Research Article| Volume 33, ISSUE 5, P755-763, May 1992

In vivo metabolism of a mutant apolipoprotein, apoA-IIowa, associated with hypoalphalipoproteinemia and hereditary systemic amyloidosis.

Open AccessPublished:May 01, 1992DOI:
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      Apolipoprotein (apo) A-I is the major protein constituent of plasma high density lipoproteins (HDL). A kindred has been identified in which a glycine to arginine mutation at residue 26 in apoA-I is associated with hypoalphalipoproteinemia and hereditary systemic amyloidosis. We isolated the mutant protein, termed apoA-IIowa, from the plasma of an affected subject and studied its in vivo metabolism compared to that of normal apoA-I in two heterozygous apoA-IIowa subjects and two normal controls. Normal and mutant apoA-I were radioiodinated with 131I and 125I, respectively, reassociated with autologous plasma lipoproteins, and simultaneously injected into all subjects. Kinetic analysis of the plasma radioactivity curves demonstrated that the mutant apoA-IIowa was rapidly cleared from plasma (mean fractional catabolic rate [FCR] 0.559 day-1) compared with normal apoA-I (mean FCR 0.244 day-1) in all four subjects. The FCR of normal apoA-I was also substantially faster in the heterozygous apoA-IIowa subjects (mean FCR 0.281 days-1) than in the normal controls (mean FCR 0.203 days-1). Despite the rapid removal from plasma of apoA-IIowa, the cumulative urinary excretion of its associated radioactivity after 2 weeks (44%) of the injected dose) was substantially less than that associated with normal apoA-I (78% of injected dose), indicating extravascular sequestration of radiolabeled apoA-IIowa.(ABSTRACT TRUNCATED AT 250 WORDS)


        • Fielding C.J.
        • Shore V.G.
        • Fielding P.E.
        A protein cofactor of lecithinxholesterol acyltransferase.
        Biochem. Biophys. Res. Commun. 1972; 46: 1493-1498
        • Barbaras R.
        • Puchois P.
        • Fruchart J.C.
        • Ailhaud G.
        Cholesterol efflux from cultured adipose cells is mediated by LpAI particles but not by LpAI:AII particles.
        Biochem. Biophys. Res. Commun. 1987; 142: 63-69
        • Graham D.L.
        • Oram J.F.
        Identification and characterization of a high density lipoprotein-binding protein in cell membranes by ligand blotting.
        J. Biol. Chem. 1987; 262: 7439-7442
        • Gordon D.J.
        • Rifkind B.M.
        High-density lipoprotein — the clinical implications of recent studies.
        N. Engl. J. Med. 1989; 321: 1311-1316
        • Miller N.E.
        Associations of high-density lipoprotein subclasses and apolipoproteins with ischemic heart disease and coronary atherosclerosis.
        Am. Heart J. 1987; 113: 589-597
        • Franceschini G.
        • Sirtori C.R.
        • Capurso 2d, A.
        • Weisgraber K.H.
        • Mahley R.W.
        ATMilano apoprotein. Decreased high density lipoprotein cholesterol levels with significant lipoprotein modifications and without clinical atherosclerosis in an Italian family.
        J. Clin. Invest. 1980; 66: 892-900
        • Utermann G.
        • Feussner G.
        • Franceschini G.
        • Haas J.
        • Steinmetz A.
        Genetic variants of group A apolipoproteins. Rapid methods for screening and characterization without ultracentrifugation.
        J. Biol. Chem. 1982; 257: 501-507
        • Utermann G.
        • Haas J.
        • Steinmetz A.
        • Paetzold R.
        • Rail Jr., S.C.
        • Weisgraber K.H.
        • Mahley R.W.
        Apolipoprotein A-IGiessen (Pro143 → Arg). A mutant that is defective in activating lecithinxholesterol acyltransferase.
        Eur. J. Biochem. 1984; 144: 325-331
        • von Eckardstein A.
        • Funke H.
        • Henke A.
        • Altland K.
        • Benninghoven A.
        • Assmann G.
        Apolipoprotein A-I variants. Naturally occurring substitutions of proline residues affect plasma concentration of apolipoprotein A-I.
        J. Clin. Invest. 1989; 84: 1722-1730
        • von Eckardstein A.
        • Funke H.
        • Walter M.
        • Altland K.
        • Benninghoven A.
        • Assmann G.
        Structural analysis of human apolipoprotein A-I variants. Ami no acid substitutions are nonrandomly distributed throughout the apolipoprotein A-I primary structure.
        J. Biol. Chem. 1990; 265: 8610-8617
        • Funke H.
        • von Eckardstein A.
        • Pritchard P.H.
        • Karas M.
        • Albers J.J.
        • Assmann G.
        • Reckwerth A.
        • Welp S.
        A frameshift mutation in the human apolipoprotein A-I gene causes high density lipoprotein deficiency, partial lecithinxholesterol-acyltransferase deficiency, and corneal opacities.
        J. Clin. Invest. 1991; 87: 371-376
        • Deeb S.S.
        • Cheung M.C.
        • Peng R.
        • Wolf A.C.
        • Stern R.
        • Albers J.J.
        • Knopp R.H.
        A mutation in the human apolipoprotein A-I gene. Dominant effect on the level and characteristics of plasma high density lipoproteins.
        J. Biol. Chem. 1991; 266: 13654-13660
        • Takada Y.
        • Sasaki J.
        • Seki M.
        • Ogata S.
        • Teranishi Y.
        • Arakawa K.
        Characterization of a new human apolipoprotein A-l Yame by direct sequencing of polymerase chain reaction-amplified DNA.
        J. Lipid Res. 1991; 32: 1275-1280
        • Van Allen M.
        • Frohlich J.
        • Davis J.
        Inherited predisposition to generalized amyloidosis.
        Neurology. 1969; 19: 10-25
        • Nichols W.C
        • Dwulet F.E.
        • Liepnieks J.
        • Benson M.D.
        Variant apolipoprotein A-I as a major constituent of a human hereditary amyloid.
        Biochem. Biophys. Res. Commun. 1988; 156: 762-768
        • Nichols W.C
        • Gregg R.E.
        • Brewer Jr., H.B.
        • Benson M.D.
        A mutation in apolipoprotein A-I in the Iowa type of familial amyloidotic polyneuropathy.
        Genomics. 1990; 8: 318-323
        • Lipid Research Clinics Program Epidemiology Committee
        Plasma lipid distributions in selected North American populations: The Lipid Research Clinics Program Prevalence Study.
        Circulation. 1979; 60: 427-439
        • Brewer Jr., H.B.
        • Fairwell T.
        • LaRue A.
        • Ronan R.
        • Houser A.
        • Bronzert T.J.
        The ami no acid sequence of human apoA-I, and apolipoprotein isolated from high density lipoproteins.
        Biochem. Biophys. Res. Commun. 1978; 80: 623-630
        • Schaefer E.J.
        • Zech L.A.
        • Jenkins L.L.
        • Bronzert T.J.
        • Rubalcaba E.A.
        • Lindgren F.T.
        • Aamodt R.L.
        • Brewer Jr., H.B.
        Human apolipoprotein A-I and A-II metabolism.
        J. Lipid Res. 1982; 23: 850-862
        • Vega G.L.
        • Gylling H.
        • Nichols A.V.
        • Grundy S.M.
        Evaluation of a method for study of kinetics of autologous apolipoprotein A-I.
        J. Lipid Res. 1991; 32: 867-875
        • Rader D.J.
        • Castro G.
        • Zech L.A.
        • Fruchart J.C.
        • Brewer Jr., H.B.
        In vivo metabolism of apolipoprotein A-I on high density lipoprotein particles LpA-I and LpA-I, A-II.
        J. Lipid Res. 1991; 32: 1849-1859
        • Havel R.J.
        • Eder H.A.
        • Bragdon J.H.
        The distribution and chemical composition of ultracentrifugally separated lipoproteins in human serum.
        J. Clin. Invest. 1955; 34: 1345-1353
        • Berman M.
        • Weiss M.
        SAAM Manual, DHEW Publ. No. (NIH) 78. National Institutes of Health, Bethesda, MD1978
        • Warnick G.R.
        • Cheung M.C.
        • Albers J.J.
        Comparison of current methods for high-density lipoprotein cholesterol quantitation.
        Clin. Chem. 1979; 25: 596-604
        • Bojanovski M.
        • Gregg R.E.
        • Wilson D.M.
        • Brewer Jr., H.B.
        Competitive enzyme-linked immunosorbent assay (ELISA) for the quantitation of apolipoprotein A-I using a monoclonal antibody.
        Clin. Chim. Acta. 1988; 178: 159-169
        • Norum R.A.
        • Lakier J.B.
        • Goldstein S.
        • Angel A.
        • Goldberg R.B.
        • Block W.D.
        • Noffze D.K.
        • Dolphin P.J.
        • Edelglass J.
        • Bogorad D.D.
        • Alaupovic P.
        Familial deficiency of apolipoproteins A-I and C-III and precocious coronary-artery disease.
        N. Engl. J. Med. 1982; 306: 1513-1519
        • Schaefer E.J.
        • Heaton W.H.
        • Wetzel M.G.
        • Brewer Jr., H.B.
        Plasma apolipoprotein A-I absence associated with a marked reduction of high density lipoproteins and premature coronary artery disease.
        Arteriosclerosis. 1982; 2: 16-26
        • Matsunaga T
        • Hiasa Y.
        • Yanagi H.
        • Maeda T.
        • Hattori N.
        • Yamakawa K.
        • Yamanouchi Y.
        • Tanaka I.
        • Obara T.
        • Hamaguchi H.
        Apolipoprotein A-I deficiency due to a codon 84 nonsense mutation of the apolipoprotein AT gene.
        Proc. Natl. Acad. Sci. USA. 1991; 88: 2793-2797
        • Roma P.
        • Gregg R.E.
        • Meng M.S.
        • Ronan R.
        • Zech L.A.
        • Franceschini G.
        • Sirtori C.R.
        • Brewer Jr., H.B.
        In vivo metabolism of apoATMiIano.
        Circulation. 1990; 78: (abstract): 11-389
        • Brinton E.A.
        • Eisenberg S.
        • Breslow J.L.
        Increased apoA-I and apoA-II fractional catabolic rate in patients with low high density lipoprotein-cholesterol levels with or without hypertriglyceridemia.
        J. Clin. Invest. 1991; 87: 536-544
        • Glenner G.G.
        • Ein D.
        • Eanes E.D.
        • Bladen H.A.
        • Terry W.
        • Page D.L.
        Creation of “amyloid” fibrils from Bence Jones proteins in vitro.
        Science. 1971; 174: 712-714
        • Law S.W.
        • Brewer Jr., H.B.
        Nucleotide sequence and the encoded ami no acids of human apolipoprotein A-I mRNA.
        Proc. Natl. Acad. Sci. USA. 1984; 81: 66-70
        • Boguski M.S.
        • Elshourbagy N.
        • Taylor J.M.
        • Gordon J.I.
        Comparative analysis of repeated sequences in rat apolipoproteins A-I, A-IV, and E..
        Proc. Natl. Acad. Sci. USA. 1985; 82: 992-996
        • Forgez P.
        • Chapman M.J.
        • Rail Jr., S.C.
        • Camus M.C.
        The lipid transport system in the mouse, Mus musculus: isolation and characterization of apolipoproteins B, A-I, A-II, and C-III.
        J. Lipid Res. 1984; 25: 954-966
        • Yang C.Y
        • Yang T.
        • Pownall H.J.
        • Gotto Jr., A.M.
        The primary structure of apolipoprotein A-I from rabbit high-density lipoprotein.
        Eur. J. Biochem. 1986; 160: 427-431
        • Yang C.Y
        • Gu Z.W.
        • Patsch W.
        • Weng S.A.
        • Kim T.W.
        • Chan L.
        The complete ami no acid sequence of proapolipoprotein A-I of chicken high density lipoproteins.
        FEBS Lett. 1987; 224: 261-266
        • Beaubatie L.
        • Laplaud P.M.
        • Rail Jr., S.C.
        • Maurel D.
        Isolation and characterization of the major plasma apolipoproteins, A-I and B, in the European badger.
        Meles meles. J. Lipid Res. 1986; 27: 140-149
        • Luo C.C
        • Li W.H.
        • Chan L.
        Structure and expression of dog apolipoprotein A-I, E, and C-I mRNAs: implications for the evolution and functional constraints of apolipoprotein structure.
        J. Lipid Res. 1989; 30: 1735-1746
        • Garnier J.
        • Osguthorpe D.J.
        • Robson B.
        Analysis of the accuracy and implications of simple methods for predicting the secondary structure of globular proteins.
        J. Mol. Biol. 1978; 120: 97-120
        • Eanes E.D
        • Glenner G.G.
        X-ray diffraction studies on amyloid filaments.
        J. Histochem. Cytochem. 1968; 16: 673-677