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Lipoprotein Lp(a) in homozygous familial hypercholesterolemia: density profile, particle heterogeneity and apolipoprotein(a) phenotype

  • Heng-Chang Guo
    Affiliations
    Lipoprotein and Atherogenesis Research Unit, INSERM U.321, Pavilion Benjamin Delessert, Hopital de la Pitié, 75651 Paris Cedex 13 France
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  • John Chapman
    Correspondence
    Correspondence to: M.J. Chapman, Lipoprotein and Atherogenesis Research Unit, INSERM U.321, Pavilion Benjamin Delessert, Hôpital de la Pitié, 75651 Paris Cedex 13, France.
    Affiliations
    Lipoprotein and Atherogenesis Research Unit, INSERM U.321, Pavilion Benjamin Delessert, Hopital de la Pitié, 75651 Paris Cedex 13 France
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  • Eric Bruckert
    Affiliations
    Lipoprotein and Atherogenesis Research Unit, INSERM U.321, Pavilion Benjamin Delessert, Hopital de la Pitié, 75651 Paris Cedex 13 France

    Service of Endocrinology and Metabolism, Hopital de la Pitié, 75651 Paris Cedex 13 France
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  • Jean-Pierre Farriaux
    Affiliations
    Pediatric Service, Hôpital Cl. Huriez, Place de Verdun, 59037 Lille Cedex France
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  • Jean-Luc De Gennes
    Affiliations
    Service of Endocrinology and Metabolism, Hopital de la Pitié, 75651 Paris Cedex 13 France
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      Abstract

      Homozygous familial hypercholesterolemia (FH) is a genetic disorder featuring a functional defect in cellular LDL receptors, marked elevation in circulating LDL concentrations, and premature atherosclerosis. The potential atherogenic role of apo B-containing lipoproteins other than LDL in this disease is indeterminate. We describe the quantitative and qualitative characteristics of Lp(a) as a function of apo(a) phenotype in a group of eight, unrelated homozygous FH patients. Plasma Lp(a) levels were significantly elevated (2.5-fold; mean 50 ± 32 mg/dl) as compared to those in healthy subjects. The S2 isoform of apo(a) occurred most frequently (6 of eight patients); the rare B isoform presented in three patients. Plasma Lp(a) levels in homozygous FH did not correspond to those predicted by apo(a) phenotype. Analyses of the density distribution of Lp(a) and of Lp(a) particle size and heterogeneity as a function of density did not reveal any anomalies characteristic of homozygous FH. However, comparison of the hydrated density of Lp(a) particles as a function of apo(a) isoform content revealed a clear influence of isoform on this parameter; thus, in a B/S2 heterozygous patient, the density distribution of Lp(a) fractions containing isoform B alone, B and S2, and S2 alone, demonstrated that the apparent molecular weight of apo(a) plays a determining role in controlling the hydrated density and size of the resulting Lp(a) particle. Indeed, patients expressing the high molecular weight, S2 isoform uniformly displayed a dense form of Lp(a) (hydrated density ≈ 1.055 g/ml). In subjects presenting two apo(a) isoforms, each isoform resided on distinct lipoprotein particles; in such cases, the plasma levels of the denser isoform predominated, suggesting differences in rates of formation, or rates of tissular catabolism, or in the plasma stability of the particles, or a combination of these mechanisms. Considered together, our data may be interpreted to suggest that the elevated circulating levels of Lp(a) in homozygous FH patients may reflect either an increased biosynthesis, or diminished catabolism via the cellular LDL receptor pathway, or a combination of both.

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      References

        • Goldstein J.L.
        • Brown M.S.
        Familial hypercholesterolemia.
        in: Stanbury J.B. Wyngaarden J.B. Fredrickson D.S. Goldstein J.L. Brown M.S. The Metabolic Basis of Inherited Disease. 5th Edition. McGraw-Hill, New York1983: 672
        • Brown M.S.
        • Goldstein J.L.
        A receptor-mediated pathway for cholesterol homeostasis.
        Science. 1986; 232: 1230
        • Slater H.R.
        • McKinney L.
        • Packard C.J.
        • Shepherd J.
        Contribution of the receptor pathway to low density lipoprotein catabolism in humans. New methods for quantitation.
        Arteriosclerosis. 1984; 4: 604
        • Brown M.S.
        • Kovanen P.T.
        • Goldstein J.L.
        Regulation of plasma cholesterol by lipoprotein receptors.
        Science. 1981; 212: 628
        • Goldstein J.L.
        • Brown M.S.
        Progress in understanding the LDL receptor and HMGCoA reductase, two membrane proteins that regulate the plasma cholesterol.
        J. Lipid Res. 1984; 25: 1450
        • Slack J.
        • Mills G.L.
        Anomalous low-density lipoproteins in familial hyperbetalipoproteinemia.
        Clin. Chim. Acta. 1970; 29: 15
        • Mills G.L.
        • Taylaur C.E.
        • Chapman M.J.
        Low-density lipoproteins in patients homozygous for familial hyperbetalipoproteinemia.
        Clin. Sci. Mol. Med. 1976; 51: 221
        • Luc G.
        • Chapman M.J.
        • de Gennes J.L.
        • Turpin G.
        A study of the structural heterogeneity of low-density lipoproteins in two patients homozygous for familial hypercholesterolemia, one of phenotype E2/2.
        Eur. J. Clin. Invest. 1986; 16: 329
        • Armstrong V.W.
        • Cremer P.
        • Eberle E.
        • Manke A.
        • Schulze F.
        • Wieland H.
        • Krenzer H.
        • Seidel D.
        The association between serum Lp(a) concentrations and angiographically assessed coronary atherosclerosis: dependence on serum LDL levels.
        Atherosclerosis. 1986; 62: 249
        • Ehnholm C.
        • Garoff H.
        • Renkonen K.
        • Simons K.
        Protein and carbohydrate composition of Lp(a) lipoprotein from human plasma.
        Biochemistry. 1972; 11: 3229
        • Gaubatz J.W.
        • Heideman C.
        • Gotto Jr., A.M.
        • Morrisett J.D.
        • Dahlen G.H.
        Human plasma lipoprotein (a): structural properties.
        J. Biol. Chem. 1983; 258: 4582
        • Utermann G.
        • Weber W.
        Protein composition of Lp(a) lipoprotein from human plasma.
        FEBS Lett. 1983; 154: 357
        • Fless G.M.
        • Rolih C.A.
        • Scanu A.M.
        Heterogeneity of human plasma lipoprotein (a): isolation and characterisation of the lipoprotein subspecies and their apoproteins.
        J. Biol. Chem. 1984; 259: 11470
        • Utermann G.
        • Menzel H.J.
        • Kraft H.G.
        • Duba H.C.
        • Kemmler H.G.
        • Seitz C.
        Lp(a) glycoprotein phenotypes. Inheritance and relation to Lp(a)-Lipoprotein concentrations in plasma.
        J. Clin. Invest. 1987; 80: 458
        • Kraft H.G.
        • Dieplinger H.
        • Hoye E.
        • Utermann G.
        Lp(a) phenotyping by immunoblotting with polyclonal and monoclonal antibodies.
        Arteriosclerosis. 1988; 8: 212
        • Guo H.C.
        • Armstrong V.W.
        • Luc G.
        • Billardon C.
        • Goulinet S.
        • Nustede R.
        • Seidel D.
        • Chapman M.J.
        Characterisation of five mouse monoclonal antibodies to apolipoprotein (a) from human Lp(a): evidence for weak plasminogen reactivity.
        J. Lipid Res. 1989; 30: 23
        • Drayna D.T.
        • Hegele R.A.
        • Hass P.E.
        • Emi M.
        • Wu L.L.
        • Eaton D.L.
        • Lawn R.M.
        • Williams R.R.
        • While R.L.
        • Lalouel J.M.
        Genetic linkage between lipoprotein (a) phenotype and a DNA polymorphism in the plasminogen gene.
        Genomics. 1988; 3: 230
        • Krempler F.
        • Kostner G.M.
        • Bolzano K.
        • Sandhofer F.
        Turnover of lipoprotein (a) in man.
        J. Clin. Invest. 1980; 65: 1483
        • Mann A.W.
        • Kraft H.G.
        • Rader D.J.
        • Schaefer J.R.
        • Zech L.A.
        • Gregg R.E.
        • Hoeg J.M.
        • Brewer H.B.
        Human in vivo catabolism of Lp(a).
        Arteriosclerosis. 1989; 9: 702a
        • Armstrong W.
        • Walli A.K.
        • Seidel D.
        Isolation, characterisation and uptake in human fibroblasts of an apo(a)free lipoprotein obtained on reduction of lipoprotein (a).
        J. Lipid. Res. 1985; 26: 1314
        • Utermann G.
        • Hoppichler F.
        • Dieplinger H.
        • Seed M.
        • Thompson G.
        • Boerwinkle E.
        Defects in the low density lipoprotein receptor gene affect lipoprotein(a) levels: multiplicative interaction of two gene loci associated with premature atherosclerosis.
        in: Proc. Natl. Acad. Sci. USA. 86. 1989: 4171
        • Abell L.L.
        • Levy B.B.
        • Brodie B.B.
        • Kendall F.E.
        A simplified method for the estimation of cholesterol in serum and demonstration of its specificity.
        J. Biol. Chem. 1952; 195: 357
        • Kessler G.
        • Lederer H.
        Fluorometric measurement of triglycerides.
        in: Skeggs Jr., L.T. Automation in Analytical Chemistry, Technicon Symposia. Mediad Inc, New York1965: 341
        • Allain C.C.
        • Poon L.S.
        • Chan C.S.G.
        • Richmond W.
        • Fu P.C.
        Enzymatic determination of total serum cholesterol.
        Clin. Chem. 1974; 20: 470
        • Lopes-Virella M.F.L.
        • Stone P.
        • Ellis S.
        • Colwell J.A.
        Cholesterol determination in high density lipoprotein separated by three different methods.
        Clin. Chem. 1977; 23: 882
        • Friedewald W.T.
        • Levy R.I.
        • Fredrickson D.S.
        Estimation of the concentration of low-density lipoproteincholesterol in plasma without the use of the preparative ultracentrifuge.
        Clin. Chem. 1972; 18: 499
        • Wider G.
        • Kulnigg E.
        • Molinari E.
        • Hotschek H.
        • Bayer P.M.
        Evaluation of a monitor guided nephelometric system.
        J. Clin. Chem. Clin. Biochem. 1982; 20: 1
        • Duhamel G.
        • Nalpas B.
        • Goldstein S.
        • Laplaud P.M.
        • Berthelot P.
        • Chapman M.J.
        Plasma lipoprotein and apolipoprotein profile in alcoholic patients and without liver disease: on the relative roles of alcohol and liver injury.
        Hepatology. 1984; 4: 577
        • Hu D.Y.
        • Innerarity T.L.
        • Mahley R.W.
        Defective hepatic lipoprotein receptor binding of β-very-low density lipoproteins from type III hyperlipoproteinemic patients.
        J. Biol. Chem. 1984; 259: 860
        • Chapman M.J.
        • Goldstein S.
        • Lagrange D.
        • Laplaud P.M.
        A density gradient ultracentrifugal procedure for the isolation of the major lipoprotein classes from human serum.
        J. Lipid Res. 1981; 22: 339
        • Nichols A.V.
        • Krauss R.M.
        • Musliner T.A.
        Nondenaturing polyacrylamide gradient gel electrophoresis.
        Methods Enzymol. 1986; 128A: 417
        • Chapman M.J.
        • Laplaud P.M.
        • Luc G.
        • Forgez P.
        • Bruckert E.
        • Goulinet S.
        • Lagrange D.
        Further resolution of the low density lipoprotein spectrum in normal human plasma: physicochemical characteristics of discrete subspecies separated by density gradient ultracentrifugation.
        J. Lipid. Res. 1988; 29: 442
        • Hawkes R.
        • Niday E.
        • Gordon J.
        A dot immunobinding assay for monoclonal and other antibodies.
        Anal. Biochem. 1982; 119: 142
        • Anderson D.W.
        • Nichols A.V.
        • Forte T.M.
        • Lindgren F.T.
        Particle distribution of human serum high density lipoproteins.
        Biochim. Biophys. Acta. 1977; 493: 55
        • Gabelli C.
        • Stark D.G.
        • Gregg R.E.
        • Brewer Jr., H.B.
        Separation of apolipoprotein B species by agarose-acrylamide gel electrophoresis.
        J. Lipid Res. 1986; 27: 457
        • Burnette W.N.
        “Western blotting”. Electrophoretic transfer of protein from SDS polyacrylamide gel to unmodified nitrocellulose and radiographic detection with antibody and radioiodinated protein A.
        Anal. Biochem. 1981; 112: 195
        • Koch C.
        • Skjodt K.
        • Laursen I.
        A simple immunoblotting method after separation of proteins in agarose gel.
        J. Immunol. Methods. 1985; 84: 271
        • Gaubatz J.W.
        • Ghanem K.I.
        • Guevara J.
        • Nava M.L.
        • Patsch W.
        • Morrisett J.D.
        Polymorphic forms of human apolipoprotein(a): inheritance and relationship of their molecular weights to plasma levels of lipoprotein(a).
        J. Lipid Res. 1990; 31: 603
        • Gibson J.C.
        • Goldberg R.B.
        • Rubinstein A.
        • Ginsberg H.N.
        • Brown W.V.
        • Baker S.
        • Joffe B.I.
        • Seftel H.C.
        Plasma lipoprotein distribution of apolipoprotein E in familial hypercholesterolemia.
        Arteriosclerosis. 1987; 7: 401
        • Carlson L.A.
        • Hamsten A.
        • Asplund A.
        Pronounced lowering of serum levels of lipoprotein Lp(a) in hyperlipidaemic subjects treated with nicotinic acid.
        J. Int. Med. 1989; 226: 271
        • Vessby B.
        • Kostner G.
        • Lithell H.
        • Thomis J.
        Diverging effects of cholestyramine on apolipoprotein B and lipoprotein Lp(a).
        Atherosclerosis. 1982; 44: 61
        • Stein E.
        • Kumbla L.
        • Fearn J.
        • Hirth J.
        Comparison of lovastatin and resin effects on plasma apolipoproteins E and Lp(a), tocopherol, retinol and carotenoids.
        in: 8th International Symposium on Atherosclerosis. CIC Edizione Internazionale, 1988: 893 (Abstract)
        • Kostner G.
        • Klein G.
        • Krempler F.
        Can serum Lp(a) concentration be lowered by drugs and/or diet.
        in: Carlson L.A. Olsson A.G. Treatment of Hyperlipoproteinemia. Raven Press, New York1984: 151
        • Utermann G.
        The mysteries of lipoprotein(a).
        Science. 1989; 246: 904
        • Rainwater D.L.
        • Manis G.S.
        • VandeBerg J.L.
        Hereditary and dietary effects on apolipoprotein(a) isoforms and Lp(a) in baboons.
        J. Lipid Res. 1989; 30: 549