Opposing Effects of Fatty Acids and Acyl-CoA Esters on Conformation and Cofactor Recruitment of Peroxisome Proliferator-Activated Receptors
The peroxisome proliferator-activated receptors (PPARs) bind and are activated by a variety of fatty acids and derivatives thereof. Agonist binding enhances PPAR-mediated transactivation via release of corepressors and recruitment of coactivator complexes. Recently, we and others have reported that acyl-CoA esters act as PPAR antagonists in vitro. Here, we show that the binding of the nonhydrolyzable acyl-CoA analogue, S-hexadecyl-CoA, differentially affected conformation and coactivator recruitment of the individual PPAR subtypes. In protease protection assays, S-hexadecyl CoA increased the sensitivity of PPAR? and PPAR? towards chymotrypsin, whereas the action of chymotrypsin on PPAR? was only marginally affected, suggesting distinct subtype-dependent differences in the effects of S-hexadecyl-CoA on conformation of the PPARs. In keeping with these findings, S-hexadecyl-CoA abrogated ligand-induced recruitment of coactivators to PPAR? and PPAR?, whereas coactivator recruitment to PPAR? was unaffected by S-hexadecyl-CoA.
fatty acids acyl-coa esters conformation peroxisome proliferator-activated receptor (ppar) coactivator recruitment