Ma H, Sprecher H W, Kolattukudy P E
Department of Biochemistry, Ohio State University, Columbus, Ohio 43210, USA.
J Biol Chem. 1998 Nov 13;273(46):30131-8. doi: 10.1074/jbc.273.46.30131.
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.
过氧化物酶体增殖与肝脏致癌作用有关，而雌激素摄入与激素靶组织中癌症风险增加有关。在雌激素靶组织——鸭的尾脂腺中，已观察到雌激素诱导的过氧化物酶体增殖。为阐明这一过程的分子机制，我们之前从鸭尾脂腺中分离出过氧化物酶体增殖物激活受体γ1（PPARγ1）的cDNA，发现其表达仅在鸭的该组织中高度存在。然而，PPARγ1的配体性质以及雌激素如何增强PPARγ1调控的基因表达尚不清楚。在此我们证明，对动物进行雌激素处理可增强尾脂腺中花生四烯酸的代谢。在过氧化物酶体增殖之前，雌二醇处理诱导了前列腺素D2向一种代谢物的转化。高效液相色谱和薄层色谱分析表明，该代谢物在色谱行为上与前列腺素J2和Δ12 -前列腺素J2相似。气相色谱/质谱分析显示，该代谢物与Δ12 -前列腺素J2有显著相似性，Δ12 -前列腺素J2是J2系列中唯一已检测到天然存在形式的物质。此外，该代谢物能够与相同浓度的Δ12 -前列腺素J2和15 -脱氧 -Δ12,14 -前列腺素J2一样有效地激活鸭PPARγ1，而在相同条件下，前列腺素D2无效。结果表明，雌激素处理诱导了一种激活鸭PPARγ1的前列腺素D2代谢物的形成，导致鸭尾脂腺中过氧化物酶体增殖的诱导。
