title: Hepatic MDR3 expression impacts lipid homeostasis and susceptibility to inflammatory bile duct obstruction in neonates.
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.
authors.affiliation: Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center (CCHMC), Cincinnati, Ohio.
authors.forename: Alexandra N
authors.initials: AN
authors.lastname: Carey
authors.affiliation: Division of Pathology and Laboratory Medicine, CCHMC, Cincinnati, Ohio.
authors.forename: Wujuan
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Division of Pathology and Laboratory Medicine, CCHMC, Cincinnati, Ohio.
authors.forename: Kenneth D R
authors.initials: KDR
authors.lastname: Setchell
authors.affiliation: Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center (CCHMC), Cincinnati, Ohio.
authors.forename: Julia R
authors.initials: JR
authors.lastname: Simmons
authors.affiliation: Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center (CCHMC), Cincinnati, Ohio.
authors.forename: Tiffany
authors.initials: T
authors.lastname: Shi
authors.affiliation: Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center (CCHMC), Cincinnati, Ohio.
authors.forename: Celine S
authors.initials: CS
authors.lastname: Lages
authors.affiliation: Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center (CCHMC), Cincinnati, Ohio.
authors.forename: Mary
authors.initials: M
authors.lastname: Mullen
authors.affiliation: Division of Immunobiology, CCHMC, Ohio.
authors.forename: Kaitlin
authors.initials: K
authors.lastname: Carroll
authors.affiliation: Division of Biomedical Informatics, CCHMC, Ohio.
authors.forename: Rebekah
authors.initials: R
authors.lastname: Karns
authors.affiliation: Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center (CCHMC), Cincinnati, Ohio.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Bessho
authors.affiliation: Division of Pathology and Laboratory Medicine, CCHMC, Cincinnati, Ohio.
authors.forename: Rachel
authors.initials: R
authors.lastname: Sheridan
authors.affiliation: Division of Pathology and Laboratory Medicine, CCHMC, Cincinnati, Ohio.
authors.forename: Xueheng
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Klinik fuer Innere Medizin II, Universitaetsklinikum des Saarlands, Homburg, Germany.
authors.forename: Susanne N
authors.initials: SN
authors.lastname: Weber
authors.affiliation: Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center (CCHMC), Cincinnati, Ohio.
authors.forename: Alexander G
authors.initials: AG
authors.lastname: Miethke
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D001656:Biliary Atresia / Q000235:genetics; D002779:Cholestasis / Q000378:metabolism*; D005260:Female; D006579:Heterozygote; D006706:Homeostasis; D006801:Humans; D007223:Infant; D007249:Inflammation / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000166:cytology; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism*; D013058:Mass Spectrometry; D051379:Mice; D009154:Mutation; D010641:Phenotype; D010713:Phosphatidylcholines / Q000378:metabolism; D010714:Phosphatidylethanolamines / Q000378:metabolism; D059467:Transcriptome; D000097202:ATP-Binding Cassette Sub-Family B Member 4
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D010713:Phosphatidylcholines; D010714:Phosphatidylethanolamines; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C483858:phosphatidylethanolamine; C095122:multidrug resistance protein 3