Choline attenuates bilirubin induced effects on tyrosine phosphorylation and distribution in lipid rafts of L1 cell adhesion molecule in vivo

Abstract Background Hyperbilirubinemia in preterm infants causes cerebellar dysfunction. L1 cell adhesion molecule (L1CAM) is a transmembrane glycoprotein that is critical for brain development. Its function is dependent on lipid rafts (LR). Bilirubin localizes to LR and disrupts L1CAM function and signaling in the cerebellum of hyperbilirubinemic Gunn rats. Behavioral deficits caused by hyperbilirubinemia in choline-restricted rat pups are ameliorated by choline. We hypothesize that choline supplementation to choline restricted Gunn rat pups reduces the impact of bilirubin on L1CAM in vivo. Methods Pregnant Gunn rat dams were placed on a choline-deficient diet on gestational day 5. Pups were administered choline or saline from P1-5. On P5, they were treated with saline or sulfadimethoxine (SDMX) which increases free bilirubin. Cerebella were harvested 24 h later. L1CAM tyrosine phosphorylation and dephosphorylation, and distribution of L1CAM in LR were determined. Results Saline supplemented homozygous (jj) pups treated with SDMX had a reduction in L1CAM tyrosine phosphorylation and Y1176 dephosphorylation and an increase in the proportion of L1CAM in LR. Choline supplementation before SDMX treatment significantly reduced the effect of bilirubin on L1CAM signaling and LR distribution. Conclusion Choline supplementation ameliorates the biochemical effects of bilirubin on L1CAM in vivo on choline-deficient hyperbilirubinemic jj Gunn rat pups. Impact This article found that choline is an intervention for the neurotoxic effects of bilirubin on the choline-restricted developing brain in vivo. This article provides clear evidence toward establishing one intervention for bilirubin neurotoxicity, where little is understood. This article paves the way for future investigation into the mechanism of the ameliorative effect of choline on bilirubin neurotoxicity.