Published online before print September 9, 2004, doi: 10.1161/01.ATV.0000144811.94581.52
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© 2004 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Cyclosporin A Traps ABCA1 at the Plasma Membrane and Inhibits ABCA1-Mediated Lipid Efflux to Apolipoprotein A-I
From the Department of Cell Biology NC10, Cleveland Clinic Foundation, Cleveland, Ohio.
Correspondence to Jonathan D. Smith, Department of Cell Biology NC10, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195. E-mail smithj{at}lerner.ccf.org
Objective— ABCA1 mediates cellular cholesterol and phospholipid efflux to apolipoprotein A-I and other apolipoprotein acceptors. In this study, we analyzed the effect of the immunosuppressant cyclosporin A on the ABCA1-mediated lipid effluxes reactions.
Methods and Results— Cyclosporin A acted as a potent inhibitor of ABCA1 activity in several cell lines. Using the RAW264.7 mouse macrophage cell line, in which ABCA1 and its associated cholesterol efflux activity are inducible by cAMP analogues, cyclosporin A inhibition of cholesterol efflux to apolipoprotein A-I was rapidly reversible after its removal from the culture media, implying that ABCA1 levels were not drastically reduced by cyclosporin A. In fact, cyclosporin A treatment decreased ABCA1 turnover and yielded a 2-fold increase in cell-surface ABCA1. Despite the increase in cell-surface ABCA1, cyclosporin A decreased apolipoprotein A-I uptake, resecretion, and degradation in RAW cells. Finally, consistent with the inhibition of ABCA1 in vitro, cyclosporin A treatment induced a 33% reduction of high-density lipoprotein (HDL) levels in mice.
Conclusion— ABCA1 inhibition by cyclosporin A supports a role for ABCA1 endocytic trafficking in ABCA1-mediated lipid efflux and could explain in part the low HDL levels observed in some patients with transplants.
Cyclosporin A inhibited ABCA1-mediated lipid efflux to apoAI. This inhibition was associated with increased plasma membrane ABCA1, which was defective in its ability to take-up exogenous apoAI. Administration of cyclosporin A to mice led to a 33% decrease in plasma HDL, supporting the physiological relevance of these findings.
Key Words: macrophage • cholesterol • high-density lipoprotein
This article has been cited by other articles:
 |
|
 |
|
  L. E. Faulkner, S. E. Panagotopulos, J. D. Johnson, L. A. Woollett, D. Y. Hui, S. R. Witting, J. N. Maiorano, and W. S. Davidson An analysis of the role of a retroendocytosis pathway in ABCA1-mediated cholesterol efflux from macrophages J. Lipid Res., June 1, 2008; 49(6): 1322 - 1332. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. F. Oram The ins and outs of ABCA J. Lipid Res., June 1, 2008; 49(6): 1150 - 1151. [Full Text] [PDF]
|
|
|
|
 |
|
 H. H. Hassan, D. Bailey, D.-Y. D. Lee, I. Iatan, A. Hafiane, I. Ruel, L. Krimbou, and J. Genest Quantitative Analysis of ABCA1-dependent Compartmentalization and Trafficking of Apolipoprotein A-I: IMPLICATIONS FOR DETERMINING CELLULAR KINETICS OF NASCENT HIGH DENSITY LIPOPROTEIN BIOGENESIS J. Biol. Chem., April 25, 2008; 283(17): 11164 - 11175. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Catalano, E. Duchene, Z. Julia, W. Le Goff, E. Bruckert, M. J. Chapman, and M. Guerin Cellular SR-BI and ABCA1-mediated cholesterol efflux are gender-specific in healthy subjects J. Lipid Res., March 1, 2008; 49(3): 635 - 643. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y.-C. Lin, C. Ma, W.-C. Hsu, H.-F. Lo, and V. C. Yang Molecular interaction between caveolin-1 and ABCA1 on high-density lipoprotein-mediated cholesterol efflux in aortic endothelial cells Cardiovasc Res, August 1, 2007; 75(3): 575 - 583. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Cavelier, L. Rohrer, and A. von Eckardstein ATP-Binding Cassette Transporter A1 Modulates Apolipoprotein A-I Transcytosis Through Aortic Endothelial Cells Circ. Res., November 10, 2006; 99(10): 1060 - 1066. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X.-L. Zheng and N. C W Wong Cyclosporin A inhibits apolipoprotein AI gene expression. J. Mol. Endocrinol., October 1, 2006; 37(2): 367 - 373. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. D. Smith Insight Into ABCG1-Mediated Cholesterol Efflux. Arterioscler. Thromb. Vasc. Biol., June 1, 2006; 26(6): 1198 - 1200. [Full Text] [PDF]
|
|
|
|
|
|
W. Le Goff, P. Zheng, G. Brubaker, and J. D. Smith Identification of the cAMP-Responsive Enhancer of the Murine ABCA1 Gene: Requirement for CREB1 and STAT3/4 Elements Arterioscler. Thromb. Vasc. Biol., March 1, 2006; 26(3): 527 - 533. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Le Goff, M. Settle, D. J. Greene, R. E. Morton, and J. D. Smith Reevaluation of the role of the multidrug-resistant P-glycoprotein in cellular cholesterol homeostasis J. Lipid Res., January 1, 2006; 47(1): 51 - 58. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Yokoyama Assembly of High-Density Lipoprotein Arterioscler. Thromb. Vasc. Biol., January 1, 2006; 26(1): 20 - 27. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Xia, M. Hou, H. Zhu, J. Ma, Z. Tang, Q. Wang, Y. Li, D. Chi, X. Yu, T. Zhao, et al. Anthocyanins Induce Cholesterol Efflux from Mouse Peritoneal Macrophages: THE ROLE OF THE PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR {gamma}-LIVER X RECEPTOR {alpha}-ABCA1 PATHWAY J. Biol. Chem., November 4, 2005; 280(44): 36792 - 36801. [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]
|
|