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 receptor 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 heterodimerization partner 9-cis-retinoic acid receptor (RXR alpha). LXR alpha did not form a DNA binding complex with PPAR alpha on synthetic hormone response elements composed of direct repeats of the TGACCT consensus half-site or on naturally occurring peroxisome proliferator response elements (PPREs) or LXR alpha response elements, However, LXR alpha inhibited binding of PPAR alpha/RXR alpha heterodimers to PPREs, and 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.