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SCAP ligands are potent new lipid-lowering drugs

Grand-Perret, Thierry, Bouillot, Anne, Perrot, Aurélie, Commans, Stéphane, Walker, Max, Issandou, Marc·2001·Nature Medicine
DOI 10.1038/nm1201-1332
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Abstract

Upregulation of low-density lipoprotein receptor (LDLr) is a key mechanism to control elevated plasma LDL-cholesterol levels. Here we identify a new class of compounds that directly binds to the sterol regulatory element-binding protein (SREBP) cleavage-activating protein (SCAP). We show that a 14C-labeled, photo-activatable analog specifically labeled both SCAP and a truncated form of SCAP containing the sterol-sensing domain. When administered to hyperlipidemic hamsters, SCAP ligands reduced both LDL cholesterol and triglycerides levels by up to 80% with a three-fold increase in LDLr mRNA in the livers. Using human hepatoma cells, we show that these compounds act through the sterol-responsive element of the LDLr promoter and activate the SCAP/SREBP pathway, leading to increased LDLr expression and activity, even in presence of excess of sterols. These findings have led to the identification of a class of compounds that represent a promising new class of hypolipidemic drugs.

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Metadata

Authors
Grand-Perret, T., Bouillot, A., Perrot, A., Commans, S., Walker, M., & Issandou, M.
Venue
Nature Medicine
Publisher
Springer Science and Business Media LLC
Published
2001-12
Volume
7
Issue
12
Pages
1332-1338
ISSN
  • 1078-8956
  • 1546-170X
DOI
10.1038/nm1201-1332
Cited by
52
References
0
Language
en
Licence
www.springer.com/tdm (tdm)

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