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.
Highlights
The first step in the catabolism of heme is the opening of the heme ring catalyzed by heme-oxygenase (HO)
We first investigated if the sole absence of the Bvra gene in genetically induced unconjugated hyperbilirubinemic mice would be sufficient to block bilirubin production in Ugt1−/− mice and prevent neonatal unconjugated bilirubin (UCB)-induced lethality [24]
We demonstrated here that genetic inactivation of Bvra fully rescues Ugt1−/− mice from brain damage and neonatal death caused by the accumulation of neurotoxic unconjugated bilirubin early after birth
Summary
The first step in the catabolism of heme is the opening of the heme ring catalyzed by heme-oxygenase (HO). IXβ [1,2,3,4] Both forms are non-toxic green metabolites that can be disposed via bile or urine without additional modifications [3]. Hepatic glucuronidation is often insufficient to conjugate the large amount of bilirubin generated by the catabolism of fetal heme since the transcription of the UGT1A1 gene is not yet completely activated in most neonates. This results in the accumulation of unconjugated bilirubin (UCB) in plasma and tissues, clinically observed as mild neonatal jaundice. In the large majority of cases, this condition is transient and is usually considered benign and possibly beneficial in view of the anti-oxidant properties of bilirubin [10]
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