SCAP ligands are potent new lipid-lowering drugs
| Autor: | Anne Marie Jeanne Bouillot, Aurélie Perrot, M Walker, Thierry Grand-Perret, Stéphane Commans, Marc Issandou |
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| Rok vydání: | 2001 |
| Předmět: |
Anisoles
Ligands General Biochemistry Genetics and Molecular Biology Benzophenones Downregulation and upregulation Genes Reporter Cricetinae Tumor Cells Cultured Animals Humans Promoter Regions Genetic Receptor Triglycerides Hypolipidemic Agents Messenger RNA Dose-Response Relationship Drug Chemistry Anticholesteremic Agents Intracellular Signaling Peptides and Proteins Membrane Proteins Cholesterol LDL General Medicine Sterol Up-Regulation Sterol regulatory element-binding protein DNA-Binding Proteins Liver Receptors LDL Biochemistry Benzamides LDL receptor CCAAT-Enhancer-Binding Proteins Steroids lipids (amino acids peptides and proteins) Lipid lowering Sterol Regulatory Element Binding Protein 1 Transcription Factors Lipoprotein |
| Zdroj: | Nature Medicine. 7:1332-1338 |
| ISSN: | 1546-170X 1078-8956 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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