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

Abstract

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 (PPAR␥1) 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 PPAR␥1 and how estrogen might enhance PPAR␥1-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 D 2 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 J 2 and ⌬ 12 -prostaglandin J 2 . Gas chromatography/mass spectrometry revealed a striking similarity of the metabolite to ⌬ 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␥1 to the same extent as the same concentrations of ⌬ 12 -prostaglandin J 2 and 15-deoxy-⌬ 12,14 -prostaglandin J 2 , whereas under the same conditions, prostaglandin D 2 was not effective. The results suggest that estrogen treatment induced the formation of a prostaglandin D 2 metabolite that activated duck PPAR␥1, causing the induction of peroxisome proliferation in the duck uropygial gland.Tumor formation in human tissues such as the breast, endometrium, and ovary has been correlated with estrogen intake. Despite extensive investigations, how estrogens may enhance the incidence of cancer in the hormone target tissues remains unknown. Peroxisome proliferation has been thought to be causally related to tumor formation in rodent liver because peroxisome proliferation caused by a large variety of proliferators correlates well with hepatic tumor formation, presumably through oxidative damage to DNA caused by the production of oxidants produced by peroxisomal oxidase(s) (1-3). Estradiol administration to mallard ducks induces peroxisome proliferation in an estrogen target tissue, the uropygial gland (4). These observations raise the possibility that in mammalian tissues that are estrogen targets, peroxisome proliferation might be triggered by exogenous estrogens, leading to carcinogenesis.How estrogen causes peroxisome proliferation is unknown. Peroxisome proliferator-activated receptors (PPARs) 1 are a group of nuclear receptors involved in mediating peroxisome proliferation. Among the three subtypes (␣, ␤, and ␥) of PPAR, the ␣ form is most responsive to peroxisome proliferators and is the primary form for the pleiotropic responses in rodents (5, 6). A recent study revealed that leukotriene B 4 ...

17beta-estradiol upregulates the expression of peroxisome proliferator-activated receptor alpha and lipid oxidative genes in skeletal muscle

“…Recent data suggests that PPAR ligand binding, which initiates dimerization with the nuclear binding partner retinoid X receptor (RXR), minimizes protein degradation by stabilizing the PPAR protein (Hirotani et al 2001). It is tempting to speculate that in skeletal muscle E 2 may generate a PPAR specific ligand, in contrast to the previous evidence for a PPAR ligand in the mallard duck uropygial gland (Ma et al 1998). Further studies to examine the nature of E 2 activated PPAR ligands in skeletal muscle are required, particularly given the clinically important ability of PPAR ligands to decrease insulin resistance (Ye et al 2001).…”

“…Cross-talk between the nuclear receptors is not uncommon, and it might be speculated that the ovarian hormones may interact with the PPARs in their regulation of cellular lipid metabolism. Indeed, in estrogen sensitive tissue, E 2 has been demonstrated to induce the formation of a prostaglandin D 2 metabolite capable of acting as a ligand for PPAR (Ma et al 1998), suggesting that the effects of E 2 on lipid metabolism could be realized through this signaling pathway. Therefore, a second aim of the current study was to examine the actions of E 2 and progesterone on skeletal muscle gene expression and protein abundance of PPAR and PPAR .…”

Peroxisome proliferator-activated receptor γ in human breast carcinoma: a modulator of estrogenic actions

“…In addition, estrogen is known to influence PG synthesis in estrogen target tissues (Ham et al 1975). Ma et al (1998a) reported that estrogen induced enzymatic conversion of PGD 2 and the metabolites of PGD 2 potently activated PPARg, although estrogen did not directly induce the mRNA expression of PPARg (Ma et al 1998b). In our present study, PPARg immunoreactivity was inversely associated with COX2 immunoreactivity and positively associated with ERa, although we could not examine the tissue concentrations of natural PPARg ligands in breast cancer tissues.…”

Arachidonic Acid Stimulates Glucose Uptake in 3T3-L1 Adipocytes by Increasing GLUT1 and GLUT4 Levels at the Plasma Membrane

“…As previously mentioned, several metabolites of AA have been recognized as potential endogenous ligands for PPAR␥. Such metabolites include 15d-PGJ 2 (26,27), ⌬12-PGJ 2 (28), and PGD 2 (21). It has also been demonstrated that AA itself can act as a PPAR␥ ligand (22)(23)(24)(25).…”