THE ORPHAN NUCLEAR HORMONE-RECEPTOR LXR-ALPHA INTERACTS WITH THE PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR AND INHIBITS PEROXISOME PROLIFERATOR SIGNALING

The yeast two-hybrid system was used to isolate novel cellular factors that interact with the mouse peroxisome proliferator-activated recept or alpha (PPAR alpha). One of the interacting clones isolated encoded LXR alpha, a recently described human orphan nuclear hormone receptor. LXR alpha bound directly to PPAR alpha, as well as to the common hete rodimerization partner 9-cis-retinoic acid receptor (RXR alpha). LXR a lpha did not form a DNA binding complex with PPAR alpha on synthetic h ormone response elements composed of direct repeats of the TGACCT cons ensus half-site or on naturally occurring peroxisome proliferator resp onse elements (PPREs) or LXR alpha response elements, However, LXR alp ha inhibited binding of PPAR alpha/RXR alpha heterodimers to PPREs, an d coexpression of LXR alpha in mammalian cells antagonized peroxisome proliferator signaling mediated by PPAR alpha/RXR alpha in vivo, These findings identify a novel partner for PPAR alpha and suggest that LXR alpha plays a role in modulating PPAR-signaling pathways in the cell.