Long-Term Effects of Biliverdin Reductase a Deficiency in <i>Ugt1</i><sup>−/−</sup> 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....
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-12-01
|
| Series: | Antioxidants |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2076-3921/10/12/2029 |
| _version_ | 1827674321386995712 |
|---|---|
| author | Giulia Bortolussi Xiaoxia Shi Lysbeth ten Bloemendaal Bhaswati Banerjee Dirk R. De Waart Gabriele Baj Weiyu Chen Ronald P. Oude Elferink Ulrich Beuers Coen C. Paulusma Roland Stocker Andrés F. Muro Piter J. Bosma |
| author_facet | Giulia Bortolussi Xiaoxia Shi Lysbeth ten Bloemendaal Bhaswati Banerjee Dirk R. De Waart Gabriele Baj Weiyu Chen Ronald P. Oude Elferink Ulrich Beuers Coen C. Paulusma Roland Stocker Andrés F. Muro Piter J. Bosma |
| author_sort | Giulia Bortolussi |
| collection | DOAJ |
| 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 <i>Bvra</i> 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 <i>Ugt1</i><sup>−/−</sup> mice, <i>Bvra</i> deficiency appeared sufficient to prevent lethality and to normalize bilirubin level in adults. Although biliverdin accumulated in <i>Bvra</i>-deficient fetuses, both <i>Bvra</i><sup>−/−</sup> and <i>Bvra</i><sup>−/−</sup><i>Ugt1</i><sup>−/−</sup> pups were healthy and reached adulthood having normal liver, brain, and spleen histology, albeit with increased iron levels in the latter. During aging, both <i>Bvra</i><sup>−/−</sup> and <i>Bvra</i><sup>−/−</sup><i>Ugt1</i><sup>−/−</sup> mice presented normal levels of relevant hematological and metabolic parameters. Interestingly, the oxidative status in erythrocytes from 9-months-old <i>Bvra</i><sup>−/−</sup> and <i>Bvra</i><sup>−/−</sup><i>Ugt1</i><sup>−/−</sup> mice was significantly reduced. In addition, triglycerides levels in these 9-months-old <i>Bvra</i><sup>−/−</sup> mice were significantly higher than WT controls, while <i>Bvra</i><sup>−/−</sup><i>Ugt1</i><sup>−/−</sup> tested normal. The normal parameters observed in <i>Bvra</i><sup>−/−</sup><i>Ugt1</i><sup>−/−</sup> mice fed chow diet indicate that <i>Bvra</i> inhibition to treat unconjugated hyperbilirubinemia seems safe and effective. |
| first_indexed | 2024-03-10T04:38:47Z |
| format | Article |
| id | doaj.art-9e009047432a43d0942b9885748f455b |
| institution | Directory Open Access Journal |
| issn | 2076-3921 |
| language | English |
| last_indexed | 2024-03-10T04:38:47Z |
| publishDate | 2021-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antioxidants |
| spelling | doaj.art-9e009047432a43d0942b9885748f455b2023-11-23T03:34:35ZengMDPI AGAntioxidants2076-39212021-12-011012202910.3390/antiox10122029Long-Term Effects of Biliverdin Reductase a Deficiency in <i>Ugt1</i><sup>−/−</sup> Mice: Impact on Redox Status and MetabolismGiulia Bortolussi0Xiaoxia Shi1Lysbeth ten Bloemendaal2Bhaswati Banerjee3Dirk R. De Waart4Gabriele Baj5Weiyu Chen6Ronald P. Oude Elferink7Ulrich Beuers8Coen C. Paulusma9Roland Stocker10Andrés F. Muro11Piter J. Bosma12International Centre for Genetic Engineering and Biotechnology, 34149 Trieste, ItalyTytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology and Metabolism, Amsterdam University Medical Centers, Location AMC, University of Amsterdam, 1105 AZ Amsterdam, The NetherlandsTytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology and Metabolism, Amsterdam University Medical Centers, Location AMC, University of Amsterdam, 1105 AZ Amsterdam, The NetherlandsInternational Centre for Genetic Engineering and Biotechnology, 34149 Trieste, ItalyTytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology and Metabolism, Amsterdam University Medical Centers, Location AMC, University of Amsterdam, 1105 AZ Amsterdam, The NetherlandsLight Microscopy Imaging Center, Department of Life Sciences, University of Trieste, 34127 Trieste, ItalyHeart Research Institute, Sydney, NSW 2042, AustraliaTytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology and Metabolism, Amsterdam University Medical Centers, Location AMC, University of Amsterdam, 1105 AZ Amsterdam, The NetherlandsTytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology and Metabolism, Amsterdam University Medical Centers, Location AMC, University of Amsterdam, 1105 AZ Amsterdam, The NetherlandsTytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology and Metabolism, Amsterdam University Medical Centers, Location AMC, University of Amsterdam, 1105 AZ Amsterdam, The NetherlandsHeart Research Institute, Sydney, NSW 2042, AustraliaInternational Centre for Genetic Engineering and Biotechnology, 34149 Trieste, ItalyTytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology and Metabolism, Amsterdam University Medical Centers, Location AMC, University of Amsterdam, 1105 AZ Amsterdam, The NetherlandsAccumulation 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 <i>Bvra</i> 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 <i>Ugt1</i><sup>−/−</sup> mice, <i>Bvra</i> deficiency appeared sufficient to prevent lethality and to normalize bilirubin level in adults. Although biliverdin accumulated in <i>Bvra</i>-deficient fetuses, both <i>Bvra</i><sup>−/−</sup> and <i>Bvra</i><sup>−/−</sup><i>Ugt1</i><sup>−/−</sup> pups were healthy and reached adulthood having normal liver, brain, and spleen histology, albeit with increased iron levels in the latter. During aging, both <i>Bvra</i><sup>−/−</sup> and <i>Bvra</i><sup>−/−</sup><i>Ugt1</i><sup>−/−</sup> mice presented normal levels of relevant hematological and metabolic parameters. Interestingly, the oxidative status in erythrocytes from 9-months-old <i>Bvra</i><sup>−/−</sup> and <i>Bvra</i><sup>−/−</sup><i>Ugt1</i><sup>−/−</sup> mice was significantly reduced. In addition, triglycerides levels in these 9-months-old <i>Bvra</i><sup>−/−</sup> mice were significantly higher than WT controls, while <i>Bvra</i><sup>−/−</sup><i>Ugt1</i><sup>−/−</sup> tested normal. The normal parameters observed in <i>Bvra</i><sup>−/−</sup><i>Ugt1</i><sup>−/−</sup> mice fed chow diet indicate that <i>Bvra</i> inhibition to treat unconjugated hyperbilirubinemia seems safe and effective.https://www.mdpi.com/2076-3921/10/12/2029Crigler-NajjarGilbertfetusagingPrdx2triglycerides |
| spellingShingle | Giulia Bortolussi Xiaoxia Shi Lysbeth ten Bloemendaal Bhaswati Banerjee Dirk R. De Waart Gabriele Baj Weiyu Chen Ronald P. Oude Elferink Ulrich Beuers Coen C. Paulusma Roland Stocker Andrés F. Muro Piter J. Bosma Long-Term Effects of Biliverdin Reductase a Deficiency in <i>Ugt1</i><sup>−/−</sup> Mice: Impact on Redox Status and Metabolism Antioxidants Crigler-Najjar Gilbert fetus aging Prdx2 triglycerides |
| title | Long-Term Effects of Biliverdin Reductase a Deficiency in <i>Ugt1</i><sup>−/−</sup> Mice: Impact on Redox Status and Metabolism |
| title_full | Long-Term Effects of Biliverdin Reductase a Deficiency in <i>Ugt1</i><sup>−/−</sup> Mice: Impact on Redox Status and Metabolism |
| title_fullStr | Long-Term Effects of Biliverdin Reductase a Deficiency in <i>Ugt1</i><sup>−/−</sup> Mice: Impact on Redox Status and Metabolism |
| title_full_unstemmed | Long-Term Effects of Biliverdin Reductase a Deficiency in <i>Ugt1</i><sup>−/−</sup> Mice: Impact on Redox Status and Metabolism |
| title_short | Long-Term Effects of Biliverdin Reductase a Deficiency in <i>Ugt1</i><sup>−/−</sup> Mice: Impact on Redox Status and Metabolism |
| title_sort | long term effects of biliverdin reductase a deficiency in i ugt1 i sup sup mice impact on redox status and metabolism |
| topic | Crigler-Najjar Gilbert fetus aging Prdx2 triglycerides |
| url | https://www.mdpi.com/2076-3921/10/12/2029 |
| work_keys_str_mv | AT giuliabortolussi longtermeffectsofbiliverdinreductaseadeficiencyiniugt1isupsupmiceimpactonredoxstatusandmetabolism AT xiaoxiashi longtermeffectsofbiliverdinreductaseadeficiencyiniugt1isupsupmiceimpactonredoxstatusandmetabolism AT lysbethtenbloemendaal longtermeffectsofbiliverdinreductaseadeficiencyiniugt1isupsupmiceimpactonredoxstatusandmetabolism AT bhaswatibanerjee longtermeffectsofbiliverdinreductaseadeficiencyiniugt1isupsupmiceimpactonredoxstatusandmetabolism AT dirkrdewaart longtermeffectsofbiliverdinreductaseadeficiencyiniugt1isupsupmiceimpactonredoxstatusandmetabolism AT gabrielebaj longtermeffectsofbiliverdinreductaseadeficiencyiniugt1isupsupmiceimpactonredoxstatusandmetabolism AT weiyuchen longtermeffectsofbiliverdinreductaseadeficiencyiniugt1isupsupmiceimpactonredoxstatusandmetabolism AT ronaldpoudeelferink longtermeffectsofbiliverdinreductaseadeficiencyiniugt1isupsupmiceimpactonredoxstatusandmetabolism AT ulrichbeuers longtermeffectsofbiliverdinreductaseadeficiencyiniugt1isupsupmiceimpactonredoxstatusandmetabolism AT coencpaulusma longtermeffectsofbiliverdinreductaseadeficiencyiniugt1isupsupmiceimpactonredoxstatusandmetabolism AT rolandstocker longtermeffectsofbiliverdinreductaseadeficiencyiniugt1isupsupmiceimpactonredoxstatusandmetabolism AT andresfmuro longtermeffectsofbiliverdinreductaseadeficiencyiniugt1isupsupmiceimpactonredoxstatusandmetabolism AT piterjbosma longtermeffectsofbiliverdinreductaseadeficiencyiniugt1isupsupmiceimpactonredoxstatusandmetabolism |