This Article Free upon publication Full Text Full Text (PDF) 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 Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Cuchel, M. Articles by Rader, D. J. Search for Related Content PubMed PubMed Citation Articles by Cuchel, M. Articles by Rader, D. J. Related Collections Animal models of human disease Pathophysiology Gene expression Genetics of cardiovascular disease Lipid and lipoprotein metabolism

(Circulation. 2006;113:2548-2555.)
© 2006 American Heart Association, Inc.

Basic Science for Clinicians

Macrophage Reverse Cholesterol Transport

Key to the Regression of Atherosclerosis?

Marina Cuchel, MD, PhD; Daniel J. Rader, MD

From the Institute for Translational Medicine and Therapeutics and the Cardiovascular Institute, University of Pennsylvania School of Medicine, Philadelphia, Pa.

Correspondence to Daniel J. Rader, MD, Institute for Translational Medicine and Therapeutics and the Cardiovascular Institute, University of Pennsylvania School of Medicine, 654 BRB II/III, 421 Curie Blvd, Philadelphia, PA 19104. E-mail rader@mail.med.upenn.edu

Key Words: apolipoproteins • atherosclerosis • cholesterol • lipids • lipoproteins

An extract of the first 250 words of the full text is provided, because this article has no abstract.

	Introduction

 
The concept of "reverse cholesterol transport" (RCT) was first introduced in 1968 by Glomset¹ to describe the process by which extrahepatic (peripheral) cholesterol is returned to the liver for excretion in the bile and ultimately the feces. The physiological need for this process is clear, as nonhepatic cells acquire cholesterol through uptake of lipoproteins and de novo synthesis and yet (with the exception of steroidogenic tissues that convert cholesterol to steroid hormones) are unable to catabolize it. Excess unesterified cholesterol (UC) is toxic to cells, and therefore, cells have developed several ways to protect themselves against cholesterol toxicity. One key pathway is the efflux of cholesterol to extracellular "acceptors." The return of this "peripheral" cholesterol to the liver is necessary to balance cholesterol intake and de novo synthesis and thus to maintain whole-body steady-state cholesterol metabolism.

The relationship of RCT to atherosclerosis was first suggested by Ross and Glomset,² who hypothesized that atherosclerotic lesions develop when an imbalance occurs between the deposition and removal of arterial cholesterol after endothelial injury. This concept was further developed by Miller and Miller,³ who suggested that on the basis of the inverse relation between HDL cholesterol (HDL-C) and cardiovascular disease, emphasis should be placed on increasing HDL as a way to increase clearance of cholesterol from the arterial wall to prevent cardiovascular disease. Despite 3 decades of work, the relationship of RCT to atherosclerosis remains more of a hypothesis than an established fact. Because the physiological process of RCT clearly occurs from all peripheral . . . [Full Text of this Article]

This article has been cited by other articles:

				E. Erdmann and R. Wilcox Pioglitazone and mechanisms of CV protection QJM, December 2, 2009; (2009) hcp168v1. [Abstract] [Full Text] [PDF]

				P. S. Chetty, L. Mayne, S. Lund-Katz, D. Stranz, S. W. Englander, and M. C. Phillips Helical structure and stability in human apolipoprotein A-I by hydrogen exchange and mass spectrometry PNAS, November 10, 2009; 106(45): 19005 - 19010. [Abstract] [Full Text] [PDF]

				H. Zhou, S. W. Shiu, Y. Wong, and K. C. Tan Impaired serum capacity to induce cholesterol efflux is associated with endothelial dysfunction in type 2 diabetes mellitus Diabetes and Vascular Disease Research, October 1, 2009; 6(4): 238 - 243. [Abstract] [PDF]

				S. Rashid, M. Marcil, I. Ruel, and J. Genest Identification of a novel human cellular HDL biosynthesis defect Eur. Heart J., September 2, 2009; 30(18): 2204 - 2212. [Abstract] [Full Text] [PDF]

				L. Calabresi, D. Baldassarre, S. Castelnuovo, P. Conca, L. Bocchi, C. Candini, B. Frigerio, M. Amato, C. R. Sirtori, P. Alessandrini, et al. Functional Lecithin: Cholesterol Acyltransferase Is Not Required for Efficient Atheroprotection in Humans Circulation, August 18, 2009; 120(7): 628 - 635. [Abstract] [Full Text] [PDF]

				M. D. Linder, M. I. Mayranpaa, J. Peranen, T. E. Pietila, V. M. Pietiainen, R.-L. Uronen, V. M. Olkkonen, P. T. Kovanen, and E. Ikonen Rab8 Regulates ABCA1 Cell Surface Expression and Facilitates Cholesterol Efflux in Primary Human Macrophages Arterioscler Thromb Vasc Biol, June 1, 2009; 29(6): 883 - 888. [Abstract] [Full Text] [PDF]

				J. M. Proudfoot, A. E. Barden, W. M. Loke, K. D. Croft, I. B. Puddey, and T. A. Mori HDL is the major lipoprotein carrier of plasma F2-isoprostanes J. Lipid Res., April 1, 2009; 50(4): 716 - 722. [Abstract] [Full Text] [PDF]

				F. C. McGillicuddy, M. de la Llera Moya, C. C. Hinkle, M. R. Joshi, E. H. Chiquoine, J. T. Billheimer, G. H. Rothblat, and M. P. Reilly Inflammation Impairs Reverse Cholesterol Transport In Vivo Circulation, March 3, 2009; 119(8): 1135 - 1145. [Abstract] [Full Text] [PDF]

				L. Verschuren, J. de Vries-van der Weij, S. Zadelaar, R. Kleemann, and T. Kooistra LXR agonist suppresses atherosclerotic lesion growth and promotes lesion regression in apoE*3Leiden mice: time course and mechanisms J. Lipid Res., February 1, 2009; 50(2): 301 - 311. [Abstract] [Full Text] [PDF]

				L. Calpe-Berdiel, N. Rotllan, C. Fievet, R. Roig, F. Blanco-Vaca, and J. C. Escola-Gil Liver X receptor-mediated activation of reverse cholesterol transport from macrophages to feces in vivo requires ABCG5/G8 J. Lipid Res., September 1, 2008; 49(9): 1904 - 1911. [Abstract] [Full Text] [PDF]

				S. J. Lee, Y. K. On, E. J. Lee, J. Y. Choi, B.-T. Kim, and K.-H. Lee Reversal of Vascular 18F-FDG Uptake with Plasma High-Density Lipoprotein Elevation by Atherogenic Risk Reduction J. Nucl. Med., August 1, 2008; 49(8): 1277 - 1282. [Abstract] [Full Text] [PDF]

				R. Frikke-Schmidt, B. G. Nordestgaard, M. C. A. Stene, A. A. Sethi, A. T. Remaley, P. Schnohr, P. Grande, and A. Tybjaerg-Hansen Association of Loss-of-Function Mutations in the ABCA1 Gene With High-Density Lipoprotein Cholesterol Levels and Risk of Ischemic Heart Disease JAMA, June 4, 2008; 299(21): 2524 - 2532. [Abstract] [Full Text] [PDF]

				I. Zanotti, F. Poti, M. Pedrelli, E. Favari, E. Moleri, G. Franceschini, L. Calabresi, and F. Bernini The LXR agonist T0901317 promotes the reverse cholesterol transport from macrophages by increasing plasma efflux potential J. Lipid Res., May 1, 2008; 49(5): 954 - 960. [Abstract] [Full Text] [PDF]

				R. Movva and D. J. Rader Laboratory Assessment of HDL Heterogeneity and Function Clin. Chem., May 1, 2008; 54(5): 788 - 800. [Abstract] [Full Text] [PDF]

				Y. Levy High-density lipoprotein mass, cholesteryl ester transport protein, and macrophage reverse cholesterol transport: from the bedside back to the bench Cardiovasc Res, March 1, 2008; 77(4): 614 - 615. [Full Text] [PDF]

				M. Lee-Rueckert, R. Vikstedt, J. Metso, M. Jauhiainen, and P. T. Kovanen Association of cholesteryl ester transfer protein with HDL particles reduces its proteolytic inactivation by mast cell chymase J. Lipid Res., February 1, 2008; 49(2): 358 - 368. [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]

				C. Vedhachalam, P. T. Duong, M. Nickel, D. Nguyen, P. Dhanasekaran, H. Saito, G. H. Rothblat, S. Lund-Katz, and M. C. Phillips Mechanism of ATP-binding Cassette Transporter A1-mediated Cellular Lipid Efflux to Apolipoprotein A-I and Formation of High Density Lipoprotein Particles J. Biol. Chem., August 24, 2007; 282(34): 25123 - 25130. [Abstract] [Full Text] [PDF]

				I. Parastatidis, L. Thomson, D. M. Fries, R. E. Moore, J. Tohyama, X. Fu, S. L. Hazen, H. F.G. Heijnen, M. K. Dennehy, D. C. Liebler, et al. Increased Protein Nitration Burden in the Atherosclerotic Lesions and Plasma of Apolipoprotein A-I Deficient Mice Circ. Res., August 17, 2007; 101(4): 368 - 376. [Abstract] [Full Text] [PDF]

				M.-D. Wang, V. Franklin, and Y. L. Marcel In Vivo Reverse Cholesterol Transport From Macrophages Lacking ABCA1 Expression Is Impaired Arterioscler Thromb Vasc Biol, August 1, 2007; 27(8): 1837 - 1842. [Abstract] [Full Text] [PDF]

				T. Kyriakou, D. E. Pontefract, E. Viturro, C. P. Hodgkinson, R. C. Laxton, N. Bogari, G. Cooper, M. Davies, J. Giblett, I. N.M. Day, et al. Functional polymorphism in ABCA1 influences age of symptom onset in coronary artery disease patients Hum. Mol. Genet., June 15, 2007; 16(12): 1412 - 1422. [Abstract] [Full Text] [PDF]