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J Biol Chem, Vol. 273, Issue 46, 30131-30138, November 13, 1998

Estrogen-induced Production of a Peroxisome Proliferator-activated Receptor (PPAR) Ligand in a PPAR-expressing Tissue

Hongwen Ma^§¶, Howard W. Sprecher^§, and Pappachan E. Kolattukudy^§¶

From the Departments of  Biochemistry and ^§ Medical Biochemistry and the ^¶ Neurobiotechnology Center, Ohio State University, Columbus, Ohio 43210

Peroxisome proliferation has been associated with carcinogenesis in the liver, and estrogen intake has been associated with increased risk of cancer in the hormone target tissues. Estrogen-induced peroxisome proliferation has been observed in an estrogen target tissue, the uropygial gland in the duck. To elucidate the molecular mechanism of this process, we previously isolated the cDNA of peroxisome proliferator-activated receptor 1 (PPAR1) from the duck uropygial gland and found that its expression was high exclusively in this tissue of duck. However, the nature of the ligand for PPAR1 and how estrogen might enhance PPAR1-regulated gene expression were not known. Here we demonstrate that estrogen treatment of animals enhanced the metabolism of arachidonic acid in the uropygial gland. Conversion of prostaglandin D₂ to a metabolite was induced by estradiol treatment preceding peroxisome proliferation. High performance liquid chromatography and TLC analyses showed that the metabolite behaved chromatographically similar to prostaglandin J₂ and ¹²-prostaglandin J₂. Gas chromatography/mass spectrometry revealed a striking similarity of the metabolite to ¹²-prostaglandin J₂, the only form among the J₂ series whose natural occurrence has been detected. Furthermore, this metabolite was able to activate duck PPAR1 to the same extent as the same concentrations of ¹²-prostaglandin J₂ and 15-deoxy-^12,14-prostaglandin J₂, whereas under the same conditions, prostaglandin D₂ was not effective. The results suggest that estrogen treatment induced the formation of a prostaglandin D₂ metabolite that activated duck PPAR1, causing the induction of peroxisome proliferation in the duck uropygial gland.

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Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.

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