Abstract
Background. Significant physiological changes occur during pregnancy and lactation. Intrahepatic cholestasis of pregnancy (ICP) is a liver disease closely related to disruption of bile acid homeostasis. The objective of this study was to examine the regulation of bile acid synthesis and transport in normal pregnant and lactating rats.Materials and Methods. Livers from timed pregnant SD rats were collected on gestational days (GD) 10, 14 and 19, and postnatal days (PND) 1, 7, 14 and 21. Total bile acids were determined by the enzymatic method, total RNA was isolated and subjected to real time RT-PCR analysis. Liver protein was extracted for western-blot analysis.Results. Under physiological conditions hepatic bile acids were not elevated during pregnancy but increased during lactation in rats. Bile acid synthesis rate-limiting enzyme Cyp7a1 was unchanged on gestational days, but increased on PND14 and 21 at mRNA and protein levels. Expression of Cyp8b1, Cyp27a1 and Cyp7b1 was also higher during lactation. The mRNA levels of small heterodimer partner (SHP) and protein levels of farnesoid X receptor (FXR) were increased during pregnancy and lactation. Bile acid transporters Ntcp, Bsep, Mrp3 and Mrp4 were lower at gestation, but increased during lactation. Hepatic Oatp transporters were decreased during pregnancy and lactation.Conclusion. Hepatic bile acid homeostasis is maintained during normal pregnancy in rats, probably through the FXR-SHP regulation. The expression of bile acid synthesis genes and liver bile acid accumulation were increased during lactation, together with increased expression of bile acid efflux transporter Bsep, Mrp3 and Mrp4.
Highlights
Significant physiological changes occur during pregnancy and lactation to support the nutritional demands of the developing fetus and lactating pups (Carlin & Alfirevic, 2008; Athippozhy et al, 2011)
This study was initiated to investigate bile acid metabolism and transport gene expressions in pregnant and lactating rats, and the results suggest that under physiological conditions, farnesoid X receptor (FXR)-small heterodimer partner (SHP) regulation might play a role in bile acid homeostasis in pregnant and lactating rats
Liver bile acid levels in pregnant and lactating rats Bile acids were quantified in livers from control and pregnant rats at GD10, 14, and 19 and postnatal days (PND) 1, 7, 14, and 21
Summary
Significant physiological changes occur during pregnancy and lactation to support the nutritional demands of the developing fetus and lactating pups (Carlin & Alfirevic, 2008; Athippozhy et al, 2011). (Wooton-Kee, Cohen & Vore, 2008; Athippozhy et al, 2011; Abu-Hayyeh, Papacleovoulou & Williamson, 2013) Such physiological changes would affect hepatic drug processing genes of phase-1, phase-2 metabolism and transporters (Aleksunes et al, 2012; Shuster et al, 2013). Recent work suggests that in pregnant mice farnesoid X receptor (FXR)-SHP (small heterodimer partner, NR0B2) regulation could be dysfunctional in its ability to downregulate the rate-limiting bile acid synthetic enzyme Cyp7a1 and 8b1, resulting in bile acids accumulation in the liver of late pregnancy mice (Milona et al, 2010; Aleksunes et al, 2012). Hepatic bile acid homeostasis is maintained during normal pregnancy in rats, probably through the FXR-SHP regulation. The expression of bile acid synthesis genes and liver bile acid accumulation were increased during lactation, together with increased expression of bile acid efflux transporter Bsep, Mrp and Mrp
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