Identification of Nuclear Receptor Corepressor as a Peroxisome Proliferator-activated Receptor α Interacting Protein

Abstract

Nuclear receptor corepressor (NCoR) was demonstrated to interact strongly with peroxisome proliferator-activated receptor ␣ (PPAR␣), and PPAR␣ ligands suppressed this interaction. In contrast to the interaction of PPAR␣ with the coactivator protein, p300, association of the receptor with NCoR did not require any part of the PPAR␣ ligand binding domain. NCoR was found to suppress PPAR␣-dependent transcriptional activation in the context of a PPAR␣⅐retinoid X receptor ␣ (RXR␣) heterodimeric complex bound to a peroxisome proliferator-responsive element in human embryonic kidney 293 cells. This repression was reversed agonists of either receptor demonstrating a functional interaction between NCoR and PPAR␣⅐RXR␣ heterodimeric complexes in mammalian cells. NCoR appears to influence PPAR␣ signaling pathways and, therefore, may modulate tissue responsiveness to peroxisome proliferators.

The peroxisome proliferator-activated receptor δ, an integrator of transcriptional repression and nuclear receptor signaling

“…Indeed, supershift analysis revealed that SMRT only associates with DNA-bound PPAR␦ and not with DNA-bound PPAR␣ or PPAR␥ (data not shown). This is consistent with previous observations that neither PPAR␣ nor PPAR␥ was associated with corepressors when bound to DNA (23,36) and provides a basis for the unique repression property of PPAR␦. Because all three PPARs bind to common DNA sequences, the isoform-specific repression by PPAR␦ is likely because of recruitment of corepressors to PPRE.…”

“…Although all three PPARs bind to nuclear receptor corepressors in solution (23,35,36), only PPAR␦ functions as a repressor in both GAL4 system and PPRE-mediated transcription. Possibly, PPAR␦ is the only PPAR isoform that associates with corepressors when bound to DNA.…”

Evidence That Peroxisome Proliferator-activated Receptor α Is Complexed with the 90-kDa Heat Shock Protein and the Hepatitis Virus B X-associated Protein 2

“…One protein that has been found to associate with PPAR␣ is heat shock protein 72; however, the functional significance of this association has not been determined yet (21). The only other proteins reported to associate with PPAR␣ are co-activators such as PPAR␣-binding protein (designated PBP) (22), the steroid receptor co-activator 1 (23), p300 (24), peroxisome proliferator-activated receptor interacting protein (designated PRIP) (25), and nuclear receptor co-repressor (26). Thus, little is known about the regulation of PPAR␣ through protein-protein interactions.…”

Inhibition of Gluconeogenic Genes by Calcium-regulated Heat-stable Protein 1 via Repression of Peroxisome Proliferator-activated Receptor α

“…CARHSP1 binds to the 167-244 aa sequence of PPAR␣ which is located in the PPAR␣ hinge domain. Both the coactivator, PGC-1␣, and the corepressor, N-CoR, can also bind to this particular PPAR␣ domain (17,47). Notably, CARHSP1 down-regulation of gluconeogenic genes is dependent on PPAR␣.…”