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J Biol Chem, Vol. 274, Issue 49, 35219-35226, December 3, 1999
An Extrahepatic Receptor-associated Protein-sensitive Mechanism
Is Involved in the Metabolism of Triglyceride-rich Lipoproteins
Bart J. M.
van Vlijmen §,
Astrid
Rohlmann¶,
Shallee T.
Page ,
André
Bensadoun ,
I. Sophie T.
Bos §,
Theo J. C.
van Berkel ,
Louis M.
Havekes§**, and
Joachim
Herz¶
From the Department of Biopharmaceutics,
Leiden/Amsterdam Center for Drug Research, Leiden 2300 RA, The
Netherlands, § TNO Prevention and Health, Gaubius
Laboratory, Leiden 2300 RA, The Netherlands, the ¶ Department of
Molecular Genetics, University of Texas Southwestern Medical Center,
Dallas, Texas 75235, the Division of Nutritional Sciences,
Cornell University, Ithaca, New York 14853, and ** Departments of
Cardiology and Internal Medicine, Leiden University Medical Center,
Leiden 2300 RA, The Netherlands
We have used adenovirus-mediated gene transfer in
mice to investigate low density lipoprotein receptor (LDLR) and
LDLR-related protein (LRP)-independent mechanisms that control the
metabolism of chylomicron and very low density lipoprotein (VLDL)
remnants in vivo. Overexpression of receptor-associated
protein (RAP) in mice that lack both LRP and LDLR
(MX1cre+LRPflox/floxLDLR / ) in
their livers elicited a marked hypertriglyceridemia in addition to the
pre-existing hypercholesterolemia in these animals, resulting in a
shift in the distribution of plasma lipids from LDL-sized lipoproteins
to large VLDL-sized particles. This dramatic increase in plasma lipids
was not due to a RAP-mediated inhibition of a unknown hepatic high
affinity binding site involved in lipoprotein metabolism, because no
RAP binding could be detected in livers of
MX1cre+LRPflox/floxLDLR / mice
using both membrane binding studies and ligand blotting experiments.
Remarkably, RAP overexpression also resulted in a 7-fold increase (from
13.6 to 95.6 ng/ml) of circulating, but largely inactive, lipoprotein
lipase (LPL). In contrast, plasma hepatic lipase levels and activity
were unaffected. In vitro studies showed that RAP binds to
LPL with high affinity (Kd = 5 nM) but
does not affect its catalytic activity, in vitro or in vivo. Our findings suggest that an extrahepatic
RAP-sensitive process that is independent of the LDLR or LRP is
involved in metabolism of triglyceride-rich lipoproteins. There, RAP
may affect the functional maturation of LPL, thus causing the
accumulation of triglyceride-rich lipoproteins in the circulation.
Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.

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Copyright © 1999 by the American Society for Biochemistry and Molecular Biology.
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