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

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

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.

0892-6638
1-10
Lofthouse, Emma M
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Torrens, Christopher
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Manousopoulou, Antigoni
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Nahar, Monica
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Cleal, Jane K.
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O'Kelly, Ita M
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Sengers, Bram G.
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Garbis, Spiros D.
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Lewis, Rohan M
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Lofthouse, Emma M
c4004ff1-2ed3-4b80-9ade-583c742de59c
Torrens, Christopher
15a35713-0651-4249-8227-5901e2cfcd22
Manousopoulou, Antigoni
4e4b92ba-be65-4dba-a15d-87924c56f08b
Nahar, Monica
be823be9-6b89-4646-b8e4-42f21bce502e
Cleal, Jane K.
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O'Kelly, Ita M
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Sengers, Bram G.
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Garbis, Spiros D.
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Lewis, Rohan M
caaeb97d-ea69-4f7b-8adb-5fa25e2d3502

Lofthouse, Emma M, Torrens, Christopher, Manousopoulou, Antigoni, Nahar, Monica, Cleal, Jane K., O'Kelly, Ita M, Sengers, Bram G., Garbis, Spiros D. and Lewis, Rohan M (2019) Ursodeoxycholic acid inhibits uptake and vasoconstrictor effects of taurocholate in human placenta. The FASEB Journal, 1-10. (doi:10.1096/fj.201900015RR).

Record type: Article

Abstract

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.

Text
ICP manuscript Lofthouse et al FASEB with figures - Accepted Manuscript
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ICP manuscript Lofthouse et al FASEB with figures
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More information

Accepted/In Press date: 18 March 2019
e-pub ahead of print date: 28 March 2019

Identifiers

Local EPrints ID: 430178
URI: https://eprints.soton.ac.uk/id/eprint/430178
ISSN: 0892-6638
PURE UUID: 329b69b4-9f98-43a2-93b5-2c0f2b3003ce
ORCID for Emma M Lofthouse: ORCID iD orcid.org/0000-0002-0175-5590
ORCID for Jane K. Cleal: ORCID iD orcid.org/0000-0001-7978-4327
ORCID for Bram G. Sengers: ORCID iD orcid.org/0000-0001-5859-6984
ORCID for Rohan M Lewis: ORCID iD orcid.org/0000-0003-4044-9104

Catalogue record

Date deposited: 16 Apr 2019 16:30
Last modified: 17 Apr 2019 00:35

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