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Updated: Mar 5, 2026
Extrahepatic Bile Duct and Gall Bladder Dissection in Nine-Day-Old Mouse Neonates
Published on: August 23, 2022
Hepatic MDR3 expression impacts lipid homeostasis and susceptibility to inflammatory bile duct obstruction in
Alexandra N Carey1, Wujuan Zhang2, Kenneth D R Setchell2
1Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center (CCHMC), Cincinnati, Ohio.
Abstract:
BackgroundHeterozygous 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).MethodsLivers from neonatal wild-type (wt) and heterozygous Mdr2-deficient mice were subjected to mass spectrometry-based lipidomics and RNA sequencing 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.ResultsPhosphatidylcholine (PC) and phosphatidylethanolamine (PE) were increased, whereas the PC/PE ratio was decreased in neonatal Mdr2+/- mice 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.ConclusionDecreased 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.
Insights
Reduced ABCB4 gene expression disrupts lipid balance, promoting inflammation and worsening extrahepatic biliary atresia (EHBA) in mice. This finding links ABCB4 to EHBA pathogenesis and inflammatory signatures in affected infants.
Area of Science:
- Hepatology
- Molecular Biology
- Immunology
Background:
- Heterozygous mutations in ABCB4, encoding the phospholipid transporter MDR3, are linked to chronic liver diseases.
- Reduced ABCB4 expression is hypothesized to predispose individuals to extrahepatic biliary atresia (EHBA).
Purpose of the Study:
- To investigate the role of reduced ABCB4 expression in the pathogenesis of EHBA.
- To examine the impact of ABCB4 deficiency on lipid homeostasis and immune responses in a mouse model of EHBA.
Main Methods:
- Lipidomics and RNA sequencing were performed on livers from wild-type and Mdr2-deficient neonatal mice.
- Mice were infected with rhesus rotavirus (RRV) to induce EHBA, followed by assessment of immune responses and phenotype.
- Hepatic ABCB4 expression data from infants with EHBA were analyzed.
Main Results:
- Mdr2-deficient mice exhibited altered phosphatidylcholine and phosphatidylethanolamine levels and a decreased PC/PE ratio.
- RRV challenge in Mdr2-deficient mice led to increased hepatic IFNγ, CD8+ and NK+ lymphocyte infiltration, elevated bilirubin, and higher rates of ductal obstruction.
- Infants with EHBA showed downregulated hepatic ABCB4 expression in those with an inflammatory molecular phenotype.
Conclusions:
- Decreased ABCB4 expression disrupts lipid homeostasis and promotes pro-inflammatory lymphocyte responses, aggravating the EHBA phenotype in mice.
- Downregulated ABCB4 is associated with an inflammatory transcriptome signature in infants diagnosed with EHBA.
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