Role of peroxisome proliferator-activated receptor alpha in conjugated linoleic acid modulation of events associated with tumor promotion
Abstract
Conjugated linoleic acid (CLA) inhibits mouse skin tumor promotion, however mechanisms involved in chemoprotection by CLA are not clearly understood. Previously, our laboratory identified that CLA is a high affinity ligand for peroxisome proliferator-activated receptor (PPAR) α. Since PPARα expression and activation has been associated with keratinocyte differentiation, we hypothesize that CLA is chemoprotective in mouse skin carcinogenesis through PPARα The present studies show that CLA modulates several PPAR responses in mouse skin and keratinocytes. We investigated the effect of dietary CLA on TPA-induced events in CD-1 mouse epidermis. CD-1 mice were fed 0.0, 0.5, 1.0, or 1.5% CLA (by weight) containing diets for six weeks. Mice were topically treated with acetone vehicle or TPA to induce tumorpromoting events. Dietary CLA (1.5%) significantly reduced (p < 0.05) TPA-induced PGE2 production in the epidermis. Dietary CLA also altered the neutral and phospholipid composition of the epidermis. In a separate study, CD-1 mice were fed CLA containing diets or 0.01% WY-14,643 diet for six weeks. Mice were topically treated with acetone or TPA six or eighteen hours before sacrifice. Mice fed dietary CLA and WY-14,643 had a significant increase (p < 0.05) in ACO mRNA expression at eighteen and six hours respectively. Dietary CLA did not effect PPARα expression, but the WY-14,643 diet and TPA treatment significantly increased (p < 0.05) PPARα mRNA expression at six and eighteen hours. Murine kemtinocytes (HEL-30 cells) treated with various doses of CLA (150uM) exhibited significantly increased (p < 0.05) ACO mRNA expression at 12 and 24 hours. In addition PPAR ligands, 15-deoxyΔ 12,14PGJ2 (15-deoxy-PGJ2) and WY-14,643 significantly increased (p < 0.05) ACO mRNA expression at 12 and 18 hours respectively. Both 15-deoxy-PGJ2 and CLA treatments increased ACO protein at 12 hours. CLA had no effect on PPARα mRNA expression at any time point. Dietary CLA decreases PGE2 production, alters the fatty acid composition of the epidermis, and increases ACO expression in mouse skin. CLA treatment increases ACO expression in HEL-30 cells in a manner similar to other PPAR ligands. These data suggest that CLA may modulate PPARα activity in mouse skin and this may lead to the chemoprotective effect of CLA in mouse skin tumor promotion.
Degree
Ph.D.
Advisors
Belury, Purdue University.
Subject Area
Nutrition|Oncology
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