 | LIPIDS AND INSULIN RESISTANCE: THE ROLE OF FATTY ACID METABOLISM AND FUEL PARTITIONING
Copyright © 2002 by the New York Academy of Sciences
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Annals of the New York Academy of Sciences 967:431-439 (2002)
© 2002 New York Academy of Sciences
Opposing Effects of Fatty Acids and Acyl-CoA Esters on Conformation and Cofactor Recruitment of Peroxisome Proliferator-Activated Receptors
CLAUS JØRGENSENa,
ANNE-M. KROGSDAMa,
IRINA KRATCHMAROVAa,
TIMOTHY M. WILLSONb,
JENS KNUDSENa,
SUSANNE MANDRUPa AND
KARSTEN KRISTIANSENa
aDepartment of Biochemistry and Molecular Biology, University of Southern Denmark, DK-5230 Odense, Denmark
bGlaxoSmithKline, Nuclear Receptor Discovery Research, Research Triangle Park, North Carolina 27709-3398, USA
Address for correspondence: Karsten Kristiansen, Department of Biochemistry and Molecular Biology, University of Southern Denmark, Campusvej 55, DK-5230 Odense M, Denmark. Voice: +45-6550-2408; fax: +45-6550-2467.
kak{at}bmb.sdu.dk
Ann. N.Y. Acad. Sci. 967: 431-439 (2002).
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.
Key Words: peroxisome proliferator-activated receptor (PPAR) • fatty acids • acyl-CoA esters • conformation • coactivator recruitment
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