 - 401. [Abstract] [Full Text] [PDF]

				M. Van Eck, R. R. Singaraja, D. Ye, R. B. Hildebrand, E. R. James, M. R. Hayden, and T. J.C. Van Berkel Macrophage ATP-Binding Cassette Transporter A1 Overexpression Inhibits Atherosclerotic Lesion Progression in Low-Density Lipoprotein Receptor Knockout Mice Arterioscler. Thromb. Vasc. Biol., April 1, 2006; 26(4): 929 - 934. [Abstract] [Full Text] [PDF]

				S. E. Nissen, E. M. Tuzcu, H. B. Brewer, I. Sipahi, S. J. Nicholls, P. Ganz, P. Schoenhagen, D. D. Waters, C. J. Pepine, T. D. Crowe, et al. Effect of ACAT inhibition on the progression of coronary atherosclerosis. N. Engl. J. Med., March 23, 2006; 354(12): 1253 - 1263. [Abstract] [Full Text] [PDF]

				M.-C. Gerbod-Giannone, Y. Li, A. Holleboom, S. Han, L.-C. Hsu, I. Tabas, and A. R. Tall TNF{alpha} induces ABCA1 through NF-{kappa}B in macrophages and in phagocytes ingesting apoptotic cells PNAS, February 28, 2006; 103(9): 3112 - 3117. [Abstract] [Full Text] [PDF]

				Y. Zhu, H. Liao, X. Xie, Y. Yuan, T.-S. Lee, N. Wang, X. Wang, J. Y.-J. Shyy, and M. B. Stemerman Oxidized LDL downregulates ATP-binding cassette transporter-1 in human vascular endothelial cells via inhibiting liver X receptor (LXR) Cardiovasc Res, December 1, 2005; 68(3): 425 - 432. [Abstract] [Full Text] [PDF]

				J. A. Chirinos, J. P. Zambrano, S. Chakko, A. Schob, R. B. Goldberg, G. Perez, and A. J. Mendez Ability of Serum to Decrease Cellular AcylCoA:Cholesterol Acyl Transferase Activity Predicts Cardiovascular Outcomes Circulation, October 18, 2005; 112(16): 2446 - 2453. [Abstract] [Full Text] [PDF]

				J. F. Oram and J. W. Heinecke ATP-Binding Cassette Transporter A1: A Cell Cholesterol Exporter That Protects Against Cardiovascular Disease Physiol Rev, October 1, 2005; 85(4): 1343 - 1372. [Abstract] [Full Text] [PDF]

				R. S. Kiss, J. Maric, and Y. L. Marcel Lipid efflux in human and mouse macrophagic cells: evidence for differential regulation of phospholipid and cholesterol efflux J. Lipid Res., September 1, 2005; 46(9): 1877 - 1887. [Abstract] [Full Text] [PDF]

				H. Zhou, W. M. Pandak Jr., V. Lyall, R. Natarajan, and P. B. Hylemon HIV Protease Inhibitors Activate the Unfolded Protein Response in Macrophages: Implication for Atherosclerosis and Cardiovascular Disease Mol. Pharmacol., September 1, 2005; 68(3): 690 - 700. [Abstract] [Full Text] [PDF]

				F. Forcheron, L. Legedz, G. Chinetti, P. Feugier, D. Letexier, G. Bricca, and M. Beylot Genes of Cholesterol Metabolism in Human Atheroma: Overexpression of Perilipin and Genes Promoting Cholesterol Storage and Repression of ABCA1 Expression Arterioscler. Thromb. Vasc. Biol., August 1, 2005; 25(8): 1711 - 1717. [Abstract] [Full Text] [PDF]

				C. Albrecht, J. H. McVey, J. I. Elliott, A. Sardini, I. Kasza, A. D. Mumford, R. P. Naoumova, E. G. D. Tuddenham, K. Szabo, and C. F. Higgins A novel missense mutation in ABCA1 results in altered protein trafficking and reduced phosphatidylserine translocation in a patient with Scott syndrome Blood, July 15, 2005; 106(2): 542 - 549. [Abstract] [Full Text] [PDF]

				M. Passarelli, C. Tang, T. O. McDonald, K. D. O'Brien, R. G. Gerrity, J. W. Heinecke, and J. F. Oram Advanced Glycation End Product Precursors Impair ABCA1-Dependent Cholesterol Removal From Cells Diabetes, July 1, 2005; 54(7): 2198 - 2205. [Abstract] [Full Text] [PDF]

				Y. R. Su, D. E. Dove, A. S. Major, A. H. Hasty, B. Boone, M. F. Linton, and S. Fazio Reduced ABCA1-Mediated Cholesterol Efflux and Accelerated Atherosclerosis in Apolipoprotein E-Deficient Mice Lacking Macrophage-Derived ACAT1 Circulation, May 10, 2005; 111(18): 2373 - 2381. [Abstract] [Full Text] [PDF]

				S Soumian, C Albrecht, A. Davies, and R. Gibbs ABCA1 and atherosclerosis Vascular Medicine, May 1, 2005; 10(2): 109 - 119. [Abstract] [PDF]

				D. E. Dove, Y. R. Su, W. Zhang, W. G. Jerome, L. L. Swift, M. F. Linton, and S. Fazio ACAT1 Deficiency Disrupts Cholesterol Efflux and Alters Cellular Morphology in Macrophages Arterioscler. Thromb. Vasc. Biol., January 1, 2005; 25(1): 128 - 134. [Abstract] [Full Text] [PDF]

				C. Albrecht, S. Soumian, J.S. Amey, A. Sardini, C.F. Higgins, A.H. Davies, and R.G.J. Gibbs ABCA1 Expression in Carotid Atherosclerotic Plaques Stroke, December 1, 2004; 35(12): 2801 - 2806. [Abstract] [Full Text] [PDF]

				W. Le Goff, D.-Q. Peng, M. Settle, G. Brubaker, R. E. Morton, and J. D. Smith Cyclosporin A Traps ABCA1 at the Plasma Membrane and Inhibits ABCA1-Mediated Lipid Efflux to Apolipoprotein A-I Arterioscler. Thromb. Vasc. Biol., November 1, 2004; 24(11): 2155 - 2161. [Abstract] [Full Text] [PDF]

				M. Agassandian, S. N. Mathur, J. Zhou, F. J. Field, and R. K. Mallampalli Oxysterols Trigger ABCA1-Mediated Basolateral Surfactant Efflux Am. J. Respir. Cell Mol. Biol., August 1, 2004; 31(2): 227 - 233. [Abstract] [Full Text] [PDF]

				C.-A. Wu, M. Tsujita, M. Hayashi, and S. Yokoyama Probucol Inactivates ABCA1 in the Plasma Membrane with Respect to Its Mediation of Apolipoprotein Binding and High Density Lipoprotein Assembly and to Its Proteolytic Degradation J. Biol. Chem., July 16, 2004; 279(29): 30168 - 30174. [Abstract] [Full Text] [PDF]

				R. J. Cenedella, R. Jacob, D. Borchman, D. Tang, A. R. Neely, A. Samadi, R. P. Mason, and P. Sexton Direct perturbation of lens membrane structure may contribute to cataracts caused by U18666A, an oxidosqualene cyclase inhibitor J. Lipid Res., July 1, 2004; 45(7): 1232 - 1241. [Abstract] [Full Text] [PDF]

				T. J. F. Nieland, A. Chroni, M. L. Fitzgerald, Z. Maliga, V. I. Zannis, T. Kirchhausen, and M. Krieger Cross-inhibition of SR-BI- and ABCA1-mediated cholesterol transport by the small molecules BLT-4 and glyburide J. Lipid Res., July 1, 2004; 45(7): 1256 - 1265. [Abstract] [Full Text] [PDF]

				Y. Wang, B. Kurdi-Haidar, and J. F. Oram LXR-mediated activation of macrophage stearoyl-CoA desaturase generates unsaturated fatty acids that destabilize ABCA1 J. Lipid Res., May 1, 2004; 45(5): 972 - 980. [Abstract] [Full Text] [PDF]

				Y. Munehira, T. Ohnishi, S. Kawamoto, A. Furuya, K. Shitara, M. Imamura, T. Yokota, S. Takeda, T. Amachi, M. Matsuo, et al. {alpha}1-Syntrophin Modulates Turnover of ABCA1 J. Biol. Chem., April 9, 2004; 279(15): 15091 - 15095. [Abstract] [Full Text] [PDF]

				C. Tang, A. M. Vaughan, and J. F. Oram Janus Kinase 2 Modulates the Apolipoprotein Interactions with ABCA1 Required for Removing Cellular Cholesterol J. Biol. Chem., February 27, 2004; 279(9): 7622 - 7628. [Abstract] [Full Text] [PDF]

				A. R. Leventhal, C. C. Leslie, and I. Tabas Suppression of Macrophage Eicosanoid Synthesis by Atherogenic Lipoproteins Is Profoundly Affected by Cholesterol-Fatty Acyl Esterification and the Niemann-Pick C Pathway of Lipid Trafficking J. Biol. Chem., February 27, 2004; 279(9): 8084 - 8092. [Abstract] [Full Text] [PDF]

				Y. Yamauchi, M. Hayashi, S. Abe-Dohmae, and S. Yokoyama Apolipoprotein A-I Activates Protein Kinase C{alpha} Signaling to Phosphorylate and Stabilize ATP Binding Cassette Transporter A1 for the High Density Lipoprotein Assembly J. Biol. Chem., November 28, 2003; 278(48): 47890 - 47897. [Abstract] [Full Text] [PDF]

				S. R. Witting, J. N. Maiorano, and W. S. Davidson Ceramide Enhances Cholesterol Efflux to Apolipoprotein A-I by Increasing the Cell Surface Presence of ATP-binding Cassette Transporter A1 J. Biol. Chem., October 10, 2003; 278(41): 40121 - 40127. [Abstract] [Full Text] [PDF]

				M. Miyazaki, M. J. Jacobson, W. C. Man, P. Cohen, E. Asilmaz, J. M. Friedman, and J. M. Ntambi Identification and Characterization of Murine SCD4, a Novel Heart-specific Stearoyl-CoA Desaturase Isoform Regulated by Leptin and Dietary Factors J. Biol. Chem., September 5, 2003; 278(36): 33904 - 33911. [Abstract] [Full Text] [PDF]

				N. Wang and A. R. Tall Regulation and Mechanisms of ATP-Binding Cassette Transporter A1-Mediated Cellular Cholesterol Efflux Arterioscler. Thromb. Vasc. Biol., July 1, 2003; 23(7): 1178 - 1184. [Abstract] [Full Text] [PDF]

				C. Joyce, L. Freeman, H. B. Brewer Jr, and S. Santamarina-Fojo Study of ABCA1 Function in Transgenic Mice Arterioscler. Thromb. Vasc. Biol., June 1, 2003; 23(6): 965 - 971. [Abstract] [Full Text] [PDF]

				J. F. Oram HDL Apolipoproteins and ABCA1: Partners in the Removal of Excess Cellular Cholesterol Arterioscler. Thromb. Vasc. Biol., May 1, 2003; 23(5): 720 - 727. [Abstract] [Full Text] [PDF]