In vivo metabolism of a mutant apolipoprotein, apoA-I(Iowa), associated with hypoalphalipoproteinemia and hereditary systemic amyloidosis

D. J. Rader, R. E. Gregg, M. S. Meng, J. R. Schaefer, L. A. Zech, Merrill Benson, H. B. Brewer

Research output: Contribution to journalArticle

75 Citations (Scopus)

Abstract

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-I(Iowa), from the plasma of an affected subject and studied its in vivo metabolism compared to that of normal apoA-I in two heterozygous apoA-I(Iowa) 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-I(Iowa) 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-I(Iowa) 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-I(Iowa), 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-I(Iowa). Therefore, the single amino acid substitution in apoA-I(Iowa) results in both rapid clearance of apoA-I, explaining the low levels of plasma HDL and apoA-I, as well as extravascular sequestration of the mutant apolipoprotein, consistent with the formation of amyloid deposits containing aggregates of apoA-I(Iowa), in heterozygous carriers of this unique apoA-I variant.

Original languageEnglish (US)
Pages (from-to)755-763
Number of pages9
JournalJournal of Lipid Research
Volume33
Issue number5
StatePublished - 1992
Externally publishedYes

Fingerprint

Hypoalphalipoproteinemias
Familial Amyloidosis
Apolipoproteins
Apolipoprotein A-I
Metabolism
Plasmas
Radioactivity
HDL Lipoproteins

Keywords

  • apoA-I kinetics
  • high density lipoproteins
  • kinetics

ASJC Scopus subject areas

  • Endocrinology

Cite this

In vivo metabolism of a mutant apolipoprotein, apoA-I(Iowa), associated with hypoalphalipoproteinemia and hereditary systemic amyloidosis. / Rader, D. J.; Gregg, R. E.; Meng, M. S.; Schaefer, J. R.; Zech, L. A.; Benson, Merrill; Brewer, H. B.

In: Journal of Lipid Research, Vol. 33, No. 5, 1992, p. 755-763.

Research output: Contribution to journalArticle

Rader, D. J. ; Gregg, R. E. ; Meng, M. S. ; Schaefer, J. R. ; Zech, L. A. ; Benson, Merrill ; Brewer, H. B. / In vivo metabolism of a mutant apolipoprotein, apoA-I(Iowa), associated with hypoalphalipoproteinemia and hereditary systemic amyloidosis. In: Journal of Lipid Research. 1992 ; Vol. 33, No. 5. pp. 755-763.
@article{5909b37917c74580a1a28422650a17c7,
title = "In vivo metabolism of a mutant apolipoprotein, apoA-I(Iowa), associated with hypoalphalipoproteinemia and hereditary systemic amyloidosis",
abstract = "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-I(Iowa), from the plasma of an affected subject and studied its in vivo metabolism compared to that of normal apoA-I in two heterozygous apoA-I(Iowa) 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-I(Iowa) 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-I(Iowa) 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-I(Iowa), 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-I(Iowa). Therefore, the single amino acid substitution in apoA-I(Iowa) results in both rapid clearance of apoA-I, explaining the low levels of plasma HDL and apoA-I, as well as extravascular sequestration of the mutant apolipoprotein, consistent with the formation of amyloid deposits containing aggregates of apoA-I(Iowa), in heterozygous carriers of this unique apoA-I variant.",
keywords = "apoA-I kinetics, high density lipoproteins, kinetics",
author = "Rader, {D. J.} and Gregg, {R. E.} and Meng, {M. S.} and Schaefer, {J. R.} and Zech, {L. A.} and Merrill Benson and Brewer, {H. B.}",
year = "1992",
language = "English (US)",
volume = "33",
pages = "755--763",
journal = "Journal of Lipid Research",
issn = "0022-2275",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "5",

}

TY - JOUR

T1 - In vivo metabolism of a mutant apolipoprotein, apoA-I(Iowa), associated with hypoalphalipoproteinemia and hereditary systemic amyloidosis

AU - Rader, D. J.

AU - Gregg, R. E.

AU - Meng, M. S.

AU - Schaefer, J. R.

AU - Zech, L. A.

AU - Benson, Merrill

AU - Brewer, H. B.

PY - 1992

Y1 - 1992

N2 - 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-I(Iowa), from the plasma of an affected subject and studied its in vivo metabolism compared to that of normal apoA-I in two heterozygous apoA-I(Iowa) 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-I(Iowa) 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-I(Iowa) 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-I(Iowa), 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-I(Iowa). Therefore, the single amino acid substitution in apoA-I(Iowa) results in both rapid clearance of apoA-I, explaining the low levels of plasma HDL and apoA-I, as well as extravascular sequestration of the mutant apolipoprotein, consistent with the formation of amyloid deposits containing aggregates of apoA-I(Iowa), in heterozygous carriers of this unique apoA-I variant.

AB - 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-I(Iowa), from the plasma of an affected subject and studied its in vivo metabolism compared to that of normal apoA-I in two heterozygous apoA-I(Iowa) 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-I(Iowa) 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-I(Iowa) 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-I(Iowa), 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-I(Iowa). Therefore, the single amino acid substitution in apoA-I(Iowa) results in both rapid clearance of apoA-I, explaining the low levels of plasma HDL and apoA-I, as well as extravascular sequestration of the mutant apolipoprotein, consistent with the formation of amyloid deposits containing aggregates of apoA-I(Iowa), in heterozygous carriers of this unique apoA-I variant.

KW - apoA-I kinetics

KW - high density lipoproteins

KW - kinetics

UR - http://www.scopus.com/inward/record.url?scp=0026642154&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0026642154&partnerID=8YFLogxK

M3 - Article

VL - 33

SP - 755

EP - 763

JO - Journal of Lipid Research

JF - Journal of Lipid Research

SN - 0022-2275

IS - 5

ER -