Estrogen-induced production of a peroxisome proliferator-activated receptor (PPAR) ligand in a PPARgamma-expressing tissue.
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 gamma1 (PPARgamma1) 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 PPARgamma1 and how estrogen might enhance PPARgamma1-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 Delta12-prostaglandin J2. Gas chromatography/mass spectrometry revealed a striking similarity of the metabolite to Delta12-prostaglandin J2, the only form among the J2 series whose natural occurrence has been detected. Furthermore, this metabolite was able to activate duck PPARgamma1 to the same extent as the same concentrations of Delta12-prostaglandin J2 and 15-deoxy-Delta12, 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 PPARgamma1, causing the induction of peroxisome proliferation in the duck uropygial gland.
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Department of Biochemistry, Ohio State University, Columbus, Ohio 43210, USA.
Sprecher
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Kolattukudy
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PE
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D002855:Chromatography, Thin Layer; D004268:DNA-Binding Proteins; D004372:Ducks; D004958:Estradiol / Q000494:pharmacology; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D008024:Ligands; D008830:Microbodies; D009687:Nuclear Proteins; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000378:metabolism; D012627:Sebaceous Glands / Q000187:drug effects* / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*
D004268:DNA-Binding Proteins; D004967:Estrogens; D008024:Ligands; D009687:Nuclear Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D011960:Receptors, Estrogen; D014157:Transcription Factors; D016718:Arachidonic Acid; D004958:Estradiol; C040810:9-deoxy-9,10-didehydro-12,13-didehydro-13,14-dihydroprostaglandin D2; D015230:Prostaglandin D2