TY - JOUR
T1 - Opposing effects of fatty acids and acyl-CoA esters on conformation and cofactor recruitment of peroxisome proliferator-activated receptors
AU - JØrgensen, Claus
AU - Krogsdam, Anne-M
AU - Kratchmarova, Irina
AU - Willson, Timothy M
AU - Knudsen, Jens
AU - Mandrup, Susanne
AU - Kristiansen, Karsten
PY - 2002
Y1 - 2002
N2 - 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.
AB - 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.
KW - Acyl Coenzyme A
KW - Esters
KW - Fatty Acids
KW - Protein Conformation
KW - Receptors, Cytoplasmic and Nuclear
KW - Transcription Factors
U2 - 10.1111/j.1749-6632.2002.tb04299.x
DO - 10.1111/j.1749-6632.2002.tb04299.x
M3 - Journal article
C2 - 12079871
SN - 0077-8923
VL - 967
SP - 431
EP - 439
JO - Annals of the New York Academy of Sciences
JF - Annals of the New York Academy of Sciences
IS - 1
ER -