Long-Term Effects of Biliverdin Reductase a Deficiency in <i>Ugt1</i><sup>−/−</sup> Mice: Impact on Redox Status and Metabolism
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
Affiliations
Giulia Bortolussi
International Centre for Genetic Engineering and Biotechnology, 34149 Trieste, Italy
Xiaoxia Shi
Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology and Metabolism, Amsterdam University Medical Centers, Location AMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
Lysbeth ten Bloemendaal
Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology and Metabolism, Amsterdam University Medical Centers, Location AMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
Bhaswati Banerjee
International Centre for Genetic Engineering and Biotechnology, 34149 Trieste, Italy
Dirk R. De Waart
Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology and Metabolism, Amsterdam University Medical Centers, Location AMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
Gabriele Baj
Light Microscopy Imaging Center, Department of Life Sciences, University of Trieste, 34127 Trieste, Italy
Weiyu Chen
Heart Research Institute, Sydney, NSW 2042, Australia
Ronald P. Oude Elferink
Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology and Metabolism, Amsterdam University Medical Centers, Location AMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
Ulrich Beuers
Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology and Metabolism, Amsterdam University Medical Centers, Location AMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
Coen C. Paulusma
Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology and Metabolism, Amsterdam University Medical Centers, Location AMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
Roland Stocker
Heart Research Institute, Sydney, NSW 2042, Australia
Andrés F. Muro
International Centre for Genetic Engineering and Biotechnology, 34149 Trieste, Italy
Piter J. Bosma
Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology and Metabolism, Amsterdam University Medical Centers, Location AMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
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.
