The activity of PPAR gamma in primary human trophoblasts is enhanced by oxidized lipids

The ligand-dependent nuclear receptor PPARgamma 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 PPARgamma. We therefore hypothesized that oxidized lipids activate PPARgamma 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 PPARgamma activity in cultured term human trophoblasts. Our results demonstrate that these lipids stimulate PPARgamma activity and that the AF-2 fragment, which harbors the ligand-binding domain of PPARgamma, mediates this effect. Furthermore, we assessed the consequences of PPARgamma 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 PPARgamma in primary human trophoblasts. These PPARgamma ligands may play a role in placental differentiation, yet they are unlikely to contribute to trophoblast dysfunction.