Potential of therapeutic bile acids in the treatment of neonatal Hyperbilirubinemia

Abstract Neonatal hyperbilirubinemia or jaundice is associated with kernicterus, resulting in permanent neurological damage or even death. Conventional phototherapy does not prevent hyperbilirubinemia or eliminate the need for exchange transfusion. Here we investigated the potential of therapeutic b...

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Autores principales:	Lori W. E. van der Schoor, Henkjan J. Verkade, Anna Bertolini, Sanne de Wit, Elvira Mennillo, Eva Rettenmeier, André A. Weber, Rick Havinga, Petra Valášková, Jana Jašprová, Dicky Struik, Vincent W. Bloks, Shujuan Chen, Andrea B. Schreuder, Libor Vítek, Robert H. Tukey, Johan W. Jonker
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/59f5708413df43f992dcb9093f632208
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spelling	oai:doaj.org-article:59f5708413df43f992dcb9093f6322082021-12-02T16:53:00ZPotential of therapeutic bile acids in the treatment of neonatal Hyperbilirubinemia10.1038/s41598-021-90687-52045-2322https://doaj.org/article/59f5708413df43f992dcb9093f6322082021-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-90687-5https://doaj.org/toc/2045-2322Abstract Neonatal hyperbilirubinemia or jaundice is associated with kernicterus, resulting in permanent neurological damage or even death. Conventional phototherapy does not prevent hyperbilirubinemia or eliminate the need for exchange transfusion. Here we investigated the potential of therapeutic bile acids ursodeoxycholic acid (UDCA) and obeticholic acid (OCA, 6-α-ethyl-CDCA), a farnesoid-X-receptor (FXR) agonist, as preventive treatment options for neonatal hyperbilirubinemia using the hUGT11 humanized mice and Ugt1a-deficient Gunn rats. Treatment of hUGT11 mice with UDCA or OCA at postnatal days 10–14 effectively decreased bilirubin in plasma (by 82% and 62%) and brain (by 72% and 69%), respectively. Mechanistically, our findings indicate that these effects are mediated through induction of protein levels of hUGT1A1 in the intestine, but not in liver. We further demonstrate that in Ugt1a-deficient Gunn rats, UDCA but not OCA significantly decreases plasma bilirubin, indicating that at least some of the hypobilirubinemic effects of UDCA are independent of UGT1A1. Finally, using the synthetic, non-bile acid, FXR-agonist GW4064, we show that some of these effects are mediated through direct or indirect activation of FXR. Together, our study shows that therapeutic bile acids UDCA and OCA effectively reduce both plasma and brain bilirubin, highlighting their potential in the treatment of neonatal hyperbilirubinemia.Lori W. E. van der SchoorHenkjan J. VerkadeAnna BertoliniSanne de WitElvira MennilloEva RettenmeierAndré A. WeberRick HavingaPetra ValáškováJana JašprováDicky StruikVincent W. BloksShujuan ChenAndrea B. SchreuderLibor VítekRobert H. TukeyJohan W. JonkerNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Lori W. E. van der Schoor Henkjan J. Verkade Anna Bertolini Sanne de Wit Elvira Mennillo Eva Rettenmeier André A. Weber Rick Havinga Petra Valášková Jana Jašprová Dicky Struik Vincent W. Bloks Shujuan Chen Andrea B. Schreuder Libor Vítek Robert H. Tukey Johan W. Jonker Potential of therapeutic bile acids in the treatment of neonatal Hyperbilirubinemia
description	Abstract Neonatal hyperbilirubinemia or jaundice is associated with kernicterus, resulting in permanent neurological damage or even death. Conventional phototherapy does not prevent hyperbilirubinemia or eliminate the need for exchange transfusion. Here we investigated the potential of therapeutic bile acids ursodeoxycholic acid (UDCA) and obeticholic acid (OCA, 6-α-ethyl-CDCA), a farnesoid-X-receptor (FXR) agonist, as preventive treatment options for neonatal hyperbilirubinemia using the hUGT11 humanized mice and Ugt1a-deficient Gunn rats. Treatment of hUGT11 mice with UDCA or OCA at postnatal days 10–14 effectively decreased bilirubin in plasma (by 82% and 62%) and brain (by 72% and 69%), respectively. Mechanistically, our findings indicate that these effects are mediated through induction of protein levels of hUGT1A1 in the intestine, but not in liver. We further demonstrate that in Ugt1a-deficient Gunn rats, UDCA but not OCA significantly decreases plasma bilirubin, indicating that at least some of the hypobilirubinemic effects of UDCA are independent of UGT1A1. Finally, using the synthetic, non-bile acid, FXR-agonist GW4064, we show that some of these effects are mediated through direct or indirect activation of FXR. Together, our study shows that therapeutic bile acids UDCA and OCA effectively reduce both plasma and brain bilirubin, highlighting their potential in the treatment of neonatal hyperbilirubinemia.
format	article
author	Lori W. E. van der Schoor Henkjan J. Verkade Anna Bertolini Sanne de Wit Elvira Mennillo Eva Rettenmeier André A. Weber Rick Havinga Petra Valášková Jana Jašprová Dicky Struik Vincent W. Bloks Shujuan Chen Andrea B. Schreuder Libor Vítek Robert H. Tukey Johan W. Jonker
author_facet	Lori W. E. van der Schoor Henkjan J. Verkade Anna Bertolini Sanne de Wit Elvira Mennillo Eva Rettenmeier André A. Weber Rick Havinga Petra Valášková Jana Jašprová Dicky Struik Vincent W. Bloks Shujuan Chen Andrea B. Schreuder Libor Vítek Robert H. Tukey Johan W. Jonker
author_sort	Lori W. E. van der Schoor
title	Potential of therapeutic bile acids in the treatment of neonatal Hyperbilirubinemia
title_short	Potential of therapeutic bile acids in the treatment of neonatal Hyperbilirubinemia
title_full	Potential of therapeutic bile acids in the treatment of neonatal Hyperbilirubinemia
title_fullStr	Potential of therapeutic bile acids in the treatment of neonatal Hyperbilirubinemia
title_full_unstemmed	Potential of therapeutic bile acids in the treatment of neonatal Hyperbilirubinemia
title_sort	potential of therapeutic bile acids in the treatment of neonatal hyperbilirubinemia
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/59f5708413df43f992dcb9093f632208
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Potential of therapeutic bile acids in the treatment of neonatal Hyperbilirubinemia

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