Flightless-1, a novel transcriptional modulator of PPAR gamma through competing with RXR alpha

Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a member of the nuclear receptor family and plays key roles in glucose and lipid metabolism. Its transcriptional control of target genes is mediated by ligand-dependent recruitment of coactivators. In this study, we demonstrate that a novel transcriptional modulator of PPAR gamma, Flightless-I (FLII) binds directly to and suppresses the transcriptional activity of PPAR gamma. The LXXLL motif within the leucine-rich repeat (LRR) domain of FLII interacts directly with the DNA-binding domain of PPAR gamma. Interestingly, in the presence of PPAR gamma ligands, such as rosiglitazone and SR1664, this interaction was abolished in vitro. When FLII was overexpressed, both the transcriptional activity of PPAR gamma and adipogenesis were suppressed significantly, whereas specific knockdown of FLII reversed these effects. Furthermore, DNA occupancy of PPAR gamma on its target gene promoters was enhanced by FLII knockdown, and the interaction between PPAR gamma and retinoid X receptor alpha (RXR alpha) was blocked by FLII. Together, these findings strongly suggest that FLII functions in PPAR gamma activation as a molecular switch to repress transcriptional activity by interrupting formation of the PPAR gamma/RXR alpha complex, and FLII may serve as a novel therapeutic target in the treatment of adiposity-related metabolic syndromes. (C) 2014 Elsevier Inc. All rights reserved.