Obeticholic Acid Protects against Gestational Cholestasis-Induced Fetal Intrauterine Growth Restriction in Mice.

Gestational cholestasis is a common disease and is associated with adverse pregnancy outcomes. However, there are still no effective treatments. We investigated the effects of obeticholic acid (OCA) on fetal intrauterine growth restriction (IUGR) during 17α-ethynylestradiol- (E2-) induced gestational cholestasis in mice. All pregnant mice except controls were subcutaneously injected with E2 (0.625 mg/kg) daily from gestational day (GD) 13 to GD17. Some pregnant mice were orally administered with OCA (5 mg/kg) daily from GD12 to GD17. As expected, OCA activated placental, maternal, and fetal hepatic FXR signaling. Additionally, exposure with E2 during late pregnancy induced cholestasis, whereas OCA alleviated E2-induced cholestasis. Gestational cholestasis caused reduction of fetal weight and crown-rump length and elevated the incidence of IUGR. OCA decreased the incidence of IUGR during cholestasis. Interestingly, OCA attenuated reduction of blood sinusoid area in placental labyrinth layer and inhibited downregulation of placental sodium-coupled neutral amino acid transporter- (SNAT-) 2 during cholestasis. Additional experiment found that OCA attenuated glutathione depletion and lipid peroxidation in placenta and fetal liver and placental protein nitration during cholestasis. Moreover, OCA inhibited the upregulation of placental NADPH oxidase-4 and antioxidant genes during cholestasis. OCA activated antioxidant Nrf2 signaling during cholestasis. Overall, we demonstrated that OCA treatment protected against gestational cholestasis-induced placental dysfunction and IUGR through suppressing placental oxidative stress and maintaining bile acid homeostasis.