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The Activity of PPAR in Primary Human Trophoblasts Is Enhanced by Oxidized Lipids

Departments of Obstetrics and Gynecology (R.L.S., W.T.S., M.G.C., E.J.C., D.M.N., Y.S.) and Cell Biology and Physiology (Y.S.), Washington University School of Medicine, St. Louis, Missouri 63110

Address all correspondence and requests for reprints to: Yoel Sadovsky, M.D., Washington University School of Medicine, Department of Obstetrics and Gynecology, Campus Box 8064, 4566 Scott Avenue, St. Louis, Missouri 63110. E-mail: . sadovskyy{at}msnotes.wustl.edu

Abstract

The ligand-dependent nuclear receptor PPAR plays an important role in murine and human trophoblast differentiation. Oxidized lipids, which are implicated in the pathophysiology of placental dysfunction, have recently been identified as ligands for PPAR. We therefore hypothesized that oxidized lipids activate PPAR in human trophoblasts and influence placental function. To test our hypothesis, we examined the effect of 9S-hydroxy-10E,12Z-octadecadienoic acid (9-HODE), 13S-hydroxy-9Z,11E-octadecadienoic acid (13-HODE), and 15S-hydroxy-5Z,8Z,11Z,13E-eicosatetraenoic acid (15-HETE) on PPAR activity in cultured term human trophoblasts. Our results demonstrate that these lipids stimulate PPAR activity and that the AF-2 fragment, which harbors the ligand-binding domain of PPAR, mediates this effect. Furthermore, we assessed the consequences of PPAR activation by the oxidized lipids, and we found that these lipids stimulate human CG production, a measure of trophoblast differentiation. In contrast, the expression of syncytin, a marker for syncytium formation as well as the expression of the cell cycle modulators cyclin E and p27 are unchanged by the oxidized lipids. We concluded that 9-HODE, 13-HODE, and 15-HETE activate PPAR in primary human trophoblasts. These PPAR ligands may play a role in placental differentiation, yet they are unlikely to contribute to trophoblast dysfunction.

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