From left: John Schuetz, PhD; Aaron Pitre, PhD; and Yao Wang
St. Jude Children’s Research Hospital scientists have a lead on reducing life-threatening respiratory problems in infants born to women who develop the liver disorder intrahepatic cholestasis of pregnancy (ICP). The research appears today in the scientific journal Nature Communications.
ICP develops during the second or third trimester of pregnancy and affects from 0.4 to 5 percent of pregnant women worldwide. The disorder occurs when liver function is disrupted due to impaired secretion of the digestive fluid bile from liver cells. The incidence is influenced by a variety of factors including ancestry, environment, diet, medications and genetics.
For women, the bile buildup leads to intense itchiness that usually resolves within days of delivery. The risk to newborns, however, is more serious. The disorder is associated with stillbirth and premature delivery. About 30 percent of babies born to mothers with ICP develop respiratory distress, which proves fatal in about 3.5 percent of infants.
Working in a mouse model of the human disease, researchers showed that reducing the reabsorption of bile acid in the intestines dramatically improved survival of newborn mice.
“In mice, even a 30 or 40 percent reduction in bile acid reabsorbed in the intestines and returned to the liver resulted in survival increasing from zero to 64 percent,” said corresponding author John Schuetz, Ph.D., member and vice-chair of the St. Jude Department of Pharmaceutical Sciences. “This study raises hopes that it might be possible to protect at-risk infants by developing drugs that block bile acid reabsorption in mothers.”
Schuetz and his colleagues were working on a different project when they realized they could model human ICP in mice by deleting both copies of the Abcb11 gene in female mice. The loss led to impaired release of bile from the liver, elevated blood levels of bile acid and newborn mortality, which are all characteristics of ICP in humans. Bile acid is a component of bile and aids in the digestion and absorption of fats and related vitamins.
Using the mouse model, researchers demonstrated for the first time that bile acid crosses the placenta. Bile acid blood levels were 420 percent higher in the offspring of female mice lacking Abcb11 compared to the offspring of mice without the defect. Evidence suggested the elevated blood levels leads bile acid to accumulate in the animals’ lungs.
Tests showed the lungs of mice born to mice that lacked Abcb11 developed normally. However, the air sacs or alveoli did not inflate, and the mice died within 24 hours. A closer look at their lungs revealed structural changes in surfactant, the molecule that coats and helps keeps alveoli inflated. Researchers showed that at high levels, the primary bile acid elevated in human ICP disrupted the structure of surfactant.
A protein named PXR provided additional insight into ICP. PXR belongs to a family of nuclear receptor proteins involved in the regulation of bile acid metabolism and transportation. The Nrli2 gene carries instructions for PXR, which was the only nuclear receptor protein that increased in the mouse model of ICP.
Investigators found that deleting both copies of Nrli2 led to a 39 percent reduction in blood levels of bile acid in pregnant mice lacking Abcb11. The reduction was coupled with a 64 percent increase in survival of the resulting newborn mice. Nrli2 deletion also led to a significant reduction in three proteins involved in the reabsorption and transport of bile acids from the intestine to the liver.
“The results suggest that it might be possible to develop drugs to block reabsorption of bile acid in the intestines, thus lowering bile acid concentrations in maternal blood and hopefully the risk of newborn respiratory distress as well,” Schuetz said.
The first author is Yuanyuan Zhang, formerly of St. Jude. The other authors are Yao Wang, Aaron Pitre, Matthew Frank, Christopher Calabrese, Geoffrey Neale, Sharon Frase, Peter Vogel and Charles Rock, all of St. Jude; and Fei Li, Zhong-ze Fang, Kristopher Krausz and Frank Gonzalez, all of the Laboratory of Metabolism, National Cancer Institute (NCI), Bethesda, Md.
The research was supported in part by grants (HL114066, GM60904, GM034496) from the National Institutes of Health (NIH); a grant (CA021765) from the NCI, at the NIH; and ALSAC.
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