Obeticholic Acid Protects against Lipopolysaccharide-Induced Fetal Death and Intrauterine Growth Restriction through Its Anti-Inflammatory Activity

Farnesoid X receptor (FXR) is expressed in human and rodent placentas. Nevertheless, its function remains obscure. This study investigated the effects of obeticholic acid (OCA), a novel synthetic FXR agonist, on LPS-induced fetal death and intrauterine growth restriction. All pregnant mice except controls were i.p. injected with LPS (100 mu g/kg) daily from gestational day (GD) 15 to GD17. Some pregnant mice were orally administered with OCA (5 mu g/kg) daily from GD13 to GD17. As expected, placental FXR signaling was activated by OCA. OCA pretreatment protected against LPS-induced fetal death. In addition, OCA pretreatment alleviated LPS-induced reduction of fetal weight and crown-rump length. Additional experiments showed that OCA inhibited LPS-evoked TNF-alpha in maternal serum and amniotic fluid. Moreover, OCA significantly attenuated LPS-induced upregulation of placental proinflammatory genes including Tnf-alpha, Il- 1 beta, IL-6, Il-12, Mip-2, Kc, and Mcp-1. By contrast, OCA elevated anti-inflammatory cytokine IL-10 in maternal serum, amniotic fluid, and placenta. Further analysis showed that OCA blocked nuclear translocation of NF-kappa B p65 and p50 subunits in trophoblast giant cells of the labyrinth zone. These results provide a mechanistic explanation for placental FXR-mediated anti-inflammatory activity. Overall, this study provides evidence for roles of FXR as an important regulator of placental inflammation.