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SCAP ligands are potent new lipid-lowering drugs

Nature Medicine volume 7, pages 1332–1338 (2001)Cite this article

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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Figure 1: Comparative activity of compounds to activate LDL receptor expression.
Figure 2: GW compounds activate LDL receptor expression in the presence of sterols.
Figure 3: SCAP ligands induce expression of a functional LDL receptor.
Figure 4: GW compounds bind to SCAP and activate the translocation of SREBP.
Figure 5: SCAP ligand reduces plasma LDL cholesterol and triglycerides in hamsters.

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Acknowledgements

We thank R. Guillard, V. Paillard and V. Baudet for technical assistance; T. Dean for synthesis of GW 707; and J.C. Rodriguez for critical reading of the manuscript.

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  1. GlaxoSmithKline, Les Ulis cedex, 91951, France

    Thierry Grand-Perret, Anne Bouillot, Aurélie Perrot, Stéphane Commans, Max Walker & Marc Issandou

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Correspondence to Thierry Grand-Perret.

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Grand-Perret, T., Bouillot, A., Perrot, A. et al. SCAP ligands are potent new lipid-lowering drugs. Nat Med 7, 1332–1338 (2001). https://doi.org/10.1038/nm1201-1332

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