Abstract
Transporters involved in bile acid (BA) handling by the mammary gland are poorly understood. Here we have investigated the role of ABC proteins in blood-milk BA traffic and its sensitivity to maternal cholestasis. BA concentrations in rat and mouse serum were higher than in milk. BA profiles in both fluids were also different. In mammary gland, mRNA levels of ABC pumps transporting BAs were high for Bcrp, less abundant for Mrp1, Mrp3 and Mrp4 and negligible for Bsep and Mrp2. Milk BA concentrations were lower in Abcg2−/− than in wild-type mice. Taurocholate administration (5 µmol, i.p.) increased 20-fold BA concentrations in serum, but only moderately in milk, even in Abcg2−/− mice. Bile duct ligation (BDL) in pregnant rats markedly increased serum BA concentrations, which was not proportionally reflected in milk. In rat mammary tissue, Mrp4 was up-regulated by BDL. Serum BA levels were 2-fold higher in 10-day-old neonates of the BDL group, whereas their body weight was lower. The exchange of breastfeeding mothers immediately after birth reverted the situation without changes in endogenous BA synthesis. In conclusion, Bcrp is involved in BA secretion into milk, whereas Mrp4 participates in a blood-milk barrier that protects neonates from maternal hypercholanemia during breastfeeding.
Highlights
Intrahepatic cholestasis of pregnancy (ICP) is the most frequent pregnancy-specific liver disease[1]
The results of the present study support the hypothesis that ATP-binding cassette (ABC) proteins are involved in the secretory/barrier function for bile acid (BA) across the mammary epithelium in an asymmetric manner, i.e., BCRP/Bcrp may play a moderate role in BA secretion into milk, whereas MRP4/Mrp[4] is involved in a strong barrier limiting BA traffic from blood to milk even in the presence of maternal hypercholanemia
Regarding BAs, which are transported by this pump[24], we found a moderate dependence of BA secretion on the expression of Bcrp in mouse mammary gland
Summary
Intrahepatic cholestasis of pregnancy (ICP) is the most frequent pregnancy-specific liver disease[1]. The signs and symptoms of ICP resolve within 2–4 weeks after delivery[16], it is not known whether high levels of BAs in milk persist in ICP patients during early lactation and how this might affect neonatal BA homeostasis This is important, for instance, because the BA composition and concentration of breast milk may influence the microbiota present in milk and thereby affect the development of gut microbiota in the lactating newborn[17]. Te goal of the present study was to investigate the role of ABC pumps in the traffic of BAs across the mammary gland and the effect of maternal hypercholanemia on BA secretion into milk To achieve this aim, two animal models were used: i) lactating rats with or without obstructive cholestasis during pregnancy, to mimic maternal hypercholanemia present in ICP patients, and ii) lactating wild-type and Bcrp knockout (Abcg2−/−) mice, for assessing the overall contribution of Bcrp to BA secretion into milk
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