Opposing Effects of Fatty Acids and Acyl-CoA Esters on Conformation and Cofactor Recruitment of Peroxisome Proliferator-Activated Receptors
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Opposing Effects of Fatty Acids and Acyl-CoA Esters on Conformation and Cofactor Recruitment of Peroxisome Proliferator-Activated Receptors. / JØRGENSEN, CLAUS; KROGSDAM, ANNE-M.; KRATCHMAROVA, IRINA; WILLSON, TIMOTHY M.; KNUDSEN, JENS; MANDRUP, SUSANNE; Kristiansen, Karsten.
In: Annals of the New York Academy of Sciences, Vol. 967, 2002, p. 431-439.Research output: Contribution to journal › Journal article › Research › peer-review
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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
N1 - KEYWORDS peroxisome proliferator-activated receptor (PPAR) • fatty acids • acyl-CoA esters • conformation • coactivator recruitment
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 PPARa and PPARd 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 PPARa and PPARd, whereas coactivator recruitment to PPAR¿ 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 PPARa and PPARd 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 PPARa and PPARd, whereas coactivator recruitment to PPAR¿ was unaffected by S-hexadecyl-CoA.
M3 - Journal article
VL - 967
SP - 431
EP - 439
JO - Annals of The Lyceum of Natural History of New York
JF - Annals of The Lyceum of Natural History of New York
SN - 0077-8923
ER -
ID: 14640203