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DATA No : TLP1201 INFORMANT : Kazuo Kondo

NAME : high density lipoprotein

COMMON NAME: a- lipoprotein
FORMULA: MOL.WT (average) :
Biological Activity HDL
Approximately 25% of the total cholesterol in plasma is contained in HDL particles.HDL particles transport cholesterol from peripheral cells to other lipoproteins and the liver.Many epidemiological studies have shown an inverse relationship between the prevalence of coronary heart disease(CHD) and the level of HDL cholesterol.(Ref. 1208/1209/1210/1211)
High density lipoprotein (HDL) is defined as the lipoprotein fraction with a density range between 1.063 to 1.21 g/ml. The HDL fraction comprises two major fractions : HDL2 (1.063-1.125 g/ml) and HDL3 (1.125-1.21 g/ml).(Ref. 1001)




DENSITY: HDL2 : 1.063-1.125 g/ml, HDL3 : 1.125-1.210 g/ml

SOLUBILITY:Physical properties
Particle weight HDL2: 3.6times105, HDL3: 1.75times105, Diameter (nm) HDL2 : 8-11, HDL3 : 6-9
Relative weight composition (%)
HDL2 : Protein 35-40 Phospholipid 30-40 Free cholesterol 4-6 Cholesteryl ester 15-20 Triglyceride 3-6, HDL3 : Protein 45-55 Phospholipid 25-35 Free cholesterol 1-3 Cholesteryl ester 8-15 Triglyceride 3-6
Apolipoprotein contribution (%) HDL2 : apo A-I 65 apo A-II 10 apo C 10-15 apo E 3-5, HDL3 : apo A-I 62 apo A-II 23 apo A-IV Trace apo C 5 apo E 1 (Ref. 1006)




HDL in agarose gel electrophoresis
In agarose gel electrophoresis HDL migrates at the same position as a-globulins; thus HDL is designated a-lipoprotein.
Fig.1 through 4: Electrophorograms above electrophoretic patterns of anodically migrating lipoprotein fractions.
Fig.1: Fat Red 7B stained lipoproteins.
Fig.2: Formazan dye developed cholesterol fractions.
Fig.3: Formazan dye developed triglyceride fractions
Fig.4: Fig.2 and Fig.3 superimporsed. Demonstrate relative positions and enabling ratio assessment of all triglyceride and choresterol fractions, including Lp(a), Lipo X, slowa,IDL,andb-VLDL.
[Chromatogram 1001]
Classification of HDL
The HDL fraction consists of heterogeneous particles differentiated by particle size, chemical composition and physicochemical properties and are separated into three main subfractions differentiated by density: HDL1 (1.055-1.085 g/ml), HDL2 (1.063-1.125 g/ml) and HDL3 (1.125-1.21 g/ml). HDL2 and HDL3 are major fractions. HDL1 is a minor fraction and contains apolipoprotein E (apo E) as its main protein component and is mainly observed in humans who have ingested a high-cholesterol diet for several weeks.
These subfractions are separated into other subclasses according to size by polyacrylamide gradient gel electrophoresis (GGE). Two have migration distances (RF values) in the range associated with HDL2 and three in the RF range of HDL3.
Mean hydrated densities and particle sizes of these subfractions are 1.085 g/ml and 10.57 nm for (HDL2b)gge, 1.115 g/ml and 9.16 nm for (HDL2a)gge, 1.136 g/ml and 8.44 nm for (HDL3a)gge, 1.154 g/ml and 7.97 nm for (HDL3b)gge, and 1.171 g/ml and 7.62 nm for (HDL3c)gge.
HDL can be fractionated into LpA-I and LpA-I/A-II, differentiated by the constituent apolipoproteins using affinity columns containing antibodies specific for apo A-I and apo A-II. LpA-I contains apolipoprotein A-I (apo A-I) but not apolipoprotein A-II (apo A-II) and LpA-I/A-II contains both apo A-I and apo A-II. Some evidences suggests that LpA-I can promote cholesterol efflux from cells but LpA-I/A-II is less effective. Pre-b-HDL is a minor fraction of LpA-I, migrating in the pre-b position on agarose gel electrophoresis. Pre-b-HDL is considered the initial acceptor of cellular cholesterol.(Ref. 1201/1202/1203/1204/1205)
Composition and Structure of HDL
The average molecular weight of HDL2 is 3.6times105 and consists of protein (35-40%), phospholipid (30-40%), free cholesterol (4-6%), cholesteryl ester (15-20%) and triglyceride (3-6%). The average molecular weight of HDL3 is 1.75times105 and consists of protein (45-55%),phospholipid (25-35%), free cholesterol (1-3%), cholesteryl ester (8-15%) and triglyceride (3-6%). The ratio of phosphatidyl choline to sphingomyelin and that of free to estetified cholesterol is greater for HDL2 than for HDL3.Approximately 90% of the constituent apolipoproteins on HDL2 and HDL3 are apolipoprotein A-I (apo A-I) and apolipoprotein A-II (apoA-II) .Apolipoprotein C (apo C),apo E and apolipoprotein A-IV (apo A-IV) are found in small quantities. The relative proportion of apoA-I and apo A-II varies in the HDL subfractions .
Preparation by zonal ultracentrifugation shows an apo A-I/apo A-II molar ratio of 9:1 in the HDL2 fraction and 2:1 in the HDL3 fraction.
HDL particles are secreted as discoidal particles or small spherical particles. Discoidal HDL consists of phospholipid and some unesterified cholesterol organized as a lipid bilayer associated with apo A-I.The discoidal particles are designated nascent HDL, and are transformed into spherical particles by lecithin:cholesterol acyl transferase (LCAT) reaction.In all of the sub fractions , HDL exists as spherical particles which contain the same chemical constituents,but differ in particle size, density and stoichiometry.The structure of HDL is presumed to comprise cholesteryl esters and triglycerides in the hydrophobic core, surrounded by a surface coat of apo A-I,apo A-II ,phosphatidyl choline and sphingomyelin oriented toward the aqueous medium.
[Table 2001] (Ref. 1001/1003/1005/1006/1206/1207)
Metabolism of HDL
HDL precursors are secreted from the liver and intestine, or derived from surface fragments originating by lipolysis of chylomicrons and VLDL. These particles consists of phospholipid and some unesterified cholesterol organized as a lipid bilayer associated with apo A-I. Apo A-I is an activator of the lecithin:cholesterol acyl transferase (LCAT). HDL precursors acquire unesterified cholesterol from cell membranes, incorporate cholesteryl esters into their cores by the LCAT reaction, and become mature HDL particles ( HDL precursorsa_rightHDL3a_rightHDL2). Cholesteryl esters of HDL are transferred to apo B containing lipoproteins by the cholesteryl ester transfer protein (CETP), and exchanged for their triglycerides. Then triglycerides of HDL are hydrolyzed by hepatic lipase, the HDL particles become smaller, more dense particles that are donors for further transfer of cholesteryl esters.
These processes are part of the Reverse Cholesterol Transport system. Cholesteryl esters transferred to apo B containing lipoproteins are endocytosed with those particles in the liver by receptor-mediated processes involving the LDL and chylomicron remnant receptors. Moreover it appears that another pathway exists for the transport of cholesteryl ester to liver: HDL particles transport cholesterol directly to hepatocyte by receptor-mediated endocytosis. It is postulated that HDLwith apo E is ultimately taken up into the liver via an apo E receptor (remnant receptor), and HDL without apo E is ultimately taken up via the HDL receptor. Cholesterol taken up into the liver is finally made available for the synthesis of bile acids.(Ref. 1001/1006/1207)


AUTHOR:Gotto,A.M. Jr., Pownall,H.J., and Havel,R.J. (1986) Introduction to the Plasma Lipoproteins, in Methods in Enzymology vol.128 (Segrest,J.P. and Albers,J.J., eds),pp3-41, Academic Press, London
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AUTHOR:Alaupovic,P., Lee,D.M., and WcConathy, W.J.
TITLE: Studies on the composition and structure of plasma lipoproteins. Distribution oflipoprotein families in major density classes of normal human plasma lipoproteins. PubMed ID:4337564
VOL:260 PAGE : 689 -707 (1972)

AUTHOR:Shen, M. M., Krauss, R. M., Lindgren, F. T., and Forte, T. M.
TITLE:Heterogeneity of serum low density lipoproteins in normal human subjects PubMed ID:7240955
JOURNAL:J Lipid Res.
VOL:22 PAGE : 236-244 (1981)

AUTHOR:Eisenberg,S. (1991) Plasma Lipoproteins : Structure, Composition, Classification, and Metabolism, in Primary Hyperlipoproteinemias (Steiner,G. and Shafrir,E., eds),pp23-41, McGraw-Hill, U.S.A
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AUTHOR:Eisenberg,S. (1988) Regulation of HDL Subpopulation Distribution, in High Density Lipoproteins and Atherosclerosis II (Miller.N.E., eds), pp149-157, Excerpta Medica, Amsterdam
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AUTHOR:Nichols,A.V., Gong,E.L., Blanche,P.J., and Forte,T.M. (1988) HDL Populations: Origins and Interconversions, in High Density Lipoproteins and Atherosclerosis II (Miller.N.E., eds), pp159-171, Excerpta Medica, Amsterdam
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AUTHOR:Albers, J.J., and Cheung,M.C. (1988) Intravascular Metabolism of HDL Subclasses, in High Density Lipoproteins and Atherosclerosis II (Miller.N.E., eds), pp173-179, Excerpta Medica, Amsterdam
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AUTHOR:Barter,P.J., Hopkins, Rajaram,O.V., and Rye,K.-A. (1988) Plasma Factors Involved in the Formation of Very Small HDL Particles, in High Density Lipoproteins and Atherosclerosis II (Miller.N.E., eds), pp181-188, Excerpta Medica, Amsterdam
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AUTHOR:Blanche, P. J., Gong, E. L., Forte, T. M., and Nichols, A. V.
TITLE:Characterization of human high-density lipoproteins by gradient gel electrophoresis PubMed ID:7295744
JOURNAL:Biochim Biophys Acta.
VOL:665 PAGE : 408-419 (1981)

AUTHOR:Kane,J.P. (1992) High-density Lipoproteins, in Plasma Lipoproteins and Coronary Artery Disease (Kreisberg,R.A. and Segrest,J.P., eds), pp125-150, Blackwell Scientific Publications, Boston
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AUTHOR:Assmann,G. (1982) Biochemistry of Lipoproteins, in Lipid Metabolism and Atherosclerosis (Assmann,G., eds), pp14-53,Schattauer, Germany
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AUTHOR:Assmann,G. (1982) High -Density Lipoproteins and Atherogenesis, in Lipid Metabolism and Atherosclerosis (Assmann,G., eds), pp81-100,Schattauer, Germany
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AUTHOR:Miller, G. J., and Miller, N. E.
TITLE:Plasma-high-density-lipoprotein concentration and development of ischaemic heart-disease PubMed ID:46338
VOL:1 PAGE : 16-19 (1975)

AUTHOR:Gordon, T., Castelli, W. P., Hjortland, M. C., Kannel, W. B., and Dawber, T. R.
TITLE:High density lipoprotein as a protective factor against coronary heart disease. The Framingham Study PubMed ID:193398
VOL:62 PAGE : 707-714 (1977)

AUTHOR:Miller, N. E., Thelle, D. S., Forde, O. H., and Mjos, O. D.
TITLE:The Tromso heart-study. High-density lipoprotein and coronary heart-disease: a prospective case-control study PubMed ID:67464
VOL:1 PAGE : 965-968 (1977)

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