Chemical probes that differentially modulate peroxisome proliferator-activated receptor alpha and BLTR, nuclear and cell surface receptors for leukotriene B-4

Peroxisome proliferator-activated receptor alpha (PPAR alpha) is a nuclear receptor for various fatty acids, eicosanoids, and hypolipidemic drugs. In the presence of ligand, this transcription factor increases expression of t arget genes that are primarily associated with lipid homeostasis. We have p reviously reported PPAR alpha as a nuclear receptor of the inflammatory med iator leukotriene B-4 (LTB4) and demonstrated an anti-inflammatory function for PPAR alpha in vivo (Devchand, P. R., Keller, H., Peters, J. M., Vazque z, M., Gonzalez, F. J., and Wahli, W. (1996) Nature 384, 39-43). LTB4 also has a cell surface receptor (BLTR) that mediates proinflammatory events, su ch as chemotaxis and chemokinesis (Yokomizo, T., Izumi, T., Chang, K., Taku wa, Y., and Shimizu, T. (1997) Nature 387, 620-624). In this study, we repo rt on chemical probes that differentially modulate activity of these two LT B4 receptors. The compounds selected were originally characterized as synth etic BLTR effecters, both agonists and antagonists. Here, we evaluate the c ompounds as effecters of the three PPAR isotypes (alpha, beta, and gamma) b y transient transfection assays and also determine whether the compounds ar e ligands for these nuclear receptors by coactivator-dependent receptor lig and interaction assay, a semifunctional in vitro assay. Because the compoun ds are PPAR alpha selective, we further analyze their potency in a biologic al assay for the PPAR alpha-mediated activity of lipid accumulation. These chemical probes will prove invaluable in dissecting processes that involve nuclear and cell surface LTB4 receptors and also aid in drug discovery prog rams.