ESTROGEN-INDUCED PRODUCTION OF A PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR (PPAR) LIGAND IN A PPAR-GAMMA-EXPRESSING TISSUE

Peroxisome proliferation has been associated with carcinogenesis in th e liver, and estrogen intake has been associated with increased risk o f cancer in the hormone target tissues. Estrogen-induced peroxisome pr oliferation has been observed in an estrogen target tissue, the uropyg ial gland in the duck. To elucidate the molecular mechanism of this pr ocess, we previously isolated the cDNA of peroxisome proliferator-acti vated receptor gamma 1 (PPAR gamma 1) from the duck uropygial gland an d found that its expression was high exclusively in this tissue of duc k. However, the nature of the ligand for PPAR gamma 1 and how estrogen might enhance PPAR gamma 1-regulated gene expression were not known. Here we dem onstrate that estrogen treatment of animals enhanced the m etabolism of arachidonic acid in the uropygial gland. Conversion of pr ostaglandin D-2 to a metabolite was induced by estradiol treatment pre ceding peroxisome proliferation, High performance liquid chromatograph y and TLC analyses showed that the metabolite behaved chromatographica lly similar to prostaglandin J(2) and Delta(12)-prostaglandin J(2). Ga s chromatography/mass spectrometry revealed a striking similarity of t he metabolite to Delta(12)-prostaglandin J(2), the only form among the J(2) series whose natural occurrence has been detected. Furthermore, this metabolite was able to activate duck PPAR gamma 1 to the same ext ent as the same concentrations of Delta(12)-prostaglandin J(2) and 15- deoxy-Delta(12,14)-prostaglandin J(2), whereas under the same conditio ns, prostaglandin D-2 was not effective. The results suggest that estr ogen treatment induced the formation of a prostaglandin D-2 metabolite that activated duck PPAR gamma 1, causing the induction of peroxisome proliferation in the duck uropygial gland.