Impairment of trophoblast survival and differentiation by LXR ligands is prevented by cholesterol but not ABCA1 silencing.

INTRODUCTION: The Liver X Receptors (LXRs) drive the transcriptional response to excess intracellular cholesterol. Oxysterols, the products of cholesterol oxidation, are activating ligands for LXR that can accumulate under conditions of oxidative stress and disrupt cholesterol homeostasis. While activation of LXR inhibits trophoblast differentiation, the impact of LXR on trophoblast physiology or cholesterol homeostasis is incompletely understood. We sought to determine if the effects of LXR activation can be ameliorated through modification of cholesterol bioavailability or inhibition of LXR-driven cholesterol efflux in trophoblasts.

METHODS: We measured the effect of oxysterol exposure on BeWo cells and primary human trophoblasts (PHT cells) cultured in lipoprotein-deficient medium. We also measured the effect of the synthetic, LXR-specific ligand T0901317 on PHT cell differentiation and survival. Finally, we silenced the ATP-binding cassette transporter A1 (ABCA1), a transcriptional target of LXR that drives cholesterol efflux, to determine if inhibition of cholesterol efflux could block the effects of T0901317.

RESULTS: Oxysterols inhibited BeWo survival and PHT cell differentiation, and these effects were blocked by cholesterol supplementation. T0901317 also inhibited PHT cell differentiation, and this effect was similarly blocked by cholesterol. Unlike cholesterol however, ABCA1 silencing did not modify the effect of T0901317 on PHT cell differentiation.

DISCUSSION: Oxysterols and LXR inhibit trophoblast survival and differentiation exclusively in conditions of cholesterol scarcity. These findings underscore the importance of cholesterol homeostasis in the maintenance of placental function and suggest that pathways regulating cholesterol homeostasis may represent therapeutic targets to mitigate harmful sequelae of placental injury.