Is Low HDL Cholesterol a Marker or a Mediator of Cardiovascular Disease?

  • Hussein YassineEmail author


In this chapter, we review HDL’s role in reverse cholesterol transport and point out to evidence supporting that HDL acts as a shuttle to transport cholesterol to other lipoproteins, with important roles that are not restricted to the cardiovascular system. We then discuss the atheroprotective roles of HDL in light of the several recent randomized clinical trials that were aimed at raising HDL cholesterol but failed to improve cardiovascular outcomes, and conclude that low HDL cholesterol is a marker, and not a mediator of cardiovascular disease.


Cholesterol Familial hypercholesterolemia LDL HDL VLDL FH LDLR Cholesterol disease Increased cholesterol levels Lipoprotein Cardiovascular disease Gene Clinical signs Lipid 


  1. 1.
    Glomset JA. Physiological role of lecithin-cholesterol acyltransferase. Am J Clin Nutr. 1970;23(8):1129–36.PubMedGoogle Scholar
  2. 2.
    Gordon T, Castelli WP, Hjortland MC, Kannel WB, Dawber TR. High density lipoprotein as a protective factor against coronary heart disease: the Framingham Study. Am J Med. 1977;62(5):707–14.CrossRefPubMedGoogle Scholar
  3. 3.
    Dobiášová M, Frohlich JJ. Advances in understanding of the role of lecithin cholesterol acyltransferase (LCAT) in cholesterol transport. Clinica chimica acta. 1999;286(1):257–71.CrossRefGoogle Scholar
  4. 4.
    Huang Y, von Eckardstein A, Assmann G. Cell-derived unesterified cholesterol cycles between different HDLs and LDL for its effective esterification in plasma. Arterioscler Thromb Vasc Biol. 1993;13(3):445–58.CrossRefGoogle Scholar
  5. 5.
    Castro GR, Fielding CJ. Early incorporation of cell-derived cholesterol into pre-. beta.-migrating high-density lipoprotein. BioChemistry. 1988;27(1):25–9.CrossRefPubMedGoogle Scholar
  6. 6.
    Francone OL, Royer L, Haghpassand M. Increased prebeta-HDL levels, cholesterol efflux, and LCAT-mediated esterification in mice expressing the human cholesteryl ester transfer protein (CETP) and human apolipoprotein AI (apoA-I) transgenes. J Lipid Res. 1996;37(6):1268–77.PubMedGoogle Scholar
  7. 7.
    Miida T, Fielding C, Fielding P. Mechanism of transfer of LDL-derived free cholesterol to HDL subfractions in human plasma. Biochemistry. 1990;29(46):10469–74.CrossRefPubMedGoogle Scholar
  8. 8.
    Serfaty-Lacrosniere C, Civeira F, Lanzberg A, Isaia P, Berg J, Janus ED, et al. Homozygous Tangier disease and cardiovascular disease. Atherosclerosis. 1994;107(1):85–98. PubMed PMID: 7945562.CrossRefPubMedGoogle Scholar
  9. 9.
    Hung KT, Berisha SZ, Ritchey BM, Santore J, Smith JD. Red blood cells play a role in reverse cholesterol transport. Arterioscler Thromb Vasc Biol. 2012;32(6):1460–5.CrossRefPubMedCentralPubMedGoogle Scholar
  10. 10.
    Ho Y, Brown M, Goldstein J. Hydrolysis and excretion of cytoplasmic cholesteryl esters by macrophages: stimulation by high density lipoprotein and other agents. J Lipid Res. 1980;21(4):391–8.PubMedGoogle Scholar
  11. 11.
    Chung BH, Franklin F, Cho BS, Segrest J, Hart K, Darnell BE. Potencies of lipoproteins in fasting and postprandial plasma to accept additional cholesterol molecules released from cell membranes. Arterioscler Thromb Vasc Biol. 1998;18(8):1217–30.CrossRefPubMedGoogle Scholar
  12. 12.
    Chan DC, Hoang A, Barrett PHR, Wong AT, Nestel PJ, Sviridov D, et al. Apolipoprotein B-100 and ApoA-II kinetics as determinants of cellular cholesterol efflux. J Clin Endocrinol Metab. 2012;97(9):E1658–E66.Google Scholar
  13. 13.
    Schwartz CC, VandenBroek JM, Cooper PS. Lipoprotein cholesteryl ester production, transfer, and output in vivo in humans. J Lipid Res. 2004;45(9):1594–607.Google Scholar
  14. 14.
    Zhang Y, McGillicuddy FC, Hinkle CC, O’Neill S, Glick JM, Rothblat GH, et al. Adipocyte modulation of high-density lipoprotein cholesterol. Circulation. 2010;121(11):1347–55. PubMed PMID: 20212278. Pubmed Central PMCID: 2925122.Google Scholar
  15. 15.
    Haghpassand M, Bourassa PA, Francone OL, Aiello RJ. Monocyte/macrophage expression of ABCA1 has minimal contribution to plasma HDL levels. J Clin Invest. 2001;108(9):1315–20. PubMed PMID: 11696576. Pubmed Central PMCID: 209438.Google Scholar
  16. 16.
    Vergeer M, Korporaal SJ, Franssen R, Meurs I, Out R, Hovingh GK, et al. Genetic variant of the scavenger receptor BI in humans. N Engl J Med. 2011;364(2):136–45.Google Scholar
  17. 17.
    Puranik R, Bao S, Nobecourt E, Nicholls SJ, Dusting GJ, Barter PJ, et al. Low dose apolipoprotein AI rescues carotid arteries from inflammation in vivo. Atherosclerosis. 2008;196(1):240–7.Google Scholar
  18. 18.
    Nicholls SJ, Dusting GJ, Cutri B, Bao S, Drummond GR, Rye K-A, et al. Reconstituted high-density lipoproteins inhibit the acute pro-oxidant and proinflammatory vascular changes induced by a periarterial collar in normocholesterolemic rabbits. Circulation. 2005;111(12):1543–50.Google Scholar
  19. 19.
    Calabresi L, Gomaraschi M, Villa B, Omoboni L, Dmitrieff C, Franceschini G. Elevated soluble cellular adhesion molecules in subjects with low HDL-cholesterol. Arterioscler Thromb Vasc Biol. 2002;22(4):656–61.Google Scholar
  20. 20.
    Navab M, Imes S, Hama S, Hough G, Ross L, Bork R, et al. Monocyte transmigration induced by modification of low density lipoprotein in cocultures of human aortic wall cells is due to induction of monocyte chemotactic protein 1 synthesis and is abolished by high density lipoprotein. J Clin Invest. 1991;88(6):2039.Google Scholar
  21. 21.
    Yassine H, Borges CR, Schaab MR, Billheimer D, Stump C, Reaven P, et al. Mass spectrometric immunoassay and MRM as targeted MS-based quantitative approaches in biomarker development: potential applications to cardiovascular disease and diabetes. Proteomics Clin Appl. 2013;7(7–8):528–40. PubMed PMID: 23696124.Google Scholar
  22. 22.
    Yassine HN, Jackson AM, Borges CR, Billheimer D, Koh H, Smith D, et al. The application of multiple reaction monitoring and multi-analyte profiling to HDL proteins. Lipids Health Dis. 2014;13(1):8.Google Scholar
  23. 23.
    Vaisar T, Pennathur S, Green PS, Gharib SA, Hoofnagle AN, Cheung MC, et al. Shotgun proteomics implicates protease inhibition and complement activation in the antiinflammatory properties of HDL. J Clin Invest. 2007;117(3):746–56. PubMed PMID: 17332893. Epub 2007/03/03. eng.Google Scholar
  24. 24.
    Vanhollebeke B, Truc P, Poelvoorde P, Pays A, Joshi PP, Katti R, et al. Human Trypanosoma evansi infection linked to a lack of apolipoprotein LI. N Engl J Med. 2006;355(26):2752–6.Google Scholar
  25. 25.
    Malle E, Steinmetz A, Raynes JG. Serum amyloid A (SAA): an acute phase protein and apolipoprotein. Atherosclerosis. 1993;102(2):131–46. PubMed PMID: 7504491.Google Scholar
  26. 26.
    Cai L, de Beer MC, de Beer FC, van der Westhuyzen DR. Serum amyloid A is a ligand for scavenger receptor class B type I and inhibits high density lipoprotein binding and selective lipid uptake. J Biol Chem. 2005;280(4):2954–61.Google Scholar
  27. 27.
    Nissen SE, Tardif JC, Nicholls SJ, Revkin JH, Shear CL, Duggan WT, et al. Effect of torcetrapib on the progression of coronary atherosclerosis. N Engl J Med. 2007;356(13):1304–16. PubMed PMID: 17387129. Epub 2007/03/28. eng.Google Scholar
  28. 28.
    Bellanger N, Orsoni A, Julia Z, Fournier N, Frisdal E, Duchene E, et al. Atheroprotective reverse cholesterol transport pathway is defective in familial hypercholesterolemia. Arterioscler Thromb Vasc Biol. 2011;31(7):1675–81.Google Scholar
  29. 29.
    Brown MS, Goldstein JL. Lipoprotein metabolism in the macrophage: implications for cholesterol deposition in atherosclerosis. Annu Rev Biochem. 1983;52(1):223–61.Google Scholar
  30. 30.
    Bi X, Zhu X, Duong M, Boudyguina EY, Wilson MD, Gebre AK, et al. Liver ABCA1 deletion in LDLrKO mice does not impair macrophage reverse cholesterol transport or exacerbate atherogenesis. Arterioscler Thromb Vasc Biol. 2013;33(10):2288–96.Google Scholar
  31. 31.
    Rayner KJ, Suárez Y, Dávalos A, Parathath S, Fitzgerald ML, Tamehiro N, et al. MiR-33 contributes to the regulation of cholesterol homeostasis. Science. 2010;328(5985):1570–3.Google Scholar
  32. 32.
    Rayner KJ, Sheedy FJ, Esau CC, Hussain FN, Temel RE, Parathath S, et al. Antagonism of miR-33 in mice promotes reverse cholesterol transport and regression of atherosclerosis. J Clin Invest. 2011;121(7):2921.Google Scholar
  33. 33.
    Frikke-Schmidt R, Nordestgaard BG, Stene MC, Sethi AA, Remaley AT, Schnohr P, et al. Association of loss-of-function mutations in the ABCA1 gene with high-density lipoprotein cholesterol levels and risk of ischemic heart disease. JAMA. 2008;299(21):2524–32.Google Scholar
  34. 34.
    Schwartz GG, Olsson AG, Abt M, Ballantyne CM, Barter PJ, Brumm J, et al. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med. 2012;367(22):2089–99. PubMed PMID: 23126252. Epub 2012/11/07. eng.Google Scholar
  35. 35.
    Boden WE, Probstfield JL, Anderson T, Chaitman BR, Desvignes-Nickens P, Koprowicz K, et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med. 2011;365(24):2255–67. PubMed PMID: 22085343. Epub 2011/11/17. eng.Google Scholar
  36. 36.
    Group H-TC. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med. 2014;371(3):203.Google Scholar
  37. 37.
    Aiello RJ, Brees D, Bourassa PA, Royer L, Lindsey S, Coskran T, et al. Increased atherosclerosis in hyperlipidemic mice with inactivation of ABCA1 in macrophages. Arterioscler Thromb Vasc Biol. 2002;22(4):630–7. PubMed PMID: 11950702.Google Scholar
  38. 38.
    Zhang Y, Da Silva J, Reilly M, Billheimer J, Rothblat G, Rader D. Hepatic expression of scavenger receptor class B type I (SR-BI) is a positive regulator of macrophage reverse cholesterol transport in vivo. J Clin Invest. 2005;115:2870–4.Google Scholar
  39. 39.
    Khera AV, Cuchel M, de la Llera-MoyaM, Rodrigues A, Burke MF, Jafri K, et al. Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis. N Engl J Med. 2011;364(2):127–35.Google Scholar
  40. 40.
    Rohatgi A, Khera A, Berry JD, Givens EG, Ayers CR, Wedin KE, et al. HDL cholesterol efflux capacity and incident cardiovascular events. New England J Med. 0(0):null. PubMed PMID: 25404125.Google Scholar
  41. 41.
    Nissen SE, Tsunoda T, Tuzcu EM, Schoenhagen P, Cooper CJ, Yasin M, et al. Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial. JAMA. 2003;290(17):2292–300.Google Scholar
  42. 42.
    Tardif J-C, Grégoire J, L’Allier PL, Ibrahim R, Lespérance J, Heinonen TM, et al. Effects of reconstituted high-density lipoprotein infusions on coronary atherosclerosis: a randomized controlled trial. JAMA. 2007;297(15):1675–82.Google Scholar
  43. 43.
    Waksman R, Torguson R, Kent KM, Pichard AD, Suddath WO, Satler LF, et al. A first-in-man, randomized, placebo-controlled study to evaluate the safety and feasibility of autologous delipidated high-density lipoprotein plasma infusions in patients with acute coronary syndrome. J Am Coll Cardiol. 2010;55(24):2727–35.Google Scholar
  44. 44.
    Bailey D, Jahagirdar R, Gordon A, Hafiane A, Campbell S, Chatur S, et al. RVX-208A small molecule that increases apolipoprotein AI and high-density lipoprotein cholesterol in vitro and in vivo. J Am Coll Cardiol. 2010;55(23):2580–9.Google Scholar
  45. 45.
    Watson CE, Weissbach N, Kjems L, Ayalasomayajula S, Zhang Y, Chang I, et al. Treatment of patients with cardiovascular disease with L-4F, an apo-A1 mimetic, did not improve select biomarkers of HDL function. J Lipid Res. 2011;52(2):361–73.Google Scholar
  46. 46.
    Tardif J, Gregoire J, L’Allier P, Ibrahim R, Lesperance J, Heinonen T, et al. Effects of reconstituted high-density lipoprotein infusions on coronary atherosclerosis: a randomized controlled trial. JAMA. 2007;297:1675–82.Google Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  1. 1.Medicine DepartmentUniversity of Southern CaliforniaLos AngelesUSA

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