Cargando…
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....
Autores principales: | , , , , , , , , , , , , |
---|---|
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 |
_version_ | 1784620405040873472 |
---|---|
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. |
format | Online Article Text |
id | pubmed-8698966 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT bortolussigiulia longtermeffectsofbiliverdinreductaseadeficiencyinugt1miceimpactonredoxstatusandmetabolism AT shixiaoxia longtermeffectsofbiliverdinreductaseadeficiencyinugt1miceimpactonredoxstatusandmetabolism AT tenbloemendaallysbeth longtermeffectsofbiliverdinreductaseadeficiencyinugt1miceimpactonredoxstatusandmetabolism AT banerjeebhaswati longtermeffectsofbiliverdinreductaseadeficiencyinugt1miceimpactonredoxstatusandmetabolism AT dewaartdirkr longtermeffectsofbiliverdinreductaseadeficiencyinugt1miceimpactonredoxstatusandmetabolism AT bajgabriele longtermeffectsofbiliverdinreductaseadeficiencyinugt1miceimpactonredoxstatusandmetabolism AT chenweiyu longtermeffectsofbiliverdinreductaseadeficiencyinugt1miceimpactonredoxstatusandmetabolism AT oudeelferinkronaldp longtermeffectsofbiliverdinreductaseadeficiencyinugt1miceimpactonredoxstatusandmetabolism AT beuersulrich longtermeffectsofbiliverdinreductaseadeficiencyinugt1miceimpactonredoxstatusandmetabolism AT paulusmacoenc longtermeffectsofbiliverdinreductaseadeficiencyinugt1miceimpactonredoxstatusandmetabolism AT stockerroland longtermeffectsofbiliverdinreductaseadeficiencyinugt1miceimpactonredoxstatusandmetabolism AT muroandresf longtermeffectsofbiliverdinreductaseadeficiencyinugt1miceimpactonredoxstatusandmetabolism AT bosmapiterj longtermeffectsofbiliverdinreductaseadeficiencyinugt1miceimpactonredoxstatusandmetabolism |