Agonist of farnesoid X receptor protects against bile acid induced damage and oxidative stress in mouse placenta--a study on maternal cholestasis model.
BACKGROUND
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.


CONCLUSIONS
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.
Departments of Pathology and Bio-Bank, the International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China.
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Wu
Departments of Pathology and Bio-Bank, the International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China.
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Xu
Department of Obstetrics and Gynecology, the International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China.
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Cheng
Departments of Pathology and Bio-Bank, the International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China.
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YX
Wang
Departments of Pathology and Bio-Bank, the International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China.
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Liu
Department of Obstetrics and Gynecology, the International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China.
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Huang
Departments of Pathology and Bio-Bank, the International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China. Electronic address: zhanghj815@126.com.
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Zhang
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001381:Azepines / Q000494:pharmacology / Q000627:therapeutic use*; D001647:Bile Acids and Salts / Q000097:blood; D016022:Case-Control Studies; D002780:Cholestasis, Intrahepatic / Q000097:blood / Q000188:drug therapy*; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004487:Edema; D005260:Female; D006801:Humans; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use*; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress / Q000187:drug effects*; D061105:Peroxiredoxin III / Q000378:metabolism; D054464:Peroxiredoxins / Q000378:metabolism; D010920:Placenta / Q000187:drug effects* / Q000378:metabolism; D011247:Pregnancy; D011248:Pregnancy Complications / Q000097:blood / Q000188:drug therapy*; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000378:metabolism; D000099150:Receptor, Farnesoid X-Activated
D001381:Azepines; D001647:Bile Acids and Salts; D007211:Indoles; D061105:Peroxiredoxin III; D054464:Peroxiredoxins; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated; C516116:Prdx3 protein, mouse; C540004:WAY-362450; C489899:Prdx1 protein, mouse
Farnesoid X receptor; Farnesoid X receptor agonist; Intrahepatic cholestasis of pregnancy; Oxidative stress; Placenta; WAY-362450