Long-Term Effects of Biliverdin Reductase a Deficiency in Ugt1−/− Mice: Impact on Redox Status and Metabolism

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.

Self-powered, light-controlled, bioresorbable platforms for programmed drug delivery

“…Device and gate groups show no abnormal accumulation of dissolved Mg, Si, and Fe in organ tissues compared to control group ( SI Appendix , Tables S5 and S6 for analysis). SI Appendix , Supplementary Note 4 discussed the possible reasons ( 56 – 58 ) for elemental changes in spleen (for Si, Fe, SI Appendix , Fig. S20 ) and heart (for Si), from 1-wk to 4-wk endpoints.…”

iLight2: A near‐infrared optogenetic tool for gene transcription with low background activation

“…Other studies found a positive effect of the inactivation of Blvra to treat heme-metabolism-related human diseases, including neonatal jaundice and unconjugated hyperbilirubinemia in adults. Inhibition of Blvra is considered to be a novel promising and safe treatment for these pathologies (Bortolussi et al, 2021).…”

The associations of psychopathology and metabolic parameters with serum bilirubin levels in patients with acute-episode and drug-free schizophrenia: a 5-year retrospective study using an electronic medical record system

“…On the one hand, a study reported that bilirubin had a strong antioxidant effect at a concentration below 100 nanomoles per liter (nM), which can protect nerve cells from oxidative stress damage [ 7 ]. On the other hand, high bilirubin levels can exhibit significant pro-oxidant and neurotoxic effects, ultimately leading to neuronal necrosis or apoptosis [ 8 , 9 ]. The dysfunction of the oxidative system may be involved in the pathogenesis of schizophrenia [ 10 ].…”