Ursodeoxycholic acid improves feto-placental and offspring metabolic outcomes in hypercholanemic pregnancy
Ursodeoxycholic acid improves feto-placental and offspring metabolic outcomes in hypercholanemic pregnancy
Perturbations in the intrauterine environment can result in lifelong consequences for metabolic health during postnatal life. Intrahepatic cholestasis of pregnancy (ICP) can predispose offspring to metabolic disease in adulthood, likely due to a combination of the effects of increased bile acids, maternal dyslipidemia and deranged maternal and fetal lipid homeostasis. Whereas ursodeoxycholic acid (UDCA) is a commonly used treatment for ICP, no studies have yet addressed whether it can also prevent the metabolic effects of ICP in the offspring and fetoplacental unit. We therefore analyzed the lipid profile of fetal serum from untreated ICP, UDCA-treated ICP and uncomplicated pregnancies and found that UDCA ameliorates ICP-associated fetal dyslipidemia. We then investigated the effects of UDCA in a mouse model of hypercholanemic pregnancy and showed that it induces hepatoprotective mechanisms in the fetal liver, reduces hepatic fatty acid synthase (Fas) expression and improves glucose tolerance in the adult offspring. Finally, we showed that ICP leads to epigenetic changes in pathways of relevance to the offspring phenotype. We therefore conclude that UDCA can be used as an intervention in pregnancy to reduce features of metabolic disease in the offspring of hypercholanemic mothers.
Borges Manna, Luiza
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Papacleovoulou, Georgia
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Flaviani, Flavia
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Formigo-Pataia, Vanessa
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Qadri, Asaad
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Abu-Hayyeh, Shadi
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Mcilvride, Saraid
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Jansen, Eugene
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Dixon, Peter
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Chambers, Jennifer
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Vazquez Lopez, Marta
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Wahlstroem, Annika
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Kitaba, Negusse
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Marschall, Hanns-Ulrich
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Godfrey, Keith
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Lillycrop, Karen
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Williamson, Catherine
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25 June 2020
Borges Manna, Luiza
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Papacleovoulou, Georgia
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Flaviani, Flavia
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Formigo-Pataia, Vanessa
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Qadri, Asaad
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Abu-Hayyeh, Shadi
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Mcilvride, Saraid
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Jansen, Eugene
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Dixon, Peter
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Chambers, Jennifer
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Vazquez Lopez, Marta
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Wahlstroem, Annika
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Kitaba, Negusse
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Marschall, Hanns-Ulrich
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Godfrey, Keith
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Lillycrop, Karen
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Williamson, Catherine
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Borges Manna, Luiza, Papacleovoulou, Georgia, Flaviani, Flavia, Formigo-Pataia, Vanessa, Qadri, Asaad, Abu-Hayyeh, Shadi, Mcilvride, Saraid, Jansen, Eugene, Dixon, Peter, Chambers, Jennifer, Vazquez Lopez, Marta, Wahlstroem, Annika, Kitaba, Negusse, Marschall, Hanns-Ulrich, Godfrey, Keith, Lillycrop, Karen and Williamson, Catherine
(2020)
Ursodeoxycholic acid improves feto-placental and offspring metabolic outcomes in hypercholanemic pregnancy.
Scientific Reports, 10 (1), [10361].
(doi:10.1038/s41598-020-67301-1).
Abstract
Perturbations in the intrauterine environment can result in lifelong consequences for metabolic health during postnatal life. Intrahepatic cholestasis of pregnancy (ICP) can predispose offspring to metabolic disease in adulthood, likely due to a combination of the effects of increased bile acids, maternal dyslipidemia and deranged maternal and fetal lipid homeostasis. Whereas ursodeoxycholic acid (UDCA) is a commonly used treatment for ICP, no studies have yet addressed whether it can also prevent the metabolic effects of ICP in the offspring and fetoplacental unit. We therefore analyzed the lipid profile of fetal serum from untreated ICP, UDCA-treated ICP and uncomplicated pregnancies and found that UDCA ameliorates ICP-associated fetal dyslipidemia. We then investigated the effects of UDCA in a mouse model of hypercholanemic pregnancy and showed that it induces hepatoprotective mechanisms in the fetal liver, reduces hepatic fatty acid synthase (Fas) expression and improves glucose tolerance in the adult offspring. Finally, we showed that ICP leads to epigenetic changes in pathways of relevance to the offspring phenotype. We therefore conclude that UDCA can be used as an intervention in pregnancy to reduce features of metabolic disease in the offspring of hypercholanemic mothers.
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REVISED Ursodeoxycholic acid improves feto-placental and offspring metabolic outcomes in hypercholanemic pregnanc14697
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Accepted/In Press date: 14 May 2020
e-pub ahead of print date: 25 June 2020
Published date: 25 June 2020
Additional Information:
Funding Information:
We would like to acknowledge the support of all members of the Maternal and Fetal Disease Group, School of Life Course Sciences, King’s College London. The study was funded by the Wellcome Trust (Grant P30874), ICP Support, Genesis Research Trust and the National Institute for Health Research Biomedical Research Centers at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London and Imperial College Healthcare NHS Trust. KMG is supported by the UK Medical Research Council (MC_UU_12011/4), the National Institute for Health Research (NIHR Senior Investigator (NF-SI-0515-10042) and the NIHR Southampton Biomedical Research Centre) and the European Union (Erasmus+ Programme Early Nutrition eAcademy Southeast Asia-573651-EPP-1-2016-1-DE-EPPKA2-CBHE-JP). The views expressed are those of the authors and not necessarily those of the NHS, NIHR or the Department of Health. No conflicts of interest declared.
Publisher Copyright:
© 2020, The Author(s).
Identifiers
Local EPrints ID: 442024
URI: http://eprints.soton.ac.uk/id/eprint/442024
ISSN: 2045-2322
PURE UUID: a3c77254-6309-4ee4-93ea-2ab286ffd684
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Date deposited: 06 Jul 2020 16:30
Last modified: 17 Mar 2024 05:34
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Contributors
Author:
Luiza Borges Manna
Author:
Georgia Papacleovoulou
Author:
Flavia Flaviani
Author:
Vanessa Formigo-Pataia
Author:
Asaad Qadri
Author:
Shadi Abu-Hayyeh
Author:
Saraid Mcilvride
Author:
Eugene Jansen
Author:
Peter Dixon
Author:
Jennifer Chambers
Author:
Marta Vazquez Lopez
Author:
Annika Wahlstroem
Author:
Hanns-Ulrich Marschall
Author:
Catherine Williamson
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