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The Journal of Lipid Research, Vol. 40, 1426-1433, August 1999
Copyright © 1999 by Lipid Research, Inc.

Original Article

Conjugated linoleic acid is a potent naturally occurring ligand and activator of PPAR{alpha}

Silvia Y. Moya-Camarenaa, John P. Vanden Heuvelb, Steven G. Blanchardc, Lisa A. Leesnitzerc, and Martha A. Belurya
a Department of Foods and Nutrition, Purdue University, West Lafayette, IN 47907
b Department of Veterinary Science, Center for Molecular Toxicology, Penn State University, University Park, PA 16802
c Department of Molecular Biochemistry, Glaxo Wellcome Research and Development, Research Triangle Park, NC 27709

Correspondence to: Martha A. Belury

We have previously shown that a mixture of dietary conjugated derivatives of linoleic acid (conjugated linoleic acid, CLA) induces peroxisome proliferator-responsive enzymes and modulates hepatic lipid metabolism in vivo. The present studies demonstrate that CLA is a high affinity ligand and activator of peroxisome proliferator-activated receptor {alpha} (PPAR{alpha}) and induces accumulation of PPAR-responsive mRNAs in a rat hepatoma cell line. Using a scintillation proximity assay (SPA), CLA isomers were shown to be ligands for human PPAR{alpha} with a rank order of potency of (9Z,11E)>(10E,12Z)>(9E,11E)> furan-CLA (IC50 values from 140 nM to 400 nM). Levels of acyl-CoA oxidase (ACO), liver fatty acid-binding protein (L-FABP), and cytochrome P450IVA1 (CYP4A1) mRNA were induced by CLA in FaO hepatoma cells. Even though linoleate and CLA were incorporated into lipids of hepatoma cells to the same extent, linoleate had little or no effect on ACO, CYP4A1, or L-FABP mRNA. In agreement with its binding potency, (9Z,11E)-CLA was the most efficacious PPAR{alpha} activator in the mouse PPAR{alpha}-GAL4(UAS)5-CAT reporter system.

These data indicate that CLA is a ligand and activator of PPAR{alpha} and its effects on lipid metabolism may be attributed to transcriptional events associated with this nuclear receptor. Also, (9Z,11E)-CLA is one of the most avid fatty acids yet described as a PPAR{alpha} ligand.—Moya-Camarena, S. Y., J. P. Vanden Heuvel, S. G. Blanchard, L. A. Leesnitzer, and M. A. Belury. Conjugated linoleic acid is a potent naturally occurring ligand and activator of PPAR{alpha}. J. Lipid Res. 1999. 40: 1426;–1433.

Supplementary key words: ligand affinity, gene expression, lipid metabolism


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