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Current Atherosclerosis Reports

, Volume 13, Issue 3, pp 233–241 | Cite as

Update on HDL Receptors and Cellular Cholesterol Transport

  • Ginny Kellner-Weibel
  • Margarita de la Llera-MoyaEmail author
Article

Abstract

Efflux is central to maintenance of tissue and whole body cholesterol homeostasis. The discovery of cell surface receptors that bind high-density lipoprotein (HDL) with high specificity and affinity to promote cholesterol release has significantly advanced our understanding of cholesterol efflux. We now know that 1) cells have several mechanisms to promote cholesterol release, including a passive mechanism that depends on the physico-chemical properties of cholesterol molecules and their interactions with phospholipids; 2) a variety of HDL particles can interact with receptors to promote cholesterol transport from tissues to the liver for excretion; and 3) interactions between HDL and receptors show functional synergy. Therefore, efflux efficiency depends both on the arrays of receptors on tissue cells and HDL particles in serum.

Keywords

HDL Cholesterol Efflux ABCA1 ABCG1 SR-BI Review Macrophage Pre-β-HDL apoA-I Reverse cholesterol transport 

Notes

Disclosure

Ginny Kellner-Weibel reports no potential conflict of interest relevant to this article. Margarita de la Llera-Moya reports no potential conflict of interest relevant to this article.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Yokoyama S. Release of cellular cholesterol: molecular mechanism for cholesterol homeostasis in cell and in the body. Biochim Biophys Acta. 2000;1529:231–44.PubMedGoogle Scholar
  2. 2.
    Meurs I, Van Eck M, Van Berkel TJC. High-density lipoprotein: key molecule in cholesterol efflux and the prevention of atherosclerosis. Curr Pharm Des. 2010;16:1445–67.PubMedCrossRefGoogle Scholar
  3. 3.
    Rothblat GH, de la Llera M, Atger V, Kellner-Weibel G, Williams DL, Phillips MC. Cell cholesterol efflux: integration of old and new observations provides new insights. J Lipid Res. 1999;40:781–96.PubMedGoogle Scholar
  4. 4.
    Acton S, Rigotti A, Landschulz KT, Xu S, Hobbs HH, Krieger M. Identification of scavenger receptor SR-BI as a high density lipoprotein receptor. Science. 1996;271:518–20.PubMedCrossRefGoogle Scholar
  5. 5.
    Baldan A, Bojanic DD, Edwards PA. The ABCs of sterol transport. J Lipid Res. 2009;50:S80–5.PubMedCrossRefGoogle Scholar
  6. 6.
    Adorni MP, Zimetti F, Billheimer JT, Wang N, Rader DJ, Phillips MC, et al. The role of different pathways in the release of cholesterol from macrophages. J Lipid Res. 2007;48:2453–62.PubMedCrossRefGoogle Scholar
  7. 7.
    Rothblat GH, Phillips MC. High-density lipoprotein heterogeneity and function in reverse cholesterol transport. Curr Opin Lipidol. 2010;21:229–38.PubMedCrossRefGoogle Scholar
  8. 8.
    Rye KA, Bursill CA, Lambert G, Tabet F, Barter PJ. The metabolism and anti-atherogenic properties of HDL. J Lipid Res. 2009;50:S195–200.PubMedCrossRefGoogle Scholar
  9. 9.
    •• de la Llera-Moya M, Drazul-Schrader D, Asztalos BF, Cuchel M, Rader DJ, Rothblat GH. The ability to promote efflux via ABCA1 determines the capacity of serum specimens with similar HDL-C to remove cholesterol from macrophages. Arterioscler Thromb Vasc Biol. 2010;30:796–801. This study demonstrates that sera with similar HDL cholesterol or apoA-I values differ in their ability to promote macrophage cholesterol efflux. The difference in efflux can be attributed to differences in the concentration of pre-β HDL. PubMedCrossRefGoogle Scholar
  10. 10.
    Cuchel M, de La Llera-Moya M, Phillips JA, Wolf ML, Rothblat GH, Rader DJ. Cholesterol efflux capacity of serum predicts carotid intermal-medial thickness independently of HDL-C and apo A-I levels. Circulation. 2008;118:S-371.Google Scholar
  11. 11.
    Jian B, Llera-Moya M, Ji Y, Wang N, Phillips MC, Swaney JB, et al. Scavenger receptor class B type I as a mediator of cellular cholesterol efflux to lipoproteins and phospholipid acceptors. J Biol Chem. 1998;273:5599–606.PubMedCrossRefGoogle Scholar
  12. 12.
    Thuahnai ST, Lund-Katz S, Dhanasekaran P, de la Llera-Moya M, Connelly MA, Williams DL, et al. SR-BI-mediated cholesteryl ester selective uptake and efflux of unesterified cholesterol: influence of HDL size and structure. J Biol Chem. 2004;279:12448–55.PubMedCrossRefGoogle Scholar
  13. 13.
    Wang X, Collins HL, Ranalletta M, Fuki IV, Billheimer JT, Rothblat GH, et al. Macrophage ABCA1 and ABCG1, but not SR-BI, promote macrophage reverse cholesterol transport in vivo. J Clin Invest. 2007;117:2216–24.PubMedCrossRefGoogle Scholar
  14. 14.
    • Truong TQ, Aubin D, Falstrault S, Brodeur MR, Brissette L. SR-BI and CD36, and caveolin-1 contribute positively to cholesterol efflux in hepatic cells. Cell Biochem Funct. 2010;28:480–9. This article confirms earlier observations that oligomerization of class B scavenger receptors has functional significance. PubMedCrossRefGoogle Scholar
  15. 15.
    Lewis GF, Rader DJ. New insights into the regulation of HDL metabolism and reverse cholesterol transport. Circ Res. 2005;96:1221–32.PubMedCrossRefGoogle Scholar
  16. 16.
    • Badeau RM, Metso J, Wahala K, Tikkanen MJ, Jauhiainen M. Human macrophage cholesterol efflux potential is enhanced by HDL-associated 17B-estradiol fatty acid esters. J Steroid Biochem Mol Biol. 2009;116:44–9. This is an interesting and novel demonstration of basis for gender-related functional differences in HDL. PubMedCrossRefGoogle Scholar
  17. 17.
    Connelly MA, Llera-Moya M, Monzo P, Yancey P, Drazul D, Stoudt G, et al. Analysis of chimeric receptors shows that multiple distinct functional activities of scavenger receptor, class B, type I (SR-BI), are localized to the extracellular receptor domain. Biochemistry. 2001;40:5249–59.PubMedCrossRefGoogle Scholar
  18. 18.
    Papale GA, Nicholson K, Hanson PJ, Pavlovic M, Drover VA, Sahoo D. Extracellular hydrophobic regions in scavenger receptor BI play a key role in mediating HDL-cholesterol transport. Arch Biochem Biophys. 2010;496:132–9.PubMedCrossRefGoogle Scholar
  19. 19.
    Assanasen C, Mineo C, Seetharam D, Yuhanna IS, Marcel YL, Connelly MA, et al. Cholesterol binding, efflux, and a PDZ-interacting domain of scavenger receptor-BI mediate HDL-initated signaling. J Clin Invest. 2005;115:969–77.PubMedGoogle Scholar
  20. 20.
    Saddar S, Mineo C, Shaul PW. Signaling by the high-affinity HDL receptor scavenger receptor B type I. Arterioscler Thromb Vasc Biol. 2010;30:144–50.PubMedCrossRefGoogle Scholar
  21. 21.
    Xie Q, Zhao S, Li F. D-4F, an apolipoprotein A-I mimetic peptide, promotes cholesterol efflux from macrophages via ATP-binding cassette transporter A1. J Exp Med. 2010;220:223–8.Google Scholar
  22. 22.
    Wiersma H, Gatti A, Nijstad N, Kuipers F, Tietge UJ. Hepatic SR-BI, not endothelial lipase, expression determines biliary cholesterol secretion in mice. J Lipid Res. 2009;50:1571–80.PubMedCrossRefGoogle Scholar
  23. 23.
    Fenske S, Yesilaltay A, Pal R, Daniels K, Barker C, Quinones V, et al. Normal hepatic cell-surface localization of the high-density lipoprotein receptor, SR-BI, depends on all four PDZ domains of PDZK1. J Biol Chem. 2009;284:5797–806.PubMedCrossRefGoogle Scholar
  24. 24.
    Hoekstra M, Ye D, Hildebrand RB, Zhoa Y, Lammers B, Stitzinger M, et al. Scavenger receptor class B type I-mediated uptake of serum cholesterol is essential for optimal adrenal glucocorticoid production. J Lipid Res. 2009;50:1039–46.PubMedCrossRefGoogle Scholar
  25. 25.
    Tall AR. Cholesterol efflux pathways and other potential mechanisms involved in the athero-protective effect of high density lipoproteins. J Intern Med. 2008;263:256–73.PubMedCrossRefGoogle Scholar
  26. 26.
    Wang N, Ranalletta M, Matsuura F, Peng F, Tall AR. LXR induced redistribution of ABCG1 to plasma membrane in macrophages enhances cholesterol mass efflux to HDL. Arterioscler Thromb Vasc Biol. 2006;26:1310–6.PubMedCrossRefGoogle Scholar
  27. 27.
    Tarr P, Edwards PA. ABCA1 and ABCG4 are coexpressed in neurons and astrocytes of the CNS and regulate cholesterol homeostasis through SREBP-2. J Lipid Res. 2008;49:169–82.PubMedCrossRefGoogle Scholar
  28. 28.
    • Sankaranarayanan S, Oram JF, Asztalos BF, Vaughan AM, Lund-Katz S, Adorni MP, et al. Effects of acceptor composition and mechanism of ABCG1-mediated cellular free cholesterol efflux. J Lipid Res. 2009;50:275–84. This is a careful characterization of ABCG1-mediated cholesterol efflux. PubMedCrossRefGoogle Scholar
  29. 29.
    Xu M, Zhoa H, Tan KCB, Guo R, Shiu SWM, Wong Y. ABCG1 mediated oxidized LDL-derived oxysterol efflux from macrophages. Biochem Biophys Res Commun. 2009;390:1349–54.PubMedCrossRefGoogle Scholar
  30. 30.
    Baldan A, Tarr P, Lee R, Edwards PA. ATP-binding cassette transporter G1 and lipid homeostasis. Curr Opin Lipidol. 2006;17:227–32.PubMedCrossRefGoogle Scholar
  31. 31.
    Badldan A, Pei L, Lee R, Tarr P, Tangirala RK, Weinstein MM, et al. Impaired development of atherosclerosis in hyperlipidemic LDLr-/- and apoE-/- mice transplanted with ABCG1-/- bone marrow. ATVB. 2006;26:2175–7.Google Scholar
  32. 32.
    Lammers B, Out R, Hildebrand RB, Quinn CM, Williamson D, Hoekstra M, et al. Independent protective roles for macrophage ABCA1 and ApoE in the atherosclerotic lesion development. Atheroscerosis. 2009;205:420–6.CrossRefGoogle Scholar
  33. 33.
    Tarling EJ, Bojanic DD, Tangirala RK, Wang X, Lovgren-Sandblom A, Lusis AJ, et al. Impaired development of atherosclerosis in ABCG1/apoE/mice: identification of specific oxysterols that both accumulate in ABCG1/apoE/tissues and induce apoptosis. Arterioscler Thromb Vasc Biol. 2010;30.Google Scholar
  34. 34.
    • Gelissen IC, Cartland S, Brown AJ, Sandoval C, Kim M, Dinnes DL, et al. Expression and stability of two isoforma of ABGC1 in human vascular cells. Atheroscerosis. 2010;208:75–82. This article is a characterization of a novel receptor isoform that merits further study. CrossRefGoogle Scholar
  35. 35.
    Wang N, Yvan-Charvet L, Lutjohann D, Mulder M, Vanmierlo T, Kim TW, et al. ATP-binding cassette transporters GI and G4 mediate cholesterol and desmosterol efflux to HDL and regulate sterol accumulation in the brain. FASEB J. 2008;22:1073–82.PubMedCrossRefGoogle Scholar
  36. 36.
    Uehara Y, Yamada T, Baba Y, Miura S, Abe S, Kitajima K, et al. ATP-binding cassette transporter G4 is highly expressed in microglia in Alzheimer’s brain. Brain Res. 2008;1217:239–46.PubMedCrossRefGoogle Scholar
  37. 37.
    • Bojanic DD, Tarr PT, Gale GD, Smith DJ, Bok D, Chen B, et al. Differential expression and function of ABCG1 and ABCG4 during development and aging. J Lipid Res. 2010;51:169–81. This article provides further demonstration that ABCG4 has a role in cognition and memory. PubMedCrossRefGoogle Scholar
  38. 38.
    Zhao Y, Van Berkel TJC, Van Eck M. Relative roles of various efflux pathways in net cholesterol efflux from macrophage foam cells in atherosclerotic lesions. Curr Opin Lipidol. 2010;21:441–53.PubMedCrossRefGoogle Scholar
  39. 39.
    •• Nandi S, Ma L, Denis M, Karwatsky J, Li Z, Jiang XC, et al. ABCA1-mediated cholesterol efflux generates microparticles in addition to HDL through processes governed by membrane rigidity. J Lipid Res. 2009;50:456–66. This study shows that ABCA1 mediates the production of apoA-I–free as well as apoA-I–containing microparticles. These microparticles are a significant contributor to the cholesterol efflux pathway. The results of these studies suggest that both HDL and microparticle release is favored by a more fluid plasma membrane. PubMedCrossRefGoogle Scholar
  40. 40.
    Yvan-Charvet L, Wang N, Tall AR. Role of HDL, ABCA1, and ABCG1 transporters in cholesterol efflux and immune responses. Arterioscler Thromb Vasc Biol. 2009;29:00.Google Scholar
  41. 41.
    •• Singaraja RR, Kang MH, Vaid K, Sanders SS, Vilas GL, Arstikaitis P, et al. Palmitoylation of ATP-binding cassette transporter A1 is essential for its trafficking and function. Circ Res. 2009;105:138–47. ABCA1 lipidates apoA-I from lipid stores at the plasma membrane and from the late endosomal or lysosomal compartments. Palmitoylation of ABCA1 targets the protein to the plasma membrane. PubMedCrossRefGoogle Scholar
  42. 42.
    Azuma Y, Takada M, Shin HW, Kioka N, Nakayama K, Ueda K. Retroendocytosis pathway of ABCA1/apoA-I contributes to HDL formation. Genes Cells. 2009;14:191–204.PubMedCrossRefGoogle Scholar
  43. 43.
    Faulkner LE, Panagotopulos SE, Johnson JD, Woollett LA, Hui DY, Witting SR, et al. An analysis of the role of a retroendocytosis pathway in ABCA1-mediated cholesterol efflux from macrophages. J Lipid Res. 2008;49:1322–32.PubMedCrossRefGoogle Scholar
  44. 44.
    Zhang YZ, McGillcuddy FC, Hinkle CC, O’Neil S, Glick JM, Rothblat GH, et al. Adipocyte modulatioin of high-density lipoprotein cholesterol. Circulation. 2010;121:1347–55.PubMedCrossRefGoogle Scholar
  45. 45.
    • Vedachalam C, Chetty P, Nickel M, Dhanasekaran P, Lund-Katz S, Rothblat GH, et al. Influence of apolipoprotein (Apo) A-I structure on nascent high density lipoprotein (HDL) and particle size distribution. J Biol Chem. 2010;42:31965–73. The authors find that the tertiary structure of apoA-I influences the kinetics of ABCA-1–mediated efflux of cholesterol and phospholipids and HDL heterogeneity by modulating the size distribution of the nascent HDL particles created. CrossRefGoogle Scholar
  46. 46.
    Tang C, Liu Y, Kessler PS, Vaughan AM, Oram JF. The macrophage cholesterol exporter ABCA1 functions as an anti-inflammatory receptor. J Biol Chem. 2009;284:32336–43.PubMedCrossRefGoogle Scholar
  47. 47.
    Vaughan AM, Tang C, Oram JF. ABCA1 mutants reveal an interdependency between lipid export function, apoA-I binding activity, and Janus kinase 2 activation. J Lipid Res. 2009;50:285–92.PubMedCrossRefGoogle Scholar
  48. 48.
    Linder MD, Mayranpaa MI, Peranen J, Pietila TE, Pietiainen VM, Uronen R-L, et al. Rab8 regulates ABCA1 cell surface expression and facilitates cholesterol efflux in primary human macrophages. Arterioscler Thromb Vasc Biol. 2009;29:883–8.PubMedCrossRefGoogle Scholar
  49. 49.
    •• Marquart TJ, Allen RM, Ory DS, Baldan A. MiR-33 links SREBP-2 induction to repression of sterol transporters. PNAS. 2010;107:12228–32. This study shows that ABCA1 mRNA and protein and serum HDL levels are reduced when miR-33 is overexpressed and that these parameters increase with miR-33 silencing. PubMedCrossRefGoogle Scholar
  50. 50.
    •• Najafi-Shoushtari SH, Kristo F, Li Y, Shioda T, Cohen DE, Gerszren RE, et al. MicroRNA-33 and SREBP host genes cooperate to control cholesterol homeostasis. Science. 2010;328:1566–9. Antisense inhibition of miR-33 in mouse and human cell lines results in increased ABCA1 expression and therefore increased cholesterol efflux to apoA-I. The authors find that miR-33 acts in concert with SREBP to regulate cholesterol levels. PubMedCrossRefGoogle Scholar
  51. 51.
    •• Rayner KJ, Suarez Y, Davalos A, Parathath S, Fitzgerald ML, Tamehiro N, et al. MiR-33 contributes to the regulation of cholesterol homeostasis. Science. 2010;328:1570–3. MiR-33 is an intronic microRNA located in the gene encoding SREBPF-2, a transcriptional regulator of cholesterol synthesis. MiR-33 inhibits the expression of ABCA1 in mouse and human cells and ABCG1 in mouse macrophages. MiR-33 is implicated in the regulation of HDL biogenesis in the liver and cellular cholesterol efflux. PubMedCrossRefGoogle Scholar
  52. 52.
    Sacks FM, Rudel LL, Connor A, Akeefe H, Kostner G, Baik T, et al. Selective delipidation of plasma HDL enhances reverse cholesterol transport in vivo. J Lipid Res. 2009;50:894–907.PubMedCrossRefGoogle Scholar
  53. 53.
    Khera AV, Rodrigues A, de La Llera-Moya M, Rothblat GH, Rader DJ. Serum cholesterol efflux capacity, a measure of HDL-C quality, varies according to coronary artery disease status independently of HDL-C quantity. Circulation. 2009:120.Google Scholar
  54. 54.
    Smith LE, Davidson WS. The role of hydrophobic and negatively charged surface patches of lipid-free apolipoprotein A-I in lipid binding and ABCA1-mediated cholesterol efflux. Biochim Biophys Acta. 2010;1801:64–9.PubMedGoogle Scholar
  55. 55.
    Ingenito R, Burton C, Langella A, Chen X, Zytko K, Pessi A, et al. Novel potent apoA-I mimetics that stimulate cholesterol efflux and pre-β particle formation in vitro. Bioorg Med Chem Lett. 2010;20:236–9.PubMedCrossRefGoogle Scholar
  56. 56.
    Tang C, Oram JF. The cell cholesterol exporter ABCA1 as a protector from cardiovascular disease and diabetes. Biochim Biophys Acta. 2009;1791:563–72.PubMedGoogle Scholar
  57. 57.
    Fryirs M, Barter PJ, Rye K. Cholesterol metabolism and pancreatic B-cell function. Curr Opin Lipidol. 2009;20.Google Scholar
  58. 58.
    Vegeer M, Verchere CB, Brunham LR, Kastelein JJP, Koetsveld J, Hayden MR, et al. Carriers of loss-of-function mutations in ABCA1 display pancreatic B-cell dysfunction. Diab Care. 2010;33:869–74.CrossRefGoogle Scholar
  59. 59.
    Vaughan AM, Oram JF. ABCA1 and ABCG1 or ABCG4 act sequentially to remove cellular cholesterol and generate cholesterol-rich HDL. J Lipid Res. 2006;47:2433–43.PubMedCrossRefGoogle Scholar
  60. 60.
    • Favari E, Calabresi L, Adorni MP, Jessup W, Simonelli S, Franceschini G, et al. Small discoidal pre-beta1 HDL particles are efficient acceptors of cell cholesterol via ABCA1 and ABCG1. Biochemistry. 2009;48:11067–74. The results indicated that the ABCA1-mediated cell cholesterol efflux can be efficiently driven not only by monomolecular lipid-free/lipid-poor apoA-I, but also by a small discoidal phospholipid-containing particle resembling plasma pre-β1 HDL. This same particle also promotes ABCG1-mediated but not SR-BI-mediated efflux. These results help to clarify the role of plasma pre-β1 HDL in reverse cholesterol transport. PubMedCrossRefGoogle Scholar
  61. 61.
    Cuchel M, Lund-Katz S, de la Llera-Moya M, Millar JS, Chang D, Fuki I, et al. Pathways by which reconstituted high-density lipoprotein mobilizes feee cholesterol from whole body and from macrophages. Arterioscler Thromb Vasc Biol. 2010;30:526–32.PubMedCrossRefGoogle Scholar
  62. 62.
    • Stefulj J, Panzenboek U, Becker T, Hirschmugl B, Schweinzer C, Land I, et al. Human Endothelial Cells of the Placental Barrier Efficiently Deliver Cholesterol to the Fetal Circulation via ABCA1 and ABCG1. Circ Res. 2009;104:600–8. These studies demonstrate a novel role for cholesterol transporters. Additional studies are warranted because understanding cholesterol transport across the fetal-maternal barrier could have significant health implications. PubMedCrossRefGoogle Scholar
  63. 63.
    Sun Y, Ishibashi M, Seimon T, Lee M, Sharma SM, Fitzgerald KA, et al. Free cholesterol accululation in macrophage membranes activates toll-like receptors and p38 mitogen-activated protein kinase and induces cathepsin K. Circ Res. 2009;104:455–65.PubMedCrossRefGoogle Scholar
  64. 64.
    Smith JD. Dysfunctional HDL as a diagnostic and therapeutic target. Arterioscler Thromb Vasc Biol. 2010;30:151–5.PubMedCrossRefGoogle Scholar
  65. 65.
    Sankaranarayanan S, de la Llera-Moya M, Drazul-Schrader D, Asztalos BF, Weibel GL, Rothblat GH. Importance of macrophage cholesterol content on the flux of cholesterol mass. J Lipid Res. 2010;51:3243–9.PubMedCrossRefGoogle Scholar
  66. 66.
    Tarr PT, Tarling EJ, Bojanic DD, Edwards PA, Baldan A. Emerging new paradigms for ABCG transporters. Biochim Biophys Acta. 2009;1791:584–93.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Ginny Kellner-Weibel
    • 2
  • Margarita de la Llera-Moya
    • 1
    Email author
  1. 1.Division of Gastroenterology, Hepatology and NutritionThe Children’s Hospital of PhiladelphiaPhiladelphiaUSA
  2. 2.Division of Gastroenterology, Hepatology and NutritionThe Children’s Hospital of PhiladelphiaPhiladelphiaUSA

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