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J. Biol. Chem., Vol. 280, Issue 19, 18667-18682, May 13, 2005

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Peroxisome Proliferator-activated Receptor Interacts with High Affinity and Is Conformationally Responsive to Endogenous Ligands^*

Heather A. Hostetler, Anca D. Petrescu, Ann B. Kier, and Friedhelm Schroeder¶

From the Department of Physiology and Pharmacology, Texas A & M University, TVMC, College Station, Texas 77843-4466 and the Department of Pathobiology, Texas A&M University, Texas Veterinary Medical College, College Station, Texas 77843-4467

Although the peroxisome proliferator-activated receptor (PPAR) binds and is activated by a variety of synthetic xenobiotics, the identity of the high affinity endogenous ligand(s) is incompletely resolved. Likewise, it is not known how putative endogenous ligands alter PPAR conformation in order to affect transcriptional regulation. Direct fluorescence binding and fluorescence displacement assays showed for the first time that PPAR exhibits high affinity (1–14 nM K_d values) for unsaturated long chain fatty acyl-CoAs as well as unsaturated long chain fatty acids commonly found in mammalian cells. Fluorescence resonance energy transfer between PPAR aromatic amino acids and bound corresponding naturally occurring fluorescent ligands (i.e. cis-parinaroyl-CoA, trans-parinaric acid) yielded intermolecular distances of 25–29 Å, confirming close molecular interaction. Interestingly, although PPAR also exhibited high affinity for saturated long chain fatty acyl-CoAs, regardless of chain length (1–13 nM K_d values), saturated long chain fatty acids were not significantly bound. In contrast to the similar affinities of PPAR for fatty acyl-CoAs and unsaturated fatty acids, CoA thioesters of peroxisome proliferator drugs were bound with 5–6-fold higher affinities than their free acid forms. Circular dichroism demonstrated that high affinity ligands (long chain fatty acyl-CoAs, unsaturated fatty acids), but not weak affinity ligands (saturated fatty acids), elicited conformational changes in PPAR structure, a hallmark of ligand-activated nuclear receptors. Finally, these ligand specificities and induced conformational changes correlated functionally with co-activator binding. In summary, since nuclear concentrations of these ligands are in the nanomolar range, long chain fatty acyl-CoAs and unsaturated fatty acids may both represent endogenous PPAR ligands. Furthermore, the finding that saturated fatty acyl-CoAs, rather than saturated fatty acids, are high affinity PPAR ligands provides a mechanism accounting for saturated fatty acid transactivation in cell-based assays.

Received for publication, October 25, 2004 , and in revised form, February 9, 2005.

^* This work was supported in part by United States Public Health Service, National Institutes of Health (NIH), Grant DK41402 (to F. S. and A. B. K.) and NIH National Research Service Award DK066732 (to H. A. H.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Dept. of Physiology and Pharmacology, Texas A & M University, TVMC, College Station, TX 77843-4466. Tel.: 979-862-1433; Fax: 979-862-4929; E-mail: fschroeder{at}cvm.tamu.edu.

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