FATTY-ACIDS, EICOSANOIDS, AND HYPOLIPIDEMIC AGENTS IDENTIFIED AS LIGANDS OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORS BY COACTIVATOR-DEPENDENT RECEPTOR-LIGAND ASSAY
G. Krey et al., FATTY-ACIDS, EICOSANOIDS, AND HYPOLIPIDEMIC AGENTS IDENTIFIED AS LIGANDS OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORS BY COACTIVATOR-DEPENDENT RECEPTOR-LIGAND ASSAY, Molecular endocrinology, 11(6), 1997, pp. 779-791
Peroxisome proliferator-activated receptors (PPARs) are nuclear hormon
e receptors controlling the expression of genes involved in lipid home
ostasis. PPARs activate gene transcription in response to a variety of
compounds including hypolipidemic drugs as well as natural fatty acid
s. From the plethora of PPAR activators, Scatchard analysis of recepto
r-ligand interactions has thus far identified only four ligands, These
are the chemotactic agent leukotriene B-4 and the hypolipidemic drug
Wy 14,643 for. the alpha-subtype and a prostaglandin J2 metabolite and
synthetic antidiabetic thiazolidinediones for the gamma-subtype, Base
d on the hypothesis that ligand binding to PPAR would induce interacti
ons of the receptor with transcriptional coactivators, we have develop
ed a novel ligand sensor assay, termed coactivator-dependent receptor
ligand assay (CARLA), With CARLA we have screened several natural and
synthetic candidate ligands and have identified naturally occurring fa
tty acids and metabolites as well as hypolipidemic drugs as bona fide
ligands of the three PPAR subtypes from Xenopus laevis, Our results;su
ggest that PPARs, by their ability to interact with a number of struct
urally diverse compounds, have acquired unique ligand-binding properti
es among the superfamily of nuclear receptors that are compatible with
their biological activity.