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J. Biol. Chem., Vol. 276, Issue 24, 21292-21302, June 15, 2001
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From the Lipoprotein and Atherosclerosis Research Group,
Departments of Pathology and Laboratory Medicine and Biochemistry,
Microbiology, and Immunology, University of Ottawa Heart Institute,
Ottawa, Ontario K1Y 4W7, Canada
We have devised a combined in vivo,
ex vivo, and in vitro approach to elucidate the
mechanism(s) responsible for the hypoalphalipoproteinemia in
heterozygous carriers of a naturally occurring apolipoprotein A-I
(apoA-I) variant (Leu159 to Arg) known as apoA-I Finland
(apoA-IFIN). Adenovirus-mediated expression of
apoA-IFIN decreased apoA-I and high density lipoprotein cholesterol concentrations in both wild-type C57BL/6J mice and in
apoA-I-deficient mice expressing native human apoA-I (hapoA-I). Interestingly, apoA-IFIN was degraded in the plasma, and
the extent of proteolysis correlated with the most significant
reductions in murine apoA-I concentrations. ApoA-IFIN had
impaired activation of lecithin:cholesterol acyltransferase in
vitro compared with hapoA-I, but in a mixed lipoprotein
preparation consisting of both hapoA-I and apoA-IFIN there
was only a moderate reduction in the activation of this enzyme.
Importantly, secretion of apoA-I was also decreased from primary
apoA-I-deficient hepatocytes when hapoA-I was co-expressed with
apoA-IFIN following infection with recombinant
adenoviruses, a condition that mimics secretion in heterozygotes. Thus,
this is the first demonstration of an apoA-I point mutation that
decreases LCAT activation, impairs hepatocyte secretion of apoA-I, and
makes apoA-I susceptible to proteolysis leading to dominantly inherited hypoalphalipoproteinemia.
Proteolytic Degradation and Impaired Secretion of an
Apolipoprotein A-I Mutant Associated with Dominantly Inherited
Hypoalphalipoproteinemia*
§,
*
This work was supported in part by a group grant from the
Medical Research Council of Canada.The costs of publication of this article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Supported by a postgraduate scholarship from the Heart and Stroke
Foundation of Canada.
§
Both authors contributed equally to this work.
¶
Supported by a scholarship from the National Sciences and
Engineering Research Council of Canada and an Ontario Graduate Scholarship.
To whom correspondence should be addressed: Lipoprotein and
Atherosclerosis Research Group, University of Ottawa Heart Institute, Rm. H460, 40 Ruskin St., Ottawa, Ontario K1Y 4W7, Canada. Tel.: 613-761-5255; Fax: 613-761-5281; E-mail: ymarcel@ottawaheart.ca.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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