High density lipoprotein classification

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rim Halaby, M.D. [2]


High-density lipoprotein (HDL) does not represent one structure but rather a series of lipoproteins that are sequentially produced. HDL dynamically switches between different conformations. Fractionated HDL particles can be classified based on physiochemical properties, cholesterol component, apolipoprotein composition, electrophoretic mobility, density, and biological function.[1][2] HDL concentration in the serum can be classified into either low and high when the serum HDL concentration ≥ 60mg/dL and < 40 mg/dL, respectively.[3]


Classification by Concentration

High HDL

High HDL level is defined by the National Cholesterol Education Program (NCEP) as serum HDL concentration ≥ 60mg/dL.[3]


Low HDL level is defined by the National Cholesterol Education Program (NCEP) as serum HDL concentration < 40 mg/dL.[3]

Classification by Structural and Functional Characteristics

HDLs are highly heterogenous in their physiochemical characteristics due to the differences in relative composition of intercalated apolipoproteins thus may be separated based upon buoyant density, size, charge, or apolipoprotein composition. Moreover, the amphiphatic helical structure of apoA-I possesses a hinge domain that allows it to switch between different conformations corresponding to HDLs of variable size.[4] With density gradient ultracentrifugation, HDLs can be separated into HDL2, HDL3, and very-high-density lipoprotein (VHDL). Nondenaturing polyacrylamide gradient gel electrophoresis may also be used to fractionate HDLs into five distinct populations of descending size: HDL2b, HDL2a, HDL3a, HDL3b, and HDL3c.[5][6] Isopycnic density gradient ultracentrifugation has been used to analyze the fasting plasma to yield equivalent delineations as well.[7][8] Yet another method of classifying HDL lipoprotein particles by size is nuclear magnetic resonance (NMR).[9] Two-dimensional gel electrophoresis technique can be used to resolve HDL particles in the plasma into lipid-poor pre-β-HDLs and α-HDL that predominantly contains mature spherical cholesteryl esters.[10]


HDLs may be ultracentrifugally fractionated into two major populations.[11][12][13]

Type Size Density
HDL2 1.063-1.125 g/ml 8.8 to 13 nm
HDL3 1.125-1.21 g/ml 7.3 to 8.2 nm


HDL may be isolated on the basis of size by non-denaturing polyacrylamide gradient gel electrophoresis or by isopycnic density gradient ultracentrifugation.[11]

In the order of decreasing size:[13]

  • HDL2b
  • HDL2a
  • HDL3a
  • HDL3b
  • HDL3c

Another classification is:

  • Very large HDL particles (VL-HDL)
  • Large HDL particles (L-HDL)
  • Medium HDL particles (M-HDL)
  • Small HDL particles (S-HDL)
  • Very-small HDL particles (VS-HDL)
  • Pre-β-1 HDL (role in macrophage cholesterol efflux)[1]

Apolipoprotein Content

High density lipoproteins can be immunoseparated on the basis of apolipoprotein composition into particles containing different apolipoproteins. The two major apolipoproteins found within HDL particles are the apoA-I and apoA-II.[14][15] Several other minor apolipoproteins associated with HDL include apoA-IV, apoA-V, apoC-I, apoC-II, apoC-III, and apoE.[16] However, LpA-I and LpA-I:LpA-II constitute the major portions of ciculating HDLs.

  • LpA-I (contains only apoA-I)
  • LpA-I:LpA-II (contains both apoA-I and apoA-II)
  • LpA-IV
  • LpE[11][13]

Surface Charge

HDL can be separated according to charge by agarose gel electrophoresis.[11]

Note that pre-beta < pre-alpha < alpha.

  • Pre-beta (positive)
  • Pre-alpha
  • Alpha (negative)


  1. 1.0 1.1 Rosenson RS, Brewer HB, Chapman MJ, Fazio S, Hussain MM, Kontush A; et al. (2011). "HDL measures, particle heterogeneity, proposed nomenclature, and relation to atherosclerotic cardiovascular events". Clin Chem. 57 (3): 392–410. doi:10.1373/clinchem.2010.155333. PMID 21266551.
  2. Rosenson RS, Brewer HB, Ansell B, Barter P, Chapman MJ, Heinecke JW; et al. (2013). "Translation of High-Density Lipoprotein Function Into Clinical Practice: Current Prospects and Future Challenges". Circulation. 128 (11): 1256–1267. doi:10.1161/CIRCULATIONAHA.113.000962. PMID 24019446.
  3. 3.0 3.1 3.2 National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) (2002). "Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report". Circulation. 106 (25): 3143–421. PMID 12485966.
  4. Reschly, EJ.; Sorci-Thomas, MG.; Davidson, WS.; Meredith, SC.; Reardon, CA.; Getz, GS. (2002). "Apolipoprotein A-I alpha -helices 7 and 8 modulate high density lipoprotein subclass distribution". J Biol Chem. 277 (12): 9645–54. doi:10.1074/jbc.M107883200. PMID 11744719. Unknown parameter |month= ignored (help)
  5. Blanche, PJ.; Gong, EL.; Forte, TM.; Nichols, AV. (1981). "Characterization of human high-density lipoproteins by gradient gel electrophoresis". Biochim Biophys Acta. 665 (3): 408–19. PMID 7295744. Unknown parameter |month= ignored (help)
  6. Anderson, DW.; Nichols, AV.; Forte, TM.; Lindgren, FT. (1977). "Particle distribution of human serum high density lipoproteins". Biochim Biophys Acta. 493 (1): 55–68. PMID 195628. Unknown parameter |month= ignored (help)
  7. Goulinet, S.; Chapman, MJ. (1997). "Plasma LDL and HDL subspecies are heterogenous in particle content of tocopherols and oxygenated and hydrocarbon carotenoids. Relevance to oxidative resistance and atherogenesis". Arterioscler Thromb Vasc Biol. 17 (4): 786–96. PMID 9108795. Unknown parameter |month= ignored (help)
  8. Tall, AR.; Blum, CB.; Forester, GP.; Nelson, CA. (1982). "Changes in the distribution and composition of plasma high density lipoproteins after ingestion of fat". J Biol Chem. 257 (1): 198–207. PMID 6796585. Unknown parameter |month= ignored (help)
  9. Rifai, Nader.; Warnick, G. Russell.; Dominiczak, Marek H. (2000). Handbook of lipoprotein testin. Washington, DC: AACC Press. ISBN 1-890883-35-2.
  10. Asztalos, BF.; Schaefer, EJ. (2003). "High-density lipoprotein subpopulations in pathologic conditions". Am J Cardiol. 91 (7A): 12E–17E. PMID 12679198. Unknown parameter |month= ignored (help)
  11. 11.0 11.1 11.2 11.3 Krimbou L, Tremblay M, Davignon J, Cohn JS (1997). "Characterization of human plasma apolipoprotein E-containing lipoproteins in the high density lipoprotein size range: focus on pre-beta1-LpE, pre-beta2-LpE, and alpha-LpE". J Lipid Res. 38 (1): 35–48. PMID 9034198.
  12. Chapman MJ, Goldstein S, Lagrange D, Laplaud PM (1981). "A density gradient ultracentrifugal procedure for the isolation of the major lipoprotein classes from human serum". J Lipid Res. 22 (2): 339–58. PMID 6787159.
  13. 13.0 13.1 13.2 Rye KA, Barter PJ (2012). "Predictive value of different HDL particles for the protection against or risk of coronary heart disease". Biochim Biophys Acta. 1821 (3): 473–80. doi:10.1016/j.bbalip.2011.10.012. PMID 22051746.
  14. Brewer, HB.; Lux, SE.; Ronan, R.; John, KM. (1972). "Amino acid sequence of human apoLp-Gln-II (apoA-II), an apolipoprotein isolated from the high-density lipoprotein complex". Proc Natl Acad Sci U S A. 69 (5): 1304–8. PMID 4338591. Unknown parameter |month= ignored (help)
  15. Brewer, HB.; Fairwell, T.; LaRue, A.; Ronan, R.; Houser, A.; Bronzert, TJ. (1978). "The amino acid sequence of human APOA-I, an apolipoprotein isolated from high density lipoproteins". Biochem Biophys Res Commun. 80 (3): 623–30. PMID 204308. Unknown parameter |month= ignored (help)
  16. Alaupovic, P. (1996). "Significance of apolipoproteins for structure, function, and classification of plasma lipoproteins". Methods Enzymol. 263: 32–60. PMID 8748999.

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