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Ursodeoxycholic acid inhibits uptake and vasoconstrictor effects of taurocholate in human placenta

Lofthouse, Emma M. and Torrens, Christopher and Manousopoulou, Antigoni and Nahar, Monica and Cleal, Jane K. and O’Kelly, Ita M. and Sengers, Bram G. and Garbis, Spiros D. and Lewis, Rohan M. (2019) Ursodeoxycholic acid inhibits uptake and vasoconstrictor effects of taurocholate in human placenta. FASEB Journal, 33 (7). pp. 8211-8220. ISSN 0892-6638. PMCID PMC6593889.

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Intrahepatic cholestasis of pregnancy (ICP) causes increased transfer of maternal bile acids to the fetus and an increased incidence of sudden fetal death. Treatment includes ursodeoxycholic acid (UDCA), but it is not clear if UDCA protects the fetus. This study explores the placental transport of the bile acid taurocholate (TC) by the organic anion–transporting polypeptide, (OATP)4A1, its effects on the placental proteome and vascular function, and how these are modified by UDCA. Various methodological approaches including placental villous fragments and Xenopus laevis oocytes were used to investigate UDCA transport. Placental perfusions and myography investigated the effect of TC on vasculature. The effects of acute TC exposure on placental tissue were investigated using quantitative proteomics. UDCA inhibited OATP4A1 activity in placental villous fragments and oocytes. TC induced vasoconstriction in placental and rat vasculature, which was attenuated by UDCA. Quantitative proteomic analysis of villous fragments showed direct effects of TC on multiple placental pathways, including oxidative stress and autophagy. The effects of TC on the placental proteome and vasculature demonstrate how bile acids may cause fetal distress in ICP. UDCA inhibition of OATP4A1 suggests it will protect the mother and fetus against the vascular effects of TC by inhibiting its cellular uptake. UDCA may protect the fetus in ICP by inhibiting OATP4A1-mediated bile acid transfer and TC-induced placental vasoconstriction. Understanding the physiologic mechanisms of UDCA may allow better therapeutic interventions to be designed specifically for the fetus in the future.—Lofthouse, E. M., Torrens, C., Manousopoulou, A., Nahar, M., Cleal, J. K., O’Kelly, I. M., Sengers, B. G., Garbis, S. D., Lewis, R. M. Ursodeoxycholic acid inhibits uptake and vasoconstrictor effects of taurocholate in human placenta.

Item Type:Article
Related URLs:
URLURL TypeDescription CentralArticle
Manousopoulou, Antigoni0000-0001-5028-1865
Garbis, Spiros D.0000-0002-1050-0805
Additional Information:© 2019 by the Federation of American Societies for Experimental Biology. This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) ( which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Received 3 January 2019; Accepted 18 March 2019; Published online 28 March 2019; Published in print 1 July 2019. The authors thank the midwives at the Princess Anne Hospital (Southampton, United Kingdom) for their assistance in collecting placentas. This work was funded by project grants from the Biotechnology and Biological Sciences Research Council (BBSRC) (BB/L020823/1 and BB/R002762/1). The authors declare no conflicts of interest. Author Contributions: E. M. Lofthouse, C. Torrens, A. Manousopoulou, and M. Nahar performed experimental work; J. Cleal, I. M. O’Kelly, S. D. Garbis, and R. M. Lewis guided the design and performances of specific aspects of the experiments; E. M. Lofthouse, C. Torrens, I. M. O’Kelly, B. G. Sengers, and R. M. Lewis conceived the study; E. M. Lofthouse and R. M. Lewis wrote the manuscript; and all authors contributed to its revision and final form.
Funding AgencyGrant Number
Biotechnology and Biological Sciences Research Council (BBSRC)BB/L020823/1
Biotechnology and Biological Sciences Research Council (BBSRC)BB/R002762/1
Subject Keywords:OATP4A1; membrane transport; vasoconstriction
Issue or Number:7
PubMed Central ID:PMC6593889
Record Number:CaltechAUTHORS:20190401-151955607
Persistent URL:
Official Citation:Ursodeoxycholic acid inhibits uptake and vasoconstrictor effects of taurocholate in human placenta. Emma M. Lofthouse, Christopher Torrens, Antigoni Manousopoulou, Monica Nahar, Jane K. Cleal, Ita M. O’Kelly, Bram G. Sengers, Spiros D. Garbis, and Rohan M. Lewis. The FASEB Journal 2019 33:7, 8211-8220; doi: 10.1096/fj.201900015rr
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:94332
Deposited By: Tony Diaz
Deposited On:01 Apr 2019 22:28
Last Modified:03 Oct 2019 21:03

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