title: Maternal bile acid transporter deficiency promotes neonatal demise.
abstract: Intrahepatic cholestasis of pregnancy (ICP) is associated with adverse neonatal survival and is estimated to impact between 0.4 and 5% of pregnancies worldwide. Here we show that maternal cholestasis (due to Abcb11 deficiency) produces neonatal death among all offspring within 24 h of birth due to atelectasis-producing pulmonary hypoxia, which recapitulates the neonatal respiratory distress of human ICP. Neonates of Abcb11-deficient mothers have elevated pulmonary bile acids and altered pulmonary surfactant structure. Maternal absence of Nr1i2 superimposed on Abcb11 deficiency strongly reduces maternal serum bile acid concentrations and increases neonatal survival. We identify pulmonary bile acids as a key factor in the disruption of the structure of pulmonary surfactant in neonates of ICP. These findings have important implications for neonatal respiratory failure, especially when maternal bile acids are elevated during pregnancy, and highlight potential pathways and targets amenable to therapeutic intervention to ameliorate this condition.
authors.affiliation: Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Fei
authors.initials: F
authors.lastname: Li
authors.affiliation: Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA.
authors.forename: Yao
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA.
authors.forename: Aaron
authors.initials: A
authors.lastname: Pitre
authors.affiliation: Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Zhong-Ze
authors.initials: ZZ
authors.lastname: Fang
authors.affiliation: Department of Infectious Diseases, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA.
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Frank
authors.affiliation: Small Animal Imaging Core, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Calabrese
authors.affiliation: Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Kristopher W
authors.initials: KW
authors.lastname: Krausz
authors.affiliation: Hartwell Center, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Neale
authors.affiliation: Cellular Imaging Shared Resource, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA.
authors.forename: Sharon
authors.initials: S
authors.lastname: Frase
authors.affiliation: Department of Pathology, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Vogel
authors.affiliation: Department of Infectious Diseases, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA.
authors.forename: Charles O
authors.initials: CO
authors.lastname: Rock
authors.affiliation: Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
authors.affiliation: Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Schuetz
mesh_terms: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000172:deficiency / Q000235:genetics*; D000818:Animals; D000831:Animals, Newborn; D001647:Bile Acids and Salts / Q000097:blood*; D002780:Cholestasis, Intrahepatic / Q000097:blood / Q000235:genetics*; D004195:Disease Models, Animal; D005243:Feces / Q000737:chemistry; D005260:Female; D007082:Ileum / Q000378:metabolism; D008168:Lung / Q000648:ultrastructure; D008297:Male; D008810:Mice, Inbred C57BL; D011247:Pregnancy; D011248:Pregnancy Complications / Q000097:blood / Q000235:genetics*; D000077297:Pregnane X Receptor; D001261:Pulmonary Atelectasis / Q000209:etiology*; D011663:Pulmonary Surfactants; D011987:Receptors, Steroid / Q000235:genetics
chemical_list: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; C490549:Abcb11 protein, mouse; D001647:Bile Acids and Salts; C000625852:NR1I2 protein, human; C000625853:Nr1i2 protein, mouse; D000077297:Pregnane X Receptor; D011663:Pulmonary Surfactants; D011987:Receptors, Steroid