J Biol Chem, Vol. 274, Issue 33, 23341-23348, August 13, 1999

Chemical Probes That Differentially Modulate Peroxisome Proliferator-activated Receptor  and BLTR, Nuclear and Cell Surface Receptors for Leukotriene B₄

Pallavi R. Devchand, Abdelmadjid K. Hihi, Mai Perroud, Wolf-Dieter D. Schleuning^¶, Bruce M. Spiegelman, and Walter Wahli

From the  Institut de Biologie Animale, Bâtiment de Biologie, Université de Lausanne, CH-1015 Lausanne, Switzerland, the  Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, and ^¶ Schering AG, Institute for Cell and Molecular Biology, Berlin D-1000, Germany

Peroxisome proliferator-activated receptor  (PPAR)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 PPAR as a nuclear receptor of the inflammatory mediator leukotriene B₄ (LTB₄) and demonstrated an anti-inflammatory function for PPAR in vivo (Devchand, P. R., Keller, H., Peters, J. M., Vazquez, M., Gonzalez, F. J., and Wahli, W. (1996) Nature 384, 39-43). LTB₄ 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 LTB₄ 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 (, , and ) 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 PPAR selective, we further analyze their potency in a biological assay for the PPAR-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 programs.