Circulation Research. 2005;96:1221-1232
doi: 10.1161/01.RES.0000170946.56981.5c
doi: 10.1161/01.RES.0000170946.56981.5c
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© 2005 American Heart Association, Inc.
Review |
New Insights Into the Regulation of HDL Metabolism and Reverse Cholesterol Transport
From the Departments of Medicine and Physiology (G.F.L), University of Toronto, Canada; The Institute for Translational Medicine and Therapeutics (D.J.R.), The Cardiovascular Institute, and the Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania School of Medicine, Philadelphia.
Correspondence to Dr Gary Lewis, Toronto General Hospital, 200 Elizabeth St, Room EN11-229, Toronto, Ontario, M5G 2C4, Canada. E-mail gary.lewis{at}uhn.on.ca
This Review is part of a thematic series on New Pathways in HDL Metabolism, which includes the following articles:
Antiinflammatory Properties of HDL
Genetics of Variation in HDL Cholesterol in Humans and Mice
New Insights Into the Regulation of HDL Metabolism and Reverse Cholesterol Transport
Endothelial and Antithrombotic Effects of HDL
Daniel Rader Guest Editor
The metabolism of high-density lipoproteins (HDL), which are inversely related to risk of atherosclerotic cardiovascular disease, involves a complex interplay of factors regulating HDL synthesis, intravascular remodeling, and catabolism. The individual lipid and apolipoprotein components of HDL are mostly assembled after secretion, are frequently exchanged with or transferred to other lipoproteins, are actively remodeled within the plasma compartment, and are often cleared separately from one another. HDL is believed to play a key role in the process of reverse cholesterol transport (RCT), in which it promotes the efflux of excess cholesterol from peripheral tissues and returns it to the liver for biliary excretion. This review will emphasize 3 major evolving themes regarding HDL metabolism and RCT. The first theme is that HDL is a universal plasma acceptor lipoprotein for cholesterol efflux from not only peripheral tissues but also hepatocytes, which are a major source of cholesterol efflux to HDL. Furthermore, although efflux of cholesterol from macrophages represents only a tiny fraction of overall cellular cholesterol efflux, it is the most important with regard to atherosclerosis, suggesting that it be specifically termed macrophage RCT. The second theme is the critical role that intravascular remodeling of HDL by lipid transfer factors, lipases, cell surface receptors, and non-HDL lipoproteins play in determining the ultimate metabolic fate of HDL and plasma HDL-c concentrations. The third theme is the growing appreciation that insulin resistance underlies the majority of cases of low HDL-c in humans and the mechanisms by which insulin resistance influences HDL metabolism. Progress in our understanding of HDL metabolism and macrophage reverse cholesterol transport will increase the likelihood of developing novel therapies to raise plasma HDL concentrations and promote macrophage RCT and in proving that these new therapeutic interventions prevent or cause regression of atherosclerosis in humans.
Key Words: high density lipoprotein • insulin resistance • lipase • lipoprotein • reverse cholesterol transport
This article has been cited by other articles:
 |
|
 |
|
  J. Ahnstrom, O. Axler, M. Jauhiainen, V. Salomaa, A. S. Havulinna, C. Ehnholm, R. Frikke-Schmidt, A. Tybjaerg-Hansen, and B. Dahlback Levels of apolipoprotein M are not associated with the risk of coronary heart disease in two independent case-control studies J. Lipid Res., September 1, 2008; 49(9): 1912 - 1917. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Xiao, T. Watanabe, Y. Zhang, B. Trigatti, L. Szeto, P. W. Connelly, S. Marcovina, T. Vaisar, J. W. Heinecke, and G. F. Lewis Enhanced Cellular Uptake of Remnant High-Density Lipoprotein Particles: A Mechanism for High-Density Lipoprotein Lowering in Insulin Resistance and Hypertriglyceridemia Circ. Res., July 18, 2008; 103(2): 159 - 166. [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]
|
|
|
|
 |
|
 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]
|
|
|
|
|
|
U. J. F. Tietge, N. Nijstad, R. Havinga, J. F. W. Baller, F. H. van der Sluijs, V. W. Bloks, T. Gautier, and F. Kuipers Secretory phospholipase A2 increases SR-BI-mediated selective uptake from HDL but not biliary cholesterol secretion J. Lipid Res., March 1, 2008; 49(3): 563 - 571. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Smoak, J. Madenspacher, S. Jeyaseelan, B. Williams, D. Dixon, K. R. Poch, J. A. Nick, G. S. Worthen, and M. B. Fessler Effects of Liver X Receptor Agonist Treatment on Pulmonary Inflammation and Host Defense J. Immunol., March 1, 2008; 180(5): 3305 - 3312. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Valiyaveettil, N. Kar, M. Z. Ashraf, T. V. Byzova, M. Febbraio, and E. A. Podrez Oxidized high-density lipoprotein inhibits platelet activation and aggregation via scavenger receptor BI Blood, February 15, 2008; 111(4): 1962 - 1971. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Cuchel and D. J. Rader Is the Cholesteryl Ester Transfer Protein Proatherogenic or Antiatherogenic in Humans? J. Am. Coll. Cardiol., November 13, 2007; 50(20): 1956 - 1958. [Full Text] [PDF]
|
|
|
|
|
|
M. P. Adorni, F. Zimetti, J. T. Billheimer, N. Wang, D. J. Rader, M. C. Phillips, and G. H. Rothblat The roles of different pathways in the release of cholesterol from macrophages J. Lipid Res., November 1, 2007; 48(11): 2453 - 2462. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K Lipska, P N Sylaja, P S Sarma, K R Thankappan, V R Kutty, R S Vasan, and K Radhakrishnan Risk factors for acute ischaemic stroke in young adults in South India J. Neurol. Neurosurg. Psychiatry, September 1, 2007; 78(9): 959 - 963. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. M. Singh, M. H. Shishehbor, and B. J. Ansell High-Density Lipoprotein as a Therapeutic Target: A Systematic Review JAMA, August 15, 2007; 298(7): 786 - 798. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Charlton-Menys, L. Pisciotta, P. N. Durrington, R. Neary, C. D. Short, L. Calabresi, S. Calandra, and S. Bertolini Molecular characterization of two patients with severe LCAT deficiency Nephrol. Dial. Transplant., August 1, 2007; 22(8): 2379 - 2382. [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]
|
|
|
|
 |
|
 S. Luci, B. Giemsa, H. Kluge, and K. Eder Clofibrate causes an upregulation of PPAR-{alpha} target genes but does not alter expression of SREBP target genes in liver and adipose tissue of pigs Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2007; 293(1): R70 - R77. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. A. Morehouse, E. D. Sugarman, P.-A. Bourassa, T. M. Sand, F. Zimetti, F. Gao, G. H. Rothblat, and A. J. Milici Inhibition of CETP activity by torcetrapib reduces susceptibility to diet-induced atherosclerosis in New Zealand White rabbits J. Lipid Res., June 1, 2007; 48(6): 1263 - 1272. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 U. Lim, T. Gayles, H. A. Katki, R. Stolzenberg-Solomon, S. J. Weinstein, P. Pietinen, P. R. Taylor, J. Virtamo, and D. Albanes Serum High-Density Lipoprotein Cholesterol and Risk of Non-Hodgkin Lymphoma Cancer Res., June 1, 2007; 67(11): 5569 - 5574. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Fukuda, M. Nakano, S. Sriwongsitanont, M. Ueno, Y. Kuroda, and T. Handa Spontaneous reconstitution of discoidal HDL from sphingomyelin-containing model membranes by apolipoprotein A-I J. Lipid Res., April 1, 2007; 48(4): 882 - 889. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M.-D. Wang, R. S. Kiss, V. Franklin, H. M. McBride, S. C. Whitman, and Y. L. Marcel Different cellular traffic of LDL-cholesterol and acetylated LDL-cholesterol leads to distinct reverse cholesterol transport pathways J. Lipid Res., March 1, 2007; 48(3): 633 - 645. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Yang, Z. Zhang, W. Jiang, L. Gao, G. Zhao, Z. Zheng, M. Wang, S. Si, and B. Hong Identification of Novel Human High-Density Lipoprotein Receptor Up-regulators Using a Cell-Based High-Throughput Screening Assay J Biomol Screen, March 1, 2007; 12(2): 211 - 219. [Abstract] [PDF]
|
|
|
|
 |
|
 N. Sanossian, J. L. Saver, M. Navab, and B. Ovbiagele High-Density Lipoprotein Cholesterol: An Emerging Target for Stroke Treatment Stroke, March 1, 2007; 38(3): 1104 - 1109. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Zhang, A. M. Ahmed, N. McFarlane, C. Capone, D. R. Boreham, R. Truant, S. A. Igdoura, and B. L. Trigatti Regulation of SR-BI-mediated selective lipid uptake in Chinese hamster ovary-derived cells by protein kinase signaling pathways J. Lipid Res., February 1, 2007; 48(2): 405 - 416. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Li, W. Chen, and J. Y. L. Chiang PXR induces CYP27A1 and regulates cholesterol metabolism in the intestine J. Lipid Res., February 1, 2007; 48(2): 373 - 384. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Li, V. Savransky, A. Nanayakkara, P. L. Smith, C. P. O'Donnell, and V. Y. Polotsky Hyperlipidemia and lipid peroxidation are dependent on the severity of chronic intermittent hypoxia J Appl Physiol, February 1, 2007; 102(2): 557 - 563. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. L. Sprecher, C. Massien, G. Pearce, A. N. Billin, I. Perlstein, T. M. Willson, D. G. Hassall, N. Ancellin, S. D. Patterson, D. C. Lobe, et al. Triglyceride:High-Density Lipoprotein Cholesterol Effects in Healthy Subjects Administered a Peroxisome Proliferator Activated Receptor {delta} Agonist Arterioscler. Thromb. Vasc. Biol., February 1, 2007; 27(2): 359 - 365. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. J. Harder, A. Meng, P. Rippstein, H. M. McBride, and R. McPherson SR-BI Undergoes Cholesterol-stimulated Transcytosis to the Bile Canaliculus in Polarized WIF-B Cells J. Biol. Chem., January 12, 2007; 282(2): 1445 - 1455. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Asleh, R. Miller-Lotan, M. Aviram, T. Hayek, M. Yulish, J. E. Levy, B. Miller, S. Blum, U. Milman, C. Shapira, et al. Haptoglobin Genotype Is a Regulator of Reverse Cholesterol Transport in Diabetes In Vitro and In Vivo Circ. Res., December 8, 2006; 99(12): 1419 - 1425. [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]
|
|
|
|
|
|
T. Kooistra, L. Verschuren, J. de Vries-van der Weij, W. Koenig, K. Toet, H.M.G. Princen, and R. Kleemann Fenofibrate Reduces Atherogenesis in ApoE*3Leiden Mice: Evidence for Multiple Antiatherogenic Effects Besides Lowering Plasma Cholesterol Arterioscler. Thromb. Vasc. Biol., October 1, 2006; 26(10): 2322 - 2330. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Kontush and M. J. Chapman Functionally Defective High-Density Lipoprotein: A New Therapeutic Target at the Crossroads of Dyslipidemia, Inflammation, and Atherosclerosis Pharmacol. Rev., September 1, 2006; 58(3): 342 - 374. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Rein, E. Schijlen, T. Kooistra, K. Herbers, L. Verschuren, R. Hall, U. Sonnewald, A. Bovy, and R. Kleemann Transgenic Flavonoid Tomato Intake Reduces C-Reactive Protein in Human C-Reactive Protein Transgenic Mice More Than Wild-Type Tomato J. Nutr., September 1, 2006; 136(9): 2331 - 2337. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Shetty, E. R.M. Eckhardt, S. R. Post, and D. R. van der Westhuyzen Phosphatidylinositol-3-Kinase Regulates Scavenger Receptor Class B Type I Subcellular Localization and Selective Lipid Uptake in Hepatocytes Arterioscler. Thromb. Vasc. Biol., September 1, 2006; 26(9): 2125 - 2131. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Rashid, B. W. Patterson, and G. F. Lewis Thematic review series: Patient-Oriented Research. What have we learned about HDL metabolism from kinetics studies in humans? J. Lipid Res., August 1, 2006; 47(8): 1631 - 1642. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N Dashti, G McGwin, C Owsley, and C A Curcio Plasma apolipoproteins and risk for age related maculopathy Br. J. Ophthalmol., August 1, 2006; 90(8): 1028 - 1033. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Falk Pathogenesis of atherosclerosis. J. Am. Coll. Cardiol., April 18, 2006; 47(8 Suppl): C7 - C12. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. D. Rochester and C. E. Cooke The Changing Face of Dyslipidemia Therapies Journal of Pharmacy Practice, April 1, 2006; 19(2): 79 - 93. [Abstract] [PDF]
|
|
|
|
|
|
P. T. Duong, H. L. Collins, M. Nickel, S. Lund-Katz, G. H. Rothblat, and M. C. Phillips Characterization of nascent HDL particles and microparticles formed by ABCA1-mediated efflux of cellular lipids to apoA-I J. Lipid Res., April 1, 2006; 47(4): 832 - 843. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. M. Wilson, C. L. L. Pham, A. J. Jenkins, J. D. Wade, A. F. Hill, M. A. Perugini, and G. J. Howlett High density lipoproteins bind A{beta} and apolipoprotein C-II amyloid fibrils J. Lipid Res., April 1, 2006; 47(4): 755 - 760. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. C.N. Rensen and L. M. Havekes Cholesteryl Ester Transfer Protein Inhibition: Effect on Reverse Cholesterol Transport? Arterioscler. Thromb. Vasc. Biol., April 1, 2006; 26(4): 681 - 684. [Full Text] [PDF]
|
|
|
|
|
|
A. M. Devlin and S. R. Lentz ApoA-I: A Missing Link Between Homocysteine and Lipid Metabolism? Circ. Res., March 3, 2006; 98(4): 431 - 433. [Full Text] [PDF]
|
|
|
|
 |
|
 J. Ji, G. F. Watts, A. G. Johnson, D. C. Chan, E. M. M. Ooi, K.-A. Rye, A. P. Serone, and P. H. R. Barrett High-Density Lipoprotein (HDL) Transport in the Metabolic Syndrome: Application of a New Model for HDL Particle Kinetics J. Clin. Endocrinol. Metab., March 1, 2006; 91(3): 973 - 979. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. C. Gelissen, M. Harris, K.-A. Rye, C. Quinn, A. J. Brown, M. Kockx, S. Cartland, M. Packianathan, L. Kritharides, and W. Jessup ABCA1 and ABCG1 Synergize to Mediate Cholesterol Export to ApoA-I Arterioscler. Thromb. Vasc. Biol., March 1, 2006; 26(3): 534 - 540. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Duffy and D. J. Rader Emerging Therapies Targeting High-Density Lipoprotein Metabolism and Reverse Cholesterol Transport Circulation, February 28, 2006; 113(8): 1140 - 1150. [Full Text] [PDF]
|
|
|
|
 |
|
 E. Gross, D.-Q. Peng, S. L. Hazen, and J. D. Smith A Novel Folding Intermediate State for Apolipoprotein A-I: Role of the Amino and Carboxy Termini Biophys. J., February 15, 2006; 90(4): 1362 - 1370. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. K. Wu and D. E. Cohen Phosphatidylcholine transfer protein regulates size and hepatic uptake of high-density lipoproteins Am J Physiol Gastrointest Liver Physiol, December 1, 2005; 289(6): G1067 - G1074. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Shao, X. Fu, T. O. McDonald, P. S. Green, K. Uchida, K. D. O'Brien, J. F. Oram, and J. W. Heinecke Acrolein Impairs ATP Binding Cassette Transporter A1-dependent Cholesterol Export from Cells through Site-specific Modification of Apolipoprotein A-I J. Biol. Chem., October 28, 2005; 280(43): 36386 - 36396. [Abstract] [Full Text] [PDF]
|
|