SCAP ligands are potent new lipid-lowering drugs.
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.
Grand-Perret
T
T
GlaxoSmithKline, 91951 Les Ulis cedex, France. tgp28876@gsk.com
Bouillot
A
A
Perrot
A
A
Commans
S
S
Walker
M
M
Issandou
M
M
D000818:Animals; D000840:Anisoles / Q000494:pharmacology; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology; D001577:Benzophenones / Q000494:pharmacology; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism*; D008078:Cholesterol, LDL / Q000097:blood; D006224:Cricetinae; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D017930:Genes, Reporter; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D008099:Liver / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011973:Receptors, LDL / Q000096:biosynthesis / Q000235:genetics*; D013256:Steroids / Q000494:pharmacology; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D014280:Triglycerides / Q000097:blood; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D000840:Anisoles; D000924:Anticholesteremic Agents; D001549:Benzamides; D001577:Benzophenones; D022762:CCAAT-Enhancer-Binding Proteins; D008078:Cholesterol, LDL; D004268:DNA-Binding Proteins; C442818:GW 300; C442819:GW 532; C442820:GW 575; C442817:GW 707; D000960:Hypolipidemic Agents; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D008565:Membrane Proteins; D011973:Receptors, LDL; C497387:SREBF1 protein, human; C102196:SREBP cleavage-activating protein; D013256:Steroids; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D014280:Triglycerides