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Long-Term Effects of Biliverdin Reductase a Deficiency in Ugt1(−/−) Mice: Impact on Redox Status and Metabolism

Accumulation of neurotoxic bilirubin due to a transient neonatal or persistent inherited deficiency of bilirubin glucuronidation activity can cause irreversible brain damage and death. Strategies to inhibit bilirubin production and prevent neurotoxicity in neonatal and adult settings seem promising....

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Autores principales: Bortolussi, Giulia, Shi, Xiaoxia, ten Bloemendaal, Lysbeth, Banerjee, Bhaswati, De Waart, Dirk R., Baj, Gabriele, Chen, Weiyu, Oude Elferink, Ronald P., Beuers, Ulrich, Paulusma, Coen C., Stocker, Roland, Muro, Andrés F., Bosma, Piter J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8698966/
https://www.ncbi.nlm.nih.gov/pubmed/34943131
http://dx.doi.org/10.3390/antiox10122029
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author Bortolussi, Giulia
Shi, Xiaoxia
ten Bloemendaal, Lysbeth
Banerjee, Bhaswati
De Waart, Dirk R.
Baj, Gabriele
Chen, Weiyu
Oude Elferink, Ronald P.
Beuers, Ulrich
Paulusma, Coen C.
Stocker, Roland
Muro, Andrés F.
Bosma, Piter J.
author_facet Bortolussi, Giulia
Shi, Xiaoxia
ten Bloemendaal, Lysbeth
Banerjee, Bhaswati
De Waart, Dirk R.
Baj, Gabriele
Chen, Weiyu
Oude Elferink, Ronald P.
Beuers, Ulrich
Paulusma, Coen C.
Stocker, Roland
Muro, Andrés F.
Bosma, Piter J.
author_sort Bortolussi, Giulia
collection PubMed
description Accumulation of neurotoxic bilirubin due to a transient neonatal or persistent inherited deficiency of bilirubin glucuronidation activity can cause irreversible brain damage and death. Strategies to inhibit bilirubin production and prevent neurotoxicity in neonatal and adult settings seem promising. We evaluated the impact of Bvra deficiency in neonatal and aged mice, in a background of unconjugated hyperbilirubinemia, by abolishing bilirubin production. We also investigated the disposal of biliverdin during fetal development. In Ugt1(−/−) mice, Bvra deficiency appeared sufficient to prevent lethality and to normalize bilirubin level in adults. Although biliverdin accumulated in Bvra-deficient fetuses, both Bvra(−/−) and Bvra(−/−)Ugt1(−/−) pups were healthy and reached adulthood having normal liver, brain, and spleen histology, albeit with increased iron levels in the latter. During aging, both Bvra(−/−) and Bvra(−/−)Ugt1(−/−) mice presented normal levels of relevant hematological and metabolic parameters. Interestingly, the oxidative status in erythrocytes from 9-months-old Bvra(−/−) and Bvra(−/−)Ugt1(−/−) mice was significantly reduced. In addition, triglycerides levels in these 9-months-old Bvra(−/−) mice were significantly higher than WT controls, while Bvra(−/−)Ugt1(−/−) tested normal. The normal parameters observed in Bvra(−/−)Ugt1(−/−) mice fed chow diet indicate that Bvra inhibition to treat unconjugated hyperbilirubinemia seems safe and effective.
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spelling pubmed-86989662021-12-24 Long-Term Effects of Biliverdin Reductase a Deficiency in Ugt1(−/−) Mice: Impact on Redox Status and Metabolism Bortolussi, Giulia Shi, Xiaoxia ten Bloemendaal, Lysbeth Banerjee, Bhaswati De Waart, Dirk R. Baj, Gabriele Chen, Weiyu Oude Elferink, Ronald P. Beuers, Ulrich Paulusma, Coen C. Stocker, Roland Muro, Andrés F. Bosma, Piter J. Antioxidants (Basel) Article Accumulation of neurotoxic bilirubin due to a transient neonatal or persistent inherited deficiency of bilirubin glucuronidation activity can cause irreversible brain damage and death. Strategies to inhibit bilirubin production and prevent neurotoxicity in neonatal and adult settings seem promising. We evaluated the impact of Bvra deficiency in neonatal and aged mice, in a background of unconjugated hyperbilirubinemia, by abolishing bilirubin production. We also investigated the disposal of biliverdin during fetal development. In Ugt1(−/−) mice, Bvra deficiency appeared sufficient to prevent lethality and to normalize bilirubin level in adults. Although biliverdin accumulated in Bvra-deficient fetuses, both Bvra(−/−) and Bvra(−/−)Ugt1(−/−) pups were healthy and reached adulthood having normal liver, brain, and spleen histology, albeit with increased iron levels in the latter. During aging, both Bvra(−/−) and Bvra(−/−)Ugt1(−/−) mice presented normal levels of relevant hematological and metabolic parameters. Interestingly, the oxidative status in erythrocytes from 9-months-old Bvra(−/−) and Bvra(−/−)Ugt1(−/−) mice was significantly reduced. In addition, triglycerides levels in these 9-months-old Bvra(−/−) mice were significantly higher than WT controls, while Bvra(−/−)Ugt1(−/−) tested normal. The normal parameters observed in Bvra(−/−)Ugt1(−/−) mice fed chow diet indicate that Bvra inhibition to treat unconjugated hyperbilirubinemia seems safe and effective. MDPI 2021-12-20 /pmc/articles/PMC8698966/ /pubmed/34943131 http://dx.doi.org/10.3390/antiox10122029 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Bortolussi, Giulia
Shi, Xiaoxia
ten Bloemendaal, Lysbeth
Banerjee, Bhaswati
De Waart, Dirk R.
Baj, Gabriele
Chen, Weiyu
Oude Elferink, Ronald P.
Beuers, Ulrich
Paulusma, Coen C.
Stocker, Roland
Muro, Andrés F.
Bosma, Piter J.
Long-Term Effects of Biliverdin Reductase a Deficiency in Ugt1(−/−) Mice: Impact on Redox Status and Metabolism
title Long-Term Effects of Biliverdin Reductase a Deficiency in Ugt1(−/−) Mice: Impact on Redox Status and Metabolism
title_full Long-Term Effects of Biliverdin Reductase a Deficiency in Ugt1(−/−) Mice: Impact on Redox Status and Metabolism
title_fullStr Long-Term Effects of Biliverdin Reductase a Deficiency in Ugt1(−/−) Mice: Impact on Redox Status and Metabolism
title_full_unstemmed Long-Term Effects of Biliverdin Reductase a Deficiency in Ugt1(−/−) Mice: Impact on Redox Status and Metabolism
title_short Long-Term Effects of Biliverdin Reductase a Deficiency in Ugt1(−/−) Mice: Impact on Redox Status and Metabolism
title_sort long-term effects of biliverdin reductase a deficiency in ugt1(−/−) mice: impact on redox status and metabolism
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8698966/
https://www.ncbi.nlm.nih.gov/pubmed/34943131
http://dx.doi.org/10.3390/antiox10122029
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