A natural product ligand of the oxysterol receptor, liver X receptor
| Autor: | Keith A. Houck, Patrick I. Eacho, Michele Dowless, Thomas P. Burris, Chahrzad Montrose, Youyan Zhang, Palaniappan Kulanthaivel, Robert J. Barr, Robert L. Schmidt, Laura F. Michael, Guoqing Cao, Kelli S. Bramlett, Kristen M. Borchert, Thomas P. Beyer, Jeffrey S. Thomas |
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| Rok vydání: | 2003 |
| Předmět: |
Receptors
Steroid Indoles Receptors Cytoplasmic and Nuclear Biology Ligands Transfection Liver X receptor beta chemistry.chemical_compound Biological Factors Humans Paxilline Liver X receptor Receptor Cells Cultured Liver X Receptors Pharmacology Pregnane X receptor Liver X receptor alpha Orphan Nuclear Receptors DNA-Binding Proteins Biochemistry Nuclear receptor chemistry Molecular Medicine lipids (amino acids peptides and proteins) Farnesoid X receptor ATP-Binding Cassette Transporters ATP Binding Cassette Transporter 1 |
| Zdroj: | The Journal of pharmacology and experimental therapeutics. 307(1) |
| ISSN: | 0022-3565 |
| Popis: | Natural products have been identified as ligands for a number of members of the nuclear hormone receptor (NHR) superfamily. Often these natural products are used as dietary supplements to treat myriad ailments ranging from perimenopausal hot flashes to hypercholesterolemia and reduced cognitive function. Examples of some natural product ligands for NHRs include genestein (estrogen receptors NR3A1 and NR3A2), guggulsterone (farnesoid X receptor NR1H4), and St. John's wort (pregnane X receptor, NR1I2). In this study, we identified the first nonoxysterol natural product that functions as a ligand for the liver X receptor (LXRalpha and LXRbeta; NR1H3, NR1H2), a NHR that acts as the receptor for oxysterols and plays a key role in regulation of cholesterol metabolism and transport as well as glucose metabolism. We show that paxilline, a fungal metabolite, is an efficacious agonist of both LXRalpha and LXRbeta in biochemical and in vitro cell-based assays. Paxilline binds directly to both receptors and is an activator of LXR-dependent transcription in cell-based reporter assays. We also demonstrate that paxilline binding to the receptors results in efficient activation of transcription of two physiological LXR target genes, ABCA1 and SREBP. The discovery of paxilline, the first reported nonoxysterol natural product ligand of the LXRs, may provide insight into the mechanism of ligand recognition by these receptors and reaffirms the utility of examining natural product libraries for identifying novel NHR ligands. |
| Databáze: | OpenAIRE |
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