title: Opposing effects of fatty acids and acyl-CoA esters on conformation and cofactor recruitment of peroxisome proliferator-activated receptors.
abstract: 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern Denmark, DK-5230 Odense, Denmark.
authors.forename: Claus
authors.initials: C
authors.lastname: JØrgensen
authors.forename: Anne-M
authors.initials: AM
authors.lastname: Krogsdam
authors.forename: Irina
authors.initials: I
authors.lastname: Kratchmarova
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Willson
authors.forename: Jens
authors.initials: J
authors.lastname: Knudsen
authors.forename: Susanne
authors.initials: S
authors.lastname: Mandrup
authors.forename: Karsten
authors.initials: K
authors.lastname: Kristiansen
mesh_terms: 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*
chemical_list: D000214:Acyl Coenzyme A; D004952:Esters; D005227:Fatty Acids; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors