Hepatic MDR3 expression impacts lipid homeostasis and susceptibility to inflammatory bile duct obstruction in neonates

BACKGROUND: Heterozygous mutations in the gene ABCB4, encoding the phospholipid floppase MDR3 (Mdr2 in mice), are associated with various chronic liver diseases. Here, we hypothesize that reduced ABCB4 expression predisposes to extrahepatic biliary atresia (EHBA). METHODS: Livers from neonatal wildtype (wt) and heterozygous Mdr2-deficient mice were subjected to mass-spectrometry based lipidomics and RNAseq studies. Following postnatal infection with rhesus rotavirus (RRV), liver immune responses and EHBA phenotype were assessed. Hepatic microarray data from 40 infants with EHBA were mined for expression levels of ABCB4. RESULTS: Phosphatidylcholine (PC) and phosphatidylethanolamine (PE) were increased while the PC/PE ratio was decreased in neonatal Mdr2(+/−) compared with wt mice. Following RRV challenge, hepatic expression of IFNγ and infiltration with CD8+ and NK+ lymphocytes were increased in Mdr2(+/−) mice. Plasma total bilirubin levels and prevalence of complete ductal obstruction were higher in these mice. In infants with EHBA, hepatic gene expression of ABCB4 was downregulated in those with an inflammatory compared with a fibrosing molecular phenotype. CONCLUSIONS: Decreased expression of ABCB4 causes dysregulation in (phospho)lipid homeostasis, and predisposes to aberrant pro-inflammatory lymphocyte responses and an aggravated phenotype of EHBA in neonatal mice. Downregulated ABCB4 is associated with an inflammatory transcriptome signature in infants with EHBA.