Maternal bile acid transporter deficiency promotes neonatal demise.

Yuanyuan Zhang,Aaron Pitre,Frank J Gonzalez,John D Schuetz,Geoffrey Neale,Christopher Calabrese,Yao Wang,Sharon Frase,Peter Vogel,Kristopher W Krausz,Charles O Rock,Fei Li,Matthew W Frank,Zhong-Ze Fang

doi:10.1038/ncomms9186

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.

Highlights

Intrahepatic cholestasis of pregnancy (ICP) is associated with adverse neonatal survival and is estimated to impact between 0.4 and 5% of pregnancies worldwide
With no history of liver disease, develop cholestasis during pregnancy that typically presents late in gestation. These women are diagnosed with intrahepatic cholestasis of pregnancy (ICP) and exhibit pruritus and elevated serum bile acids
We previously demonstrated that Abcb[11] À / À mice develop intrahepatic cholestasis[11]

Summary

Introduction

Intrahepatic cholestasis of pregnancy (ICP) is associated with adverse neonatal survival and is estimated to impact between 0.4 and 5% of pregnancies worldwide. 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. When mothers lack the nuclear receptor Nr1i2 (aka Pxr, a regulator of bile acid homoeostasis) and Abcb[11], maternal bile acids were reduced and neonatal survival was dramatically increased. These findings represent an important animal model to advance treatment and understanding of ICP, they reveal pathways that might be exploited to improve neonatal outcomes

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