Preferential association of apolipoprotein E Leiden with very low density lipoproteins of human plasma

Sergio Fazio, Y. Horie, K. H. Weisgraber, L. M. Havekes, S. C. Rall

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Apolipoprotein (apo) E Leiden is a rare variant of human apoE characterized by defective receptor binding and associated with dominant transmission of type III hyperlipoproteinemia. In heterozygotes, apoE Leiden is present in higher concentrations in both total plasma and very low density lipoproteins (VLDL) than the other apoE allele product. In the present study we analyzed cell expression and plasma lipoprotein association of apoE Leiden to determine whether the unequal concentration of the two apoE allele products could be explained by differences in secretion rate from the hepatocyte or by preferential association with VLDL. We transfected the rat hepatoma cell line McA-RH7777 with apoE Leiden or normal human apoE3, and studied their secretion and media distribution. In pulse-chase experiments, the secretion of apoE Leiden was comparable to that of both human apoE3 and rat endogenous apoE, approaching 100% in 90 min. In similar transfection experiments, secreted apoE Leiden was significantly less glycosylated than normal apoE3 (21.7% vs. 36.6%, P <0.005, n = 4), a finding also noted for apoE Leiden in human plasma. In in vitro incubation experiments, apoE Leiden showed a markedly higher preference for VLDL of normolipidemic human plasma when compared to both apoE3 (2.6-fold, P <0.001) and apoE4 (1.6-fold, P <0.001). These results suggest that the accumulation of apoE Leiden in VLDL derives from a high affinity of the mutant protein for the VLDL. This enrichment in defective apoE probably exacerbates impairment of VLDL removal from the circulation, thus contributing to the dominant transmission of type II hyperlipoproteinemia.

Original languageEnglish (US)
Pages (from-to)447-453
Number of pages7
JournalJournal of Lipid Research
Volume34
Issue number3
StatePublished - 1993
Externally publishedYes

Fingerprint

Plasma (human)
VLDL Lipoproteins
Apolipoproteins E
Apolipoprotein E3
Rats
Hyperlipoproteinemia Type III
Alleles
Apolipoprotein E4
Plasmas
Hyperlipoproteinemia Type II
Experiments
Mutant Proteins
Heterozygote
Plasma Cells

Keywords

  • expression vectors
  • glycosylation
  • secretion

ASJC Scopus subject areas

  • Endocrinology

Cite this

Preferential association of apolipoprotein E Leiden with very low density lipoproteins of human plasma. / Fazio, Sergio; Horie, Y.; Weisgraber, K. H.; Havekes, L. M.; Rall, S. C.

In: Journal of Lipid Research, Vol. 34, No. 3, 1993, p. 447-453.

Research output: Contribution to journalArticle

Fazio, S, Horie, Y, Weisgraber, KH, Havekes, LM & Rall, SC 1993, 'Preferential association of apolipoprotein E Leiden with very low density lipoproteins of human plasma', Journal of Lipid Research, vol. 34, no. 3, pp. 447-453.
Fazio, Sergio ; Horie, Y. ; Weisgraber, K. H. ; Havekes, L. M. ; Rall, S. C. / Preferential association of apolipoprotein E Leiden with very low density lipoproteins of human plasma. In: Journal of Lipid Research. 1993 ; Vol. 34, No. 3. pp. 447-453.
@article{41a9f835615c408fbd72e8542474b5c2,
title = "Preferential association of apolipoprotein E Leiden with very low density lipoproteins of human plasma",
abstract = "Apolipoprotein (apo) E Leiden is a rare variant of human apoE characterized by defective receptor binding and associated with dominant transmission of type III hyperlipoproteinemia. In heterozygotes, apoE Leiden is present in higher concentrations in both total plasma and very low density lipoproteins (VLDL) than the other apoE allele product. In the present study we analyzed cell expression and plasma lipoprotein association of apoE Leiden to determine whether the unequal concentration of the two apoE allele products could be explained by differences in secretion rate from the hepatocyte or by preferential association with VLDL. We transfected the rat hepatoma cell line McA-RH7777 with apoE Leiden or normal human apoE3, and studied their secretion and media distribution. In pulse-chase experiments, the secretion of apoE Leiden was comparable to that of both human apoE3 and rat endogenous apoE, approaching 100{\%} in 90 min. In similar transfection experiments, secreted apoE Leiden was significantly less glycosylated than normal apoE3 (21.7{\%} vs. 36.6{\%}, P <0.005, n = 4), a finding also noted for apoE Leiden in human plasma. In in vitro incubation experiments, apoE Leiden showed a markedly higher preference for VLDL of normolipidemic human plasma when compared to both apoE3 (2.6-fold, P <0.001) and apoE4 (1.6-fold, P <0.001). These results suggest that the accumulation of apoE Leiden in VLDL derives from a high affinity of the mutant protein for the VLDL. This enrichment in defective apoE probably exacerbates impairment of VLDL removal from the circulation, thus contributing to the dominant transmission of type II hyperlipoproteinemia.",
keywords = "expression vectors, glycosylation, secretion",
author = "Sergio Fazio and Y. Horie and Weisgraber, {K. H.} and Havekes, {L. M.} and Rall, {S. C.}",
year = "1993",
language = "English (US)",
volume = "34",
pages = "447--453",
journal = "Journal of Lipid Research",
issn = "0022-2275",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "3",

}

TY - JOUR

T1 - Preferential association of apolipoprotein E Leiden with very low density lipoproteins of human plasma

AU - Fazio, Sergio

AU - Horie, Y.

AU - Weisgraber, K. H.

AU - Havekes, L. M.

AU - Rall, S. C.

PY - 1993

Y1 - 1993

N2 - Apolipoprotein (apo) E Leiden is a rare variant of human apoE characterized by defective receptor binding and associated with dominant transmission of type III hyperlipoproteinemia. In heterozygotes, apoE Leiden is present in higher concentrations in both total plasma and very low density lipoproteins (VLDL) than the other apoE allele product. In the present study we analyzed cell expression and plasma lipoprotein association of apoE Leiden to determine whether the unequal concentration of the two apoE allele products could be explained by differences in secretion rate from the hepatocyte or by preferential association with VLDL. We transfected the rat hepatoma cell line McA-RH7777 with apoE Leiden or normal human apoE3, and studied their secretion and media distribution. In pulse-chase experiments, the secretion of apoE Leiden was comparable to that of both human apoE3 and rat endogenous apoE, approaching 100% in 90 min. In similar transfection experiments, secreted apoE Leiden was significantly less glycosylated than normal apoE3 (21.7% vs. 36.6%, P <0.005, n = 4), a finding also noted for apoE Leiden in human plasma. In in vitro incubation experiments, apoE Leiden showed a markedly higher preference for VLDL of normolipidemic human plasma when compared to both apoE3 (2.6-fold, P <0.001) and apoE4 (1.6-fold, P <0.001). These results suggest that the accumulation of apoE Leiden in VLDL derives from a high affinity of the mutant protein for the VLDL. This enrichment in defective apoE probably exacerbates impairment of VLDL removal from the circulation, thus contributing to the dominant transmission of type II hyperlipoproteinemia.

AB - Apolipoprotein (apo) E Leiden is a rare variant of human apoE characterized by defective receptor binding and associated with dominant transmission of type III hyperlipoproteinemia. In heterozygotes, apoE Leiden is present in higher concentrations in both total plasma and very low density lipoproteins (VLDL) than the other apoE allele product. In the present study we analyzed cell expression and plasma lipoprotein association of apoE Leiden to determine whether the unequal concentration of the two apoE allele products could be explained by differences in secretion rate from the hepatocyte or by preferential association with VLDL. We transfected the rat hepatoma cell line McA-RH7777 with apoE Leiden or normal human apoE3, and studied their secretion and media distribution. In pulse-chase experiments, the secretion of apoE Leiden was comparable to that of both human apoE3 and rat endogenous apoE, approaching 100% in 90 min. In similar transfection experiments, secreted apoE Leiden was significantly less glycosylated than normal apoE3 (21.7% vs. 36.6%, P <0.005, n = 4), a finding also noted for apoE Leiden in human plasma. In in vitro incubation experiments, apoE Leiden showed a markedly higher preference for VLDL of normolipidemic human plasma when compared to both apoE3 (2.6-fold, P <0.001) and apoE4 (1.6-fold, P <0.001). These results suggest that the accumulation of apoE Leiden in VLDL derives from a high affinity of the mutant protein for the VLDL. This enrichment in defective apoE probably exacerbates impairment of VLDL removal from the circulation, thus contributing to the dominant transmission of type II hyperlipoproteinemia.

KW - expression vectors

KW - glycosylation

KW - secretion

UR - http://www.scopus.com/inward/record.url?scp=0027528427&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0027528427&partnerID=8YFLogxK

M3 - Article

C2 - 8468528

AN - SCOPUS:0027528427

VL - 34

SP - 447

EP - 453

JO - Journal of Lipid Research

JF - Journal of Lipid Research

SN - 0022-2275

IS - 3

ER -