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• W2105498514 abstract "ApoC-III and apoE are important determinants of intravascular lipolysis and clearance of triglyceride-rich chylomicrons and VLDL from the blood plasma. Interactions of these two apolipoproteins were studied by adding purified human apoC-III to human plasma at levels observed in hypertriglyceridemic subjects and incubating under specific conditions (2 h, 37°C). As plasma concentrations of apoC-III protein were increased, the contents in both VLDL and HDL were also increased. Addition of apoC-III at concentrations up to four times the intrinsic concentration resulted in the decreasing incremental binding of apoC-III to VLDL while HDL bound increasing amounts without evidence of saturation. No changes were found in lipid content or in particle size of any lipoprotein in these experiments. However, distribution of the intrinsic apoE in different lipoprotein particles changed markedly with displacement of apoE from VLDL to HDL. The fraction of VLDL apoE that was displaced from VLDL to HDL at these high apoC-III concentrations varied among individuals from 20% to 100% its intrinsic level. The proportion of VLDL apoE that was tightly bound (0% to 80%) was found to be reproducible and to correlate with several indices of VLDL particle size. In the group of subjects studied, strongly adherent apoE was essentially absent from VLDL particles having an average content of less than 50,000 molecules of triglyceride. Addition of apoC-III to plasma almost completely displaces apoE from small VLDL particles. Larger VLDL contain tightly bound apoE which are not displaced by increasing concentration of apoC-III.—Breyer, E. D., N-A. Le, X. Li, D. Martinson, and W. V. Brown. Apolipoprotein C-III displacement of apolipoprotein E from VLDL: effect of particle size. J. Lipid Res. 1999. 40: 1875–1882. ApoC-III and apoE are important determinants of intravascular lipolysis and clearance of triglyceride-rich chylomicrons and VLDL from the blood plasma. Interactions of these two apolipoproteins were studied by adding purified human apoC-III to human plasma at levels observed in hypertriglyceridemic subjects and incubating under specific conditions (2 h, 37°C). As plasma concentrations of apoC-III protein were increased, the contents in both VLDL and HDL were also increased. Addition of apoC-III at concentrations up to four times the intrinsic concentration resulted in the decreasing incremental binding of apoC-III to VLDL while HDL bound increasing amounts without evidence of saturation. No changes were found in lipid content or in particle size of any lipoprotein in these experiments. However, distribution of the intrinsic apoE in different lipoprotein particles changed markedly with displacement of apoE from VLDL to HDL. The fraction of VLDL apoE that was displaced from VLDL to HDL at these high apoC-III concentrations varied among individuals from 20% to 100% its intrinsic level. The proportion of VLDL apoE that was tightly bound (0% to 80%) was found to be reproducible and to correlate with several indices of VLDL particle size. In the group of subjects studied, strongly adherent apoE was essentially absent from VLDL particles having an average content of less than 50,000 molecules of triglyceride. Addition of apoC-III to plasma almost completely displaces apoE from small VLDL particles. Larger VLDL contain tightly bound apoE which are not displaced by increasing concentration of apoC-III.—Breyer, E. D., N-A. Le, X. Li, D. Martinson, and W. V. Brown. Apolipoprotein C-III displacement of apolipoprotein E from VLDL: effect of particle size. J. Lipid Res. 1999. 40: 1875–1882. Apolipoprotein C-III (apoC-III) and apolipoprotein E (apoE) are found in human plasma as components of chylomicrons, very low density lipoproteins (VLDL), and high density lipoproteins (HDL). Both belong to a group of apolipoproteins which are bound to the surface of these lipoproteins but also participate in a dynamic exchange among various lipoproteins during their transport in the blood stream. The interaction of these two proteins has been the subject of recent interest because of their effect on the clearance of triglyceride-rich lipoproteins (TG-rich Lp) has been demonstrated to be counter balancing and complex, with implications for various manifestations of hypertriglyceridemia. ApoC-III provides a strong negative charge on the surface of lipoproteins preventing nonspecific interactions with cell surfaces (1Shelburne F. Hanks J. Meyers W. Quarfordt S. Effect of apoproteins on hepatic uptake of triglyceride emulsion in the rat.J. Clin. Invest. 1980; 65: 652-658Google Scholar) and perhaps with other lipoproteins. This may serve the function of reducing futile cycles in triglyceride transport by preserving the particles for high affinity interactions such as with lipoprotein lipase or specific cell surface receptors e.g., such as those binding to apoE or apoB. Plasma concentrations of apoC-III in human populations correlate well with triglyceride levels (2Schonfeld G. George P.K. Miller J. Reilly P. Witztum J. Apolipoprotein CII and CIII levels in hyperlipoproteinemia.Metabolism: clinical and experimental. 1979; 28: 1001-1010Google Scholar, 3Brezlow J.L. Sasaki J. Zeng A. Dammerman M. Takada Y. Matsunaga N. An apolipoprotein CIII marker associated with hypertriglyceridemia Caucasian also confers increased risk in a West Japanese population.Hum. Genet. 1995; 95: 371-375Google Scholar). The genetically determined deficiency of apoC-III in humans has been shown to increase the rate of triglyceride clearance from plasma by 6- to 7-fold (4Ginsberg H.N. Le N.A. Goldberg I.J. Gibson J.C. Rubinstein A. Wang-Iverson P. Norum R. Brown W.V. Apolipoprotein B metabolism in subjects with deficiency of apolipoprotein CIII and A.J. Clin. Invest. 1986; 78: 1287-1295Google Scholar). A similar enhancement of triglyceride clearance was observed in mice made apoC-III deficient by gene knockout experiments (5Maeda N. Li H. Lee D. Osada J. Oliver P. Quardfordt S.H. Targeted disruption of the apolipoprotein CIII gene in mice results in hypotriglyceridemia and protection from postprandial hypertriglyceridemia.J. Biol. Chem. 1994; 269: 23610-23616Google Scholar). Overexpression of apoC-III produces hypertriglyceridemia in transgenic mouse models via inhibition of clearance of TG-rich particles (6Aalto-Setala K. Fisher E.A. Chen X. Chajek-Shaul T. Hayek T. Zechner R. Walsh A. Ramakrishnan R. Ginsberg H.N. Breslow J.L. Mechanism of hypertriglyceridemia in human apolipoprotein CIII transgenic mice.J. Clin. Invest. 1992; 90: 1889-1900Google Scholar). It is now clear that normal physiological systems responsible for triglyceride transport are partially determined by the plasma content of apoC-III. Although it is not clear how this protein contributes to the familial hypertriglyceridemic syndromes, recent studies have found that two classes of drugs that are effective in lowering plasma triglycerides in these patients, act through suppression of apoC-III gene transcription in rodents (7Bar-Tana J. Frenkel B. Bishara-Shieban J. The effect of β, β′-tetramethylhexadecanedioic acid (MEDICA 16) on plasma very low density lipoprotein metabolism in rats: role of apolipoprotein CIII.Biochem. J. 1994; 298: 409-414Google Scholar, 8Bar-Tana J. Rose-Kahn G. Frenkel B. Shafer Z. Fainaru M. Hypolipidemic effect of β, β-methyl-substituted hexadecanedioic acid (MEDICA 16) in normal and nephrotic rats.J. Lipid Res. 1988; 29: 431-441Google Scholar). In contrast to apoC-III, apoE facilitates the removal of plasma lipoproteins. The initial phase of triglyceride clearance in peripheral tissues is dependent on the endothelial-bound lipoprotein lipase. The products of this enzyme action are chylomicron and VLDL remnants. Virtually all of the chylomicron remnants and a large fraction of the VLDL remnants are taken up by the liver and degraded. This uptake of remnants is a high affinity process that is greatly facilitated by apoE (1Shelburne F. Hanks J. Meyers W. Quarfordt S. Effect of apoproteins on hepatic uptake of triglyceride emulsion in the rat.J. Clin. Invest. 1980; 65: 652-658Google Scholar, 9Weisgraber K.H. Innerarity T.L. Rall S.C. Mahley R.W. Apolipoprotein E: receptor binding properties.Adv. Exp. Med. Biol. 1985; 183: 159-171Google Scholar, 10Innerarity T.L. Arnold K.S. Weisgraber K.H. Mahley R.W. Apolipoprotein E is the determinant that mediates the receptor uptake of β-very low density lipoproteins by mouse macrophages.Arteriosclerosis. 1986; 6: 114-122Google Scholar, 11Wang-Iverson P. Ginsberg H.N. Peteanu L.A. Le N.A. Brown W.V. ApoE-mediated uptake and degradation of normal very low density lipoproteins by human monocyte macrophages: a saturable pathway distinct from the LDL receptor.Biochem. Biophys. Res. Commun. 1985; 126: 578-586Google Scholar). ApoE may also have important enhancing effects on the action of lipoprotein and hepatic triglyceride lipases (12Ehnholm C. Mahley R.W. Chapel D.A. Weisgraber K.H. Ludwig E. Witzum J.L. Role of apolipoprotein E in the lipolytic conversion of β-very low density lipoprotein to low density lipoproteins in type III hyperlipoproteinemia.Proc. Natl. Acad. Sci. USA. 1984; 81: 5566-5570Google Scholar, 13Evans A. Wolfe B. Strong W. Huff M. Reduced lipolysis of large apoE-poor–VLDL subfractions from type IV hypertriglyceridemic subjects in vitro and in vivo.Metabolism. 1993; 42: 105-115Google Scholar, 14Landis B. Rotolo F.S. Meyers W.C. Clark A.B. Quarfordt S.H. Influence of apolipoprotein E on soluble and heparin-immobilized hepatic lipase.Am. J. Physiol. 1987; 252: G805-G810Google Scholar, 15Thuren T. Sisson P. Waite M. Activation of hepatic lipase catalyzed phosphotidylcholine hydrolysis by apolipoprotein E.Biochim. Biophys. Acta. 1991; 1083: 217-220Google Scholar, 16Goldberg I.J. Le N.A. Paterniti J.R. Ginsberg H.N. Lindgren F.T. Brown W.V. Lipoprotein metabolism during acute inhibition of hepatic triglyceride lipase in the cynomolgus monkey.J. Clin. Invest. 1982; 70: 1184-1192Google Scholar), the enzymes important in the conversion of VLDL remnants into LDL. When apoE is deficient or defective, remnants accumulate and this can lead to dysbetalipoproteinemia (17Alaupovic P. McConathy W.J. Fesmire J. Tavella M. Bard J.M. Profiles of apolipoproteins and apolipoprotein B-containing lipoprotein particles in dysbetalipoproteinemia.Clin. Chem. 1988; 34: B13-B27Google Scholar). However, when apoE is made completely deficient in gene knockout experiments, hypercholesterolemia is the result with only modest increases in plasma triglycerides (18Zhang S.H. Reddick R.L. Piedrahita J.A. Maeda N. Spontaneous hypercholesterolemia and arterial lesions in mice lacking apolipoprotein E.Science. 1992; 258: 468-471Google Scholar). The mechanism by which apoC-III reduces triglyceride clearance has been the subject of debate. There is considerable evidence that this is due in great part to competition with apoE, either interfering with its interaction with cell surface receptors or actual displacement of apoE from the surface of TG-rich lipoproteins. In hepatic perfusion studies clearance of VLDL is markedly reduced when apoC-III is added to the lipoproteins in vitro (1Shelburne F. Hanks J. Meyers W. Quarfordt S. Effect of apoproteins on hepatic uptake of triglyceride emulsion in the rat.J. Clin. Invest. 1980; 65: 652-658Google Scholar, 19Windler E. Havel R.J. Inhibitory effects of C apolipoproteins from rats and humans on the uptake of triglyceriderich lipoproteins and their remnants by the perfused rat liver.J. Lipid Res. 1985; 26: 556-565Google Scholar). When present in excess, apoC-III has been shown to inhibit lipoprotein lipase and hepatic triglyceride lipase (20McConathy W.J. Gesquiere J.C. Bass H. Tartar A. Fruchart J.C. Wang C-S. Inhibition of lipoprotein lipase activity by synthetic peptides of apolipoprotein C-III.J. Lipid Res. 1992; 33: 995-1003Google Scholar, 21Wang C.S. McConathy W.J. Kloer H.V. Alaupovic P. Modulation of lipoprotein lipase activity by apolipoproteins. Effect of apolipoprotein C-III.J. Clin. Invest. 1985; 75: 384-390Google Scholar, 22Kinnunen P. Ehnholm C. Effect of serum and C-apoproteins from very low density lipoproteins on human plasma hepatic lipase.FEBS Lett. 1976; 65: 354-357Google Scholar, 23Brown W.V. Baginsky M.L. Inhibition of lipoprotein lipase by an apoprotein of human very low density lipoprotein.Biochem. Biophys. Res. Commun. 1972; 6: 375-381Google Scholar). Thus, apoE appears to increase hepatic uptake and lipolysis of TG-rich particles, while apoC-III inhibits both processes (13Evans A. Wolfe B. Strong W. Huff M. Reduced lipolysis of large apoE-poor–VLDL subfractions from type IV hypertriglyceridemic subjects in vitro and in vivo.Metabolism. 1993; 42: 105-115Google Scholar, 14Landis B. Rotolo F.S. Meyers W.C. Clark A.B. Quarfordt S.H. Influence of apolipoprotein E on soluble and heparin-immobilized hepatic lipase.Am. J. Physiol. 1987; 252: G805-G810Google Scholar, 24Groot P.H. Van Berkel T.J. Kruijt J.K. Scheek L.M. Effect of apolipoproteins E and CIII on the interaction of chylomicrons with parenchymal and non-parenchymal cells from rat liver.Biochem. J. 1983; 216: 71-80Google Scholar, 25Shimano H. Namba Y. Ohauga J. Kawamura M. Yamamoto K. Shimad M. Gotoda T. Harada K. Yasaki Y. Yamada N. Secretion-recapture process of apolipoprotein E in hepatic uptake of chylomicron remnants in transgenic mice.J. Clin. Invest. 1994; 93: 2215-2223Google Scholar, 26Brown M.S. Weisgraber K.H. Mahley R.W. Goldstein J.L. Kowal R.C. Herz J. Apolipoprotein CI modulates the interaction of apolipoprotein E with β-migrating very low density lipoprotein (β-VLDL) and inhibits binding of β-VLDL to low density lipoprotein receptor-related protein.J. Biol. Chem. 1990; 265: 22453-22459Google Scholar). Both apoC-III and apoE are known to exchange between VLDL and HDL particles (26Brown M.S. Weisgraber K.H. Mahley R.W. Goldstein J.L. Kowal R.C. Herz J. Apolipoprotein CI modulates the interaction of apolipoprotein E with β-migrating very low density lipoprotein (β-VLDL) and inhibits binding of β-VLDL to low density lipoprotein receptor-related protein.J. Biol. Chem. 1990; 265: 22453-22459Google Scholar, 27Shepherd J. Patsch J.R. Packard C.J. Gotto A.M. Taunton O.D. Dynamic properties of human high density lipoprotein apoproteins.J. Lipid Res. 1978; 19: 383-389Google Scholar, 28Rubinstein A. Gibson J.C. Ginsberg H.N. Brown W.V. In vitro metabolism of apolipoprotein E.Biochim. Biophys. Acta. 1986; 879: 355-361Google Scholar, 29Gibson J.C. Brown W.V. Effect of lipoprotein lipase and hepatic triglyceride lipase activity on the distribution of apolipoprotein E among the plasma lipoproteins.Atherosclerosis. 1988; 73: 45-55Google Scholar, 30Eisenberg S. Patsch J.R. Sparrow J.T. Gotto A.M. Olivecrona T. Very low density lipoprotein. Removal of apolipoprotein CII and CIII during lipolysis in vitro.J. Biol. Chem. 1979; 254: 12603-12608Google Scholar, 31Blum C.B. Dynamics of apolipoprotein E metabolism in humans. 1982.J. Lipid Res. 1982; 23: 1308-1316Google Scholar). Blum (31Blum C.B. Dynamics of apolipoprotein E metabolism in humans. 1982.J. Lipid Res. 1982; 23: 1308-1316Google Scholar) has shown that short term perturbations can change the distribution of apoE among the particles. Assessing this phenomenon by in vitro experiments is complicated by the presence of exchangeable (loose binding) and non-exchangeable (tight binding) pools of apoE and apoC-III on human VLDL and HDL (32Tornoci L. Scheraldi C.A. Li X. Ide H. Goldberg I.J. Le N-A. Abnormal activation of lipoprotein lipase by non-equilibrating apoC-II: further evidence for the presence of non-equilibrating pools of apolipoproteins C-II and C-III in plasma lipoproteins.J. Lipid Res. 1993; 34: 1793-1803Google Scholar, 33Bukberg P.R. Le N-A. Ginsberg H.N. Gibson J.C. Rubinstein A. Brown W.V. Evidence for non-equilibrating pools of apolipoprotein C-III in plasma lipoproteins.J. Lipid Res. 1985; 26: 1047-1057Google Scholar). In some individuals, one-half or more of the mass of these apolipoproteins may be tightly bound to the lipoprotein and essentially non-exchangeable. The determinants of the tight and loose binding among different individuals have not been systematically studied. This paper reports a series of experiments that examine the alterations of apoE distribution among the various lipoproteins produced by adding apoC-III to human plasma. One major determinant of the fraction of apoE which is tightly bound to VLDL is shown to be the size of the lipoprotein particle. Isolation of apoC-III from VLDL was performed after lipid extraction using the procedure reported by Jackson and Holdsworth (34Jackson R.L. Holdsworth G. Isolation and properties of human apolipoproteins CI, CII and CIII.Methods Enzymol. 1986; 128: 288-297Google Scholar). The apolipoproteins were solubilized from the final residue in aqueous buffer using 6 m urea and 0.1% sodium decyl sulfate. Stock urea solutions used in the experiment were deionized and stored with a mixed cation–anion exchange resin (Rexyn, Fisher, Atlanta, GA) at 4°C. Apolipoproteins C-I, C-II, and C-III were separated from the other urea-soluble proteins by gel-filtration chromatography on a 2.5 × 100 cm Sephadex G-100 (Sigma, St. Louis, MO) column, eluent 50 mm Tris, pH 8.6, in 6 m urea. The fractions were dialyzed against 10 mm Tris, pH 8.2, in 6 m urea and apoC-I, C-II, C-III-0, C-III-1, C-III-2 were separated on a 2.5 × 30 cm anion-exchange column, DEAE-Sephacel (Whatman, Maidstone, England), using a linear gradient of added NaCl from 0 to 0.125 m NaCl (total volume of 1 liter). The apolipoprotein fractions were dialyzed against 10 mm NH4HCO3, lyophilized, and stored at -80°C. Purity of each fraction was determined using the PhastGel IEF (Pharmacia, Piscataway, NJ) with pH gradient of 4.0 to 6.5. The mass of apolipoproteins C-II and C-III was determined by specific ELISA (see below). Venous blood was collected in 0.01% EDTA from volunteer subjects (fasting >12 h) with plasma triglyceride concentrations ranging from 125 mg/dl to 510 mg/dl. Fresh plasma from each subject was incubated with or without added apoC-III at 37°C for 2 h, then stored in an ice bath for 2–6 h prior to FPLC separation. VLDL, LDL, and HDL particles from 300 μl of incubated plasma were isolated using the Fast Protein Liquid Chromatography system with a 1.5 × 35 cm Superose 6 column and an eluting buffer of 0.05 m phosphate, 0.10 m NaCl, 0.01% EDTA and 0.02% NaN3 (35Innis-Whitehouse W. Li X. Brown W.V. Le N-A. An efficient chromatographic system for lipoprotein fractionation using whole plasma.J. Lipid Res. 1998; 39: 679-690Google Scholar). Lipoprotein profiles for each subject were obtained in 22 0.6-ml fractions (see Fig. 1). Fractions 4–8, 9–16, and 17–22 were pooled to give the VLDL, IDL plus LDL, and HDL, respectively. Lipid and apolipoprotein analyses were performed on these pooled fractions and on the original plasma. Lipid assays demonstrated more than 90% recovery after FPLC. Experiments with total recovery of apolipoproteins below 80% were excluded and repeated. Lipid and apolipoprotein values were normalized for recovery and intra-assay error.Fig. 1.Distribution of cholesterol (A), triglyceride (B), and apolipoprotein B (C) between very low density lipoproteins (VLDL), intermediate size lipoproteins (ISL), and high density lipoproteins (HDL) in plasma from subject S1 separated by fast protein liquid chromatography. A volume of 300 μl of incubated plasma (incubation condition: 37°C for 2 h) was injected from a total incubation volume of 1 ml. Replicate samples were incubated with no added apoC-III (–•–), a sufficient quantity of apoC-III to give 2× (–▪–), and 4× intrinsic plasma levels (- - -▴- - -).View Large Image Figure ViewerDownload (PPT)Fig. 1.Distribution of cholesterol (A), triglyceride (B), and apolipoprotein B (C) between very low density lipoproteins (VLDL), intermediate size lipoproteins (ISL), and high density lipoproteins (HDL) in plasma from subject S1 separated by fast protein liquid chromatography. A volume of 300 μl of incubated plasma (incubation condition: 37°C for 2 h) was injected from a total incubation volume of 1 ml. Replicate samples were incubated with no added apoC-III (–•–), a sufficient quantity of apoC-III to give 2× (–▪–), and 4× intrinsic plasma levels (- - -▴- - -).View Large Image Figure ViewerDownload (PPT) All lipid analyses were performed using the Beckman CX5 chemistry analyzer instrument from Beckman (Fullerton, CA). Cholesterol and triglyceride values were determined using Beckman reagents while phospholipids were analyzed using the Wako (Richmond, VA) Phospholipid B reagent. All apolipoproteins A-I, B, C-II, C-III, and E were analyzed using ELISA as developed in our laboratory. Apolipoproteins B, A-I, and E were quantitated by a double antibody sandwich ELISA technique using purified specific IgG prepared from immunized goats by immunoaffinity chromatography in this laboratory. Both apolipoprotein C-II and C-III mass values were determined by competitive ELISA technique using human VLDL coated plates, goat anti-human IgG, specific for either apolipoprotein C-II or C-III, for first antibody and rabbit anti-goat IgG alkaline phosphatase conjugate as a second antibody. Pooled normal human plasma was used for standards and calibrators. The analyses of incubations performed with plasma from a single subject were done in one assay. All samples were performed in triplicate with a coefficient of variation below 10%. Genomic DNA from potassium EDTA anti-coagulated whole blood was isolated using the procedure outlined by Miller, Dykes, and Polesky (36Miller S.A. Dykes D.D. Polesky H.F. A simple salting-out procedure for extracting DNA from human nucleated cells.Nucleic Acids Res. 1988; 16: 1215Google Scholar). ApoE genotypes were determined using the method described by Bolla et al. (37Bolla M.J. Haddad L. Humphries S.E. Winder A.F. Day I.N.M. High-throughput method for determination of apolipoprotein E genotypes with use of restriction digestion analysis by microplate array diagonal gel electrophoresis.Clin. Chem. 1995; 41: 1599-1604Google Scholar). Curve-fitting and analysis of the ELISA-derived data were performed using the Immunofit program from Beckman (Fullerton, CA). Statistical calculations, including nonlinear regression analysis, were performed with Statistica from STATSOFT (Tulsa, OK) programs and graphic presentations were developed with software from Quattro Pro (Corel, Orem, UT). Fast protein liquid chromatographic separation of the lipoproteins was performed with plasma samples from different individuals after incubations with varying amounts of added apoC-III. Lipid values (i.e., cholesterol and triglyceride) analyzed on each fraction documented the integrity of the particle size during the incubation and separation procedure (Fig. 1A and B). Plasma incubated with up to 4 times the intrinsic apoC-III level did not show a measurable effect on the size or lipid content of the different lipoprotein particles. The reproducibility of the elution pattern of apolipoproteins such as apoB in VLDL (Fig. 1C) and ISL/LDL fractions (Fig. 2) and of apoA-I in HDL fractions (data not shown) further support this observation. Recovery after FPLC for specific apolipoproteins was greater than 80% while that for lipids was consistently greater than 90%.Fig. 2.In subject S6, increasing the concentration of plasma apoC-III by 2.5 times the baseline plasma concentration results in a 4.5-fold decrease in VLDL E per apoB particle and a corresponding increase in HDL E per A-I particle. This graphic display of the bound apoE per particle of VLDL (VLDL E/VLDL B) suggests that above molar ratio of 28 to 30 of apoC-III per particle (VLDL CIII/VLDL B) no further apoE is displaced (plasma apoB = 83.9 mg/dl, VLDL B = 0.375 × 10-2 mm).View Large Image Figure ViewerDownload (PPT) Figure 3 shows the loss of apoE from VLDL and ISL particles and its accumulation in the fractions with HDL, as the amount of exogenous apoC-III is increased in the plasma sample. Note that in subject S6, approximately 20% of the apoE in VLDL remains bound to this lipoprotein even with amounts of added apoC-III which were at or near saturation of the binding capacity as indicated by the unbound peaks in Figs. 3A and C. This residual apoE bound to VLDL is referred to as non-displaceable E. Replicate analyses on subject S6 using plasma drawn on a later date confirmed the 80% displacement of apoE upon addition of 4× the baseline value of apoC-III (Fig. 3). The initial addition of apoC-III resulted in binding primarily to VLDL but this reached an apparent maximum with further addition. The content of apoC-III in HDL continued to increase over the entire range tested in these experiments regardless of the basal apoC-III content of HDL (Figs 3A, 3C, and 2B). The plot of the VLDL bound apoE per VLDL particle (VLDL E/VLDL B) suggests that above the molar ratio of 28 to 30 of apoC-III per particle (VLDL apoC-III/VLDL B) no further apoE is displaced. Repeat experiments done with subject S1 were also consistent in demonstrating almost complete displacement of VLDL apoE to HDL at saturating levels of apoC-III (Figs. Fig. 2., Fig. 3.) indicating that these results are characteristic of the individual's lipoproteins.Fig. 3.Displacement of apoE from VLDL to HDL with increasing plasma concentrations of apoC-III. Replicate samples were incubated with no added apoC-III (–•–), a sufficient quantity of apoC-III to give 2× (–▪–), and 4× intrinsic levels (- - -▴- - -). FPLC profile of apoE in the subject S6 has a β0 = 1.23 and β1 = 67.29, while S1 has a β0 = 0.0 and β1 = 13.14 (equation 1). Addition of saturating concentration of apoC-III (A) for subject S6 resulted in 80% transfer of apoE (B) to VLDL. A 4-fold increase in apoC-III (C) plasma concentration for subject S1 results in 99% transfer of apoE (D) from VLDL to HDL.View Large Image Figure ViewerDownload (PPT)Fig. 3.Displacement of apoE from VLDL to HDL with increasing plasma concentrations of apoC-III. Replicate samples were incubated with no added apoC-III (–•–), a sufficient quantity of apoC-III to give 2× (–▪–), and 4× intrinsic levels (- - -▴- - -). FPLC profile of apoE in the subject S6 has a β0 = 1.23 and β1 = 67.29, while S1 has a β0 = 0.0 and β1 = 13.14 (equation 1). Addition of saturating concentration of apoC-III (A) for subject S6 resulted in 80% transfer of apoE (B) to VLDL. A 4-fold increase in apoC-III (C) plasma concentration for subject S1 results in 99% transfer of apoE (D) from VLDL to HDL.View Large Image Figure ViewerDownload (PPT)Fig. 3.Displacement of apoE from VLDL to HDL with increasing plasma concentrations of apoC-III. Replicate samples were incubated with no added apoC-III (–•–), a sufficient quantity of apoC-III to give 2× (–▪–), and 4× intrinsic levels (- - -▴- - -). FPLC profile of apoE in the subject S6 has a β0 = 1.23 and β1 = 67.29, while S1 has a β0 = 0.0 and β1 = 13.14 (equation 1). Addition of saturating concentration of apoC-III (A) for subject S6 resulted in 80% transfer of apoE (B) to VLDL. A 4-fold increase in apoC-III (C) plasma concentration for subject S1 results in 99% transfer of apoE (D) from VLDL to HDL.View Large Image Figure ViewerDownload (PPT) Plasma samples from 10 individuals were studied (Table 1) with triglyceride concentrations ranging from 125 to 510 mg/dl (1.41 to 5.77 mmol/l) and cholesterol concentrations from 157 to 332 mg/dl (4.07 mmol/l to 8.60 mmol/l). With the addition of apoC-III over the range discussed above, all samples showed at least partial displacement of apoE from VLDL and ISL to HDL. However, the characteristics of the displacement curves varied widely among individuals studied. Examples of these curves are given in Fig. 4. The estimated non-displaceable apoE fraction gave values ranging from 0% to 78% in the ten subjects (Table 2).TABLE 1.Baseline lipid and apolipoprotein levels of ten selected subjects for the study of apoE displacement by apoC-IIISubjectSexTRIGCHOLApoC-IIIApoC-IIApoEApoBApoA-Img/dlS1M38315713.322.905.80107.790.0S2F1251979.731.801.1073.1145.1S3M43717218.086.704.3072.298.5S4M17418011.792.801.0071.7137.0S5F22032916.925.001.70161.2120.9S6M26120021.104.401.8083.990.0S7M33325428.804.301.30110.2124.4S8M51033133.835.204.50147.1162.1S9M17426111.374.004.40119.5158.7S10M26124715.734.402.7091.4147.4All subjects have HDL cholesterol within 30–56 mg/dl and LDL cholesterol within 66–250 mg/dl. Open table in a new tab TABLE 2.Relationship between the parameter β0 with the size of the VLDL particles as measured by the triglyceride to VLDL apoB ratioOriginal Particle CompositionaThe assays were performed in triplicate with a coefficient of variation below 10% for apolipoproteins and within the CDC standards for the lipids. (molar ratio)Calculated ParametersdParameters estimated by using the equation [VLDL apoE/B] = β0 + β1e(−β2*[Plasma apoC-III/B]). ApoE Molecules/ParticleSubjectApoE GenotypeVLDL E/BVLDL CIII/B (×10)TRIG/VLDL B (×10+4)Percent of Actual VLDL E DisplacedbPercent apoE displaced at the highest apoC-III added.Percent of Theoretical VLDL E DisplacedcThe percent apoE displaced at infinite amount of apoC-III added.β0eMinimum amount of non-displaceable apoE in the particle.β1β2S1E3/E47.706.002.0296.41000.0013.140.084S2E3/E23.467.183.7378.01000.004.690.04" @default.
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• W2105498514 date "1999-10-01" @default.
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• W2105498514 title "Apolipoprotein C-III displacement of apolipoprotein E from VLDL: effect of particle size" @default.
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