Long-term effects of biliverdin reductase a deficiency in ugt1−/− 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

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Abstract

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.
Original languageEnglish
Article number2029
JournalAntioxidants
Volume10
Issue number12
DOIs
Publication statusPublished - 1 Dec 2021

Keywords

  • Aging
  • Crigler-Najjar
  • Fetus
  • Gilbert
  • Iron accumulation
  • Prdx2
  • Triglycerides

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