Chemical Probes That Differentially Modulate Peroxisome Proliferator-activated Receptor α and BLTR, Nuclear and Cell Surface Receptors for Leukotriene B4
| Autor: | Pallavi R. Devchand, Wolf-Dieter Schleuning, Abdelmadjid K. Hihi, Bruce M. Spiegelman, Walter Wahli, Mai Perroud |
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| Rok vydání: | 1999 |
| Předmět: |
Transcriptional Activation
Receptors Cytoplasmic and Nuclear Peroxisome proliferator-activated receptor Receptors Cell Surface Biology Ligands Leukotriene B4 Biochemistry Mice Bacterial Proteins Cell surface receptor Animals Humans Receptor Molecular Biology Transcription factor chemistry.chemical_classification Leukotriene B4 receptor Chemotaxis 3T3 Cells Cell Biology Nuclear receptor chemistry Molecular Probes Trans-Activators Peroxisome proliferator-activated receptor alpha HeLa Cells Transcription Factors |
| Zdroj: | Journal of Biological Chemistry. 274:23341-23348 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.274.33.23341 |
| Popis: | Peroxisome proliferator-activated receptor alpha (PPARalpha)is a nuclear receptor for various fatty acids, eicosanoids, and hypolipidemic drugs. In the presence of ligand, this transcription factor increases expression of target genes that are primarily associated with lipid homeostasis. We have previously reported PPARalpha as a nuclear receptor of the inflammatory mediator leukotriene B(4) (LTB(4)) and demonstrated an anti-inflammatory function for PPARalpha in vivo (Devchand, P. R., Keller, H., Peters, J. M., Vazquez, M., Gonzalez, F. J., and Wahli, W. (1996) Nature 384, 39-43). LTB(4) also has a cell surface receptor (BLTR) that mediates proinflammatory events, such as chemotaxis and chemokinesis (Yokomizo, T., Izumi, T., Chang, K., Takuwa, Y., and Shimizu, T. (1997) Nature 387, 620-624). In this study, we report on chemical probes that differentially modulate activity of these two LTB(4) receptors. The compounds selected were originally characterized as synthetic BLTR effectors, both agonists and antagonists. Here, we evaluate the compounds as effectors of the three PPAR isotypes (alpha, beta, and gamma) by transient transfection assays and also determine whether the compounds are ligands for these nuclear receptors by coactivator-dependent receptor ligand interaction assay, a semifunctional in vitro assay. Because the compounds are PPARalpha selective, we further analyze their potency in a biological assay for the PPARalpha-mediated activity of lipid accumulation. These chemical probes will prove invaluable in dissecting processes that involve nuclear and cell surface LTB(4) receptors and also aid in drug discovery programs. |
| Databáze: | OpenAIRE |
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