These data support a role for PPARgamma and RXR in regulation of fatty acid transport and storage in human placental trophoblasts.

Objective-Fatty acids (FA) are essential for fetal development. Cellular FA uptake is modulated by fatty acid binding proteins (FABPs). We hypothesized that hypoxia regulates the expression of FABPs in human trophoblasts.Study design-Primary term human trophoblasts were cultured for 72 h in either standard (O 2 = 20%) or hypoxic (O 2 < 1%) conditions. FABP expression was interrogated using PCR and western immunoblotting. Trophoblast lipid droplets were examined using BODIPY 493/503 staining.Results-We detected the expression of FABP1, 3, 4, 5 and pm, but not FABP2 or FABP6-9 subtypes in trophoblasts. Exposure to hypoxia markedly increased lipid droplet accumulation in trophoblasts. Consistent with this observation, hypoxia enhanced the expression of FABP1, 3 and 4. Lastly, agonists of peroxisome proliferator activated receptor-γ (PPARγ) enhanced the expression of FABP1 and 4 in trophoblasts.Conclusions-Hypoxia enhances the expression of FABP1, 3 and 4 in term human trophoblasts, suggesting that FABPs support fat accumulation in the hypoxic placenta.

Uptake and transplacental transfer of fatty acids is essential for fetal development. Human adipophilin and its murine ortholog adipocyte differentiation-related protein are lipid droplet-associated proteins that are implicated in cellular fatty acid uptake in adipocytes. The nuclear receptor peroxisome proliferator-activated receptor-gamma (PPARgamma) stimulates lipid uptake by adipocytes and enhances differentiation of placental trophoblasts. We therefore hypothesized that adipophilin is expressed in human trophoblasts and that its expression is regulated by PPARgamma. We initially determined that adipophilin is expressed in human villous trophoblasts and that adipophilin expression is enhanced during differentiation of cultured primary term human trophoblasts. We also found that exposure of cultured human trophoblasts to the PPARgamma ligand troglitazone resulted in a concentration-dependent increase in adipophilin expression. We observed a similar increase with LG268, a ligand for retinoid X receptor (RXR), the heterodimeric partner of PPARgamma. Lastly, we demonstrated that ligand-activated PPARgamma and RXR stimulated the transcriptional activity of adipophilin promoter in CV-1 cells and in the placental JEG3 cell line. We conclude that the expression of adipophilin is enhanced during trophoblast differentiation and is up-regulated by ligand-activated PPARgamma/RXR. Enhanced adipophilin expression may contribute to fatty acid uptake by the placenta.

Our findings suggest that observed benefit from salpingectomy in infertile women with hydrosalpinges may be in part mediated by the up-regulation of endometrial LIF expression.