Maternal and fetal bile acid homeostasis regulated by sulfated progesterone metabolites through FXR signaling pathway in a pregnant sow model

Authors: WANG, PENG - Sichuan Agricultural University; YUAN, PEIQIANG - Sichuan Agricultural University; LIN, SEN - Guangdong Academy Of Agricultural Sciences; ZHONG, HEJU - Sichuan Agricultural University; ZHANG, XIAOLING - Sichuan Agricultural University; ZHUO, YONG - Sichuan Agricultural University; LI, JIAN - Sichuan Agricultural University; CHE, LIANQIANG - Sichuan Agricultural University; FENG, BIN - Sichuan Agricultural University; LIN, YAN - Sichuan Agricultural University; XU, SHENGYU - Sichuan Agricultural University; WU, DE - Sichuan Agricultural University; Burrin, Douglas - Doug; FANG, ZHENGFENG - Sichuan Agricultural University

Submitted to: International Journal of Molecular Sciences
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/7/2022
Publication Date: 6/10/2022
Citation: Wang, P., Yuan, P., Lin, S., Zhong, H., Zhang, X., Zhuo, Y., Li, J., Che, L., Feng, B., Lin, Y., Xu, S., Wu, D., Burrin, D.G., Fang, Z. 2022. Maternal and fetal bile acid homeostasis regulated by sulfated progesterone metabolites through FXR signaling pathway in a pregnant sow model. International Journal of Molecular Sciences. 23. Article 6496. https://doi.org/10.3390/ijms23126496.
DOI: https://doi.org/10.3390/ijms23126496

Interpretive Summary: A clinically important problem in pregnant women is intrahepatic cholestasis (ICP), a jaundice condition, resulting from accumulation of bile acids in the blood. The condition of ICP increases the risk of fetal distress and fetal mortality. The precise cause of ICP is poorly understood and it is difficulty to perform research studies on pregnant women. In this study, we used pregnant pigs and studied the relationship between the blood levels of various pregnancy-related hormones, like estrogen, progesterone and their sulfated metabolites with bile acid homeostasis in the mother and fetus. We found that bile acid accumulation in the mother's blood is positively correlated with increased levels of sulfated progesterone metabolites. We also showed that these sulfated progesterone metabolites increase bile acid production and block the ability of bile acids to activate their receptors in liver cells. This study provides new information about how hormonal changes during pregnancy alter normal bile acid metabolism in the pregnant mother and help prevent ICP.

Technical Abstract: Abnormally elevated circulating bile acids (BA) during pregnancy endanger fetal survival and offspring health; however, the pathology and underlying mechanisms are poorly understood. A total of nineteen pregnant sows were randomly assigned to day 60 of gestation, day 90 of gestation (G60, G90), and the farrowing day (L0), to investigate the intercorrelation of reproductive hormone, including estradiol, progesterone and sulfated progesterone metabolites (PMSs), and BA in the peripheral blood of mother and fetuses during pregnancy. All data were analyzed by PROC GLM and further compared by the least significant difference test. Correlation analysis was also carried out using the CORR procedure of SAS to study the relationship between PMSs and BA levels in both maternal and fetal serum at G60, G90, and L0. Allopregnanolone sulphate (PM4S) and epiallopregnanolone sulphate (PM5S) were firstly identified in the maternal and fetal peripheral blood of pregnant sows by using newly developed ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) methods. Correlation analysis showed that pregnancy-associated maternal BA homeostasis was correlated with maternal serum PM4S levels, whereas fetal BA homeostasis was correlated with fetal serum PM5S levels. The antagonist activity role of PM5S on farnesoid X receptor (FXR)-mediated BA homeostasis and fibroblast growth factor 19 (FGF19) were confirmed in the PM5S and FXR activator co-treated pig primary hepatocytes model, and the antagonist role of PM4S on FXR-mediated BA homeostasis and FGF19 were also identified in the PM4S-treated pig primary hepatocytes model. Together with the high relative expression of FGF19 in pig hepatocytes, the pregnant sow is a promising animal model to investigate the pathogenesis of cholestasis during pregnancy.