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Originally published In Press as doi:10.1074/jbc.M100878200 on February 26, 2001

J. Biol. Chem., Vol. 276, Issue 19, 16015-16023, May 11, 2001
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Oxidized Alkyl Phospholipids Are Specific, High Affinity Peroxisome Proliferator-activated Receptor gamma  Ligands and Agonists*

Sean S. DaviesDagger §, Aaron V. Pontsler||, Gopal K. Marathe||, Kathleen A. Harrison**, Robert C. Murphy**, Jerald C. HinshawDagger Dagger , Glenn D. PrestwichDagger Dagger , Andy St. Hilaire||, Stephen M. Prescott||§§, Guy A. Zimmerman||, and Thomas M. McIntyreDagger ||¶¶

From the Departments of Dagger  Pathology, || Internal Medicine, and Dagger Dagger  Medicinal Chemistry, the  Program in Human Molecular Biology and Genetics, the §§ Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah 84112 and the ** Department of Pediatrics, National Jewish Medical and Research Center, Denver, Colorado 80206

Synthetic high affinity peroxisome proliferator-activated receptor (PPAR) agonists are known, but biologic ligands are of low affinity. Oxidized low density lipoprotein (oxLDL) is inflammatory and signals through PPARs. We showed, by phospholipase A1 digestion, that PPARgamma agonists in oxLDL arise from the small pool of alkyl phosphatidylcholines in LDL. We identified an abundant oxidatively fragmented alkyl phospholipid in oxLDL, hexadecyl azelaoyl phosphatidylcholine (azPC), as a high affinity ligand and agonist for PPARgamma . [3H]azPC bound recombinant PPARgamma with an affinity (Kd(app) approx 40 nM) that was equivalent to rosiglitazone (BRL49653), and competition with rosiglitazone showed that binding occurred in the ligand-binding pocket. azPC induced PPRE reporter gene expression, as did rosiglitazone, with a half-maximal effect at 100 nM. Overexpression of PPARalpha or PPARgamma revealed that azPC was a specific PPARgamma agonist. The scavenger receptor CD36 is encoded by a PPRE-responsive gene, and azPC enhanced expression of CD36 in primary human monocytes. We found that anti-CD36 inhibited azPC uptake, and it inhibited PPRE reporter induction. Results with a small molecule phospholipid flippase mimetic suggest azPC acts intracellularly and that cellular azPC accumulation was efficient. Thus, certain alkyl phospholipid oxidation products in oxLDL are specific, high affinity extracellular ligands and agonists for PPARgamma that induce PPAR-responsive genes.

* This work was supported by National Institutes of Health Grants HL44513, HL 35217, HL34303, NS29632, and HL 44525, the Utah Centers of Excellence Program, and the Margolis Foundation.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ Current address: Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232.

§§ H. A. and Edna Benning Professor of Human Molecular Biology.

¶¶ To whom correspondence should be addressed: 4130 EIHG, 15 North 2030 East, University of Utah, Salt Lake City, UT 84112-5330. Tel.: 801-585-0716; Fax: 801-585-0701; E-mail: tom.mcintyre@hmbg.utah.edu.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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