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 PPARalpha and PPARdelta towards chymotrypsin, whereas the action of chymotrypsin on PPARgamma 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 PPARalpha and PPARdelta, whereas coactivator recruitment to PPARgamma was unaffected by S-hexadecyl-CoA.
JØrgensen
Claus
C
Department of Biochemistry and Molecular Biology, University of Southern Denmark, DK-5230 Odense, Denmark.
Krogsdam
Anne-M
AM
Kratchmarova
Irina
I
Willson
Timothy M
TM
Knudsen
Jens
J
Mandrup
Susanne
S
Kristiansen
Karsten
K
D000214:Acyl Coenzyme A / Q000494:pharmacology*; D004952:Esters; D005227:Fatty Acids / Q000494:pharmacology*; D011487:Protein Conformation; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry / Q000378:metabolism*; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism*
D000214:Acyl Coenzyme A; D004952:Esters; D005227:Fatty Acids; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors