Agonist of farnesoid X receptor protects against bile acid induced damage and oxidative stress in mouse placenta--a study on maternal cholestasis model.
INTRODUCTION
Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific disorder, which is characterized by raised serum bile acid level and potential adverse fetal outcome. Farnesoid X receptor (FXR), also known as a bile acid receptor, was found to be expressed in placenta with low level. Whether activation of FXR by specific agonists could regulate the pathogenesis of ICP is still unclear.


METHODS
A model of maternal cholestasis was induced by administration of 17α-ethynylestradiol (E2) in pregnant mice for 6 days. We explored the regulatory effect of WAY-362450 (W450), a highly selective and potent FXR agonist on placenta.


RESULTS
In this study, we demonstrated that administration of E2 increased bile acid levels in mouse serum, liver and amniotic fluid. Bile acid levels were significantly decreased after W450 treatment. W450 protected against the impairment of placentas induced by E2, including severe intracellular edema and apoptosis of trophoblasts. Moreover, W450 significantly induced the expressions of FXR target bile acid transport gene ATP-binding cassette, sub-family B (MDR/TAP), member 11 (Abcb11;Bsep) in placenta. W450 could also attenuate placental oxidative stress and increase the expressions of antioxidant enzymes Prdx1 and Prdx3.


DISCUSSION AND CONCLUSION
In conclusion, our data demonstrated that FXR agonist W450 modulated bile acid balance and protected against placental oxidative stress. Thus, our results support that potent FXR agonists might represent promising drugs for the treatment of ICP.
['Wu|W B|WB|', 'Xu|Y Y|YY|', 'Cheng|W W|WW|', 'Wang|Y X|YX|', 'Liu|Y|Y|', 'Huang|D|D|', 'Zhang|H J|HJ|']
D000818:Animals D017209:Apoptosis D001381:Azepines D001647:Bile Acids and Salts D016022:Case-Control Studies D002780:Cholestasis, Intrahepatic D004195:Disease Models, Animal D004353:Drug Evaluation, Preclinical D004487:Edema D005260:Female D006801:Humans D007211:Indoles D008810:Mice, Inbred C57BL D018384:Oxidative Stress D061105:Peroxiredoxin III D054464:Peroxiredoxins D010920:Placenta D011247:Pregnancy D011248:Pregnancy Complications D018160:Receptors, Cytoplasmic and Nuclear
Farnesoid X receptor Oxidative stress Intrahepatic cholestasis of pregnancy Placenta WAY-362450 Farnesoid X receptor agonist