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J. Biol. Chem., Vol. 278, Issue 14, 11945-11953, April 4, 2003
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From the Lipoprotein and Atherosclerosis Group, University of
Ottawa Heart Institute, Ottawa K1Y 4W7, Canada
The
Adipocyte Low Density Lipoprotein Receptor-related Protein
Gene Expression and Function Is Regulated by Peroxisome
Proliferator-activated Receptor
*
,
2-macroglobulin
receptor/low density lipoprotein receptor-related protein (LRP) is a
large multifunctional receptor that interacts with a variety of
molecules. It is implicated in biologically important processes such as
lipoprotein metabolism, neurological function, tissue remodeling,
protease complex clearance, and cell signal transduction. However, the
regulation of LRP gene expression remains largely unknown. In this
study, we have analyzed 2 kb of the 5'-flanking region of the LRP gene
and identified a predicted peroxisome proliferator response element
(PPRE) from 
1185 to 1173. Peroxisome proliferator-activated
receptor 
(PPAR) ligands such as fatty acids and rosiglitazone
increased functional cell surface LRP by 1.5-2.0-fold in primary human
adipocytes and in the SW872 human liposarcoma cell line as assessed by
activated 2-macroglobulin binding and degradation. These
agents were found to increase LRP transcription. Gel shift analysis of
the putative PPRE demonstrated direct binding of PPAR/retinoid X
receptor heterodimers to the PPRE in the LRP gene. Furthermore,
these heterodimers could no longer interact with a mutated PPRE probe. The isolated promoter was functional in SW872 cells, and its activity was increased by 1.5-fold with the addition of rosiglitazone. Furthermore, the isolated response element was similarly responsive to
rosiglitazone when placed upstream of an ideal promoter. Mutagenesis of
the predicted PPRE abolished the ability of this construct to respond
to rosiglitazone. These data demonstrate that fatty acids and
rosiglitazone directly stimulate transcription of the LRP gene through
activation of PPAR and increase functional LRP expression.
*
This work was supported by Heart and Stroke Foundation of
Ontario Grant T-4631.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 Ontario Graduate Scholarships in Science and
Technology and Ontario Graduate Scholarships.
§
The Wyeth Ayerst/Canadian Institutes of Health Research Chair in
Cardiovascular Disease. To whom correspondence should be addressed:
University of Ottawa, Rm. H441, 40 Ruskin St., Ottawa K1Y 4W7, Canada.
Tel.: 613-761-5256; Fax: 613-761-5281; E-mail: rmcpherson@ottawaheart.ca.
Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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