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(Received for publication, April 19, 1996, and in revised form, September 5, 1996)
From the ¶ Institut für Medizinische Biologie und
Humangenetik, Universität Innsbruck, Schöpfstra A variable number of 5.6-kilobase kringle IV
repeats in the human apolipoprotein(a) (apo(a)) gene results in a size
polymorphism of the protein and correlates inversely with the plasma
levels of the atherogenic lipoprotein(a) (Lp(a)). In order to analyze whether this association reflects a direct effect of kringle IV repeat
number on Lp(a) plasma concentration, we have studied the expression of
recombinant apo(a) (r-apo(a)) isoforms in the human hepatocarcinoma
cell line HepG2. Following transient transfection of apo(a) cDNA
expression plasmids that differed only in the number of kringle IV
repeats, we observed a gradual decrease of Lp(a) in the medium of the
cells with an increasing number of kringle IV repeats, mimicking the
relationship present in humans in vivo. The analysis of
apo(a) protein in the lysate and in the medium of cells that were
transfected with a plasmid encoding an apo(a) isoform with 22 kringles
revealed a predominant intracellular precursor with little secretion of
the mature apo(a) protein. In contrast, transfection of a plasmid
encoding an isoform with 11 kringles led to effective secretion of the
mature peptide into the medium, indicating differential processing
rates of apo(a) isoforms in the secretory path way. The intracellular
accumulation of an apo(a) precursor in the endoplasmic reticulum was
demonstrated by cell fractionation and [35S]Met metabolic
labeling/temperature block experiments using HepG2 cells stably
transfected with recombinant apo(a). The direct and causal effect of
kringle IV repeat number on the expression of recombinant apo(a) in
HepG2 cells, and presumably liver cells, provides a novel mechanism for
the genetic regulation of the concentration of a protein.
Volume 271, Number 50,
Issue of December 13, 1996
pp. 32403-32410
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
,
,
,
,
and
e 41, 6020 Innsbruck, Austria, the 
Boehringer Mannheim GmbH,
Department of Molecular Biology, Sandhofer Strae 116, 68305 Mannheim, Germany, and the 
Institut National de la
Santé et de la Recherche Médicale,
U.143, Paris, France
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