Raised hepatic bile acid concentrations during pregnancy in mice are associated with reduced farnesoid X receptor function.
Pregnancy alters bile acid homeostasis and can unmask cholestatic disease in genetically predisposed but otherwise asymptomatic individuals. In this report, we show that normal pregnant mice have raised hepatic bile acid levels in the presence of procholestatic gene expression. The nuclear receptor farnesoid X receptor (FXR) regulates the transcription of the majority of these genes, and we show that both ablation and activation of Fxr prevent the accumulation of hepatic bile acids during pregnancy. These observations suggest that the function of Fxr may be perturbed during gestation. In subsequent in vitro experiments, serum from pregnant mice and humans was found to repress expression of the Fxr target gene, small heterodimer partner (Shp), in liver-derived Fao cells. Estradiol or estradiol metabolites may contribute to this effect because coincubation with the estrogen receptor (ER) antagonist fulvestrant (ICI 182780) abolished the repressive effects on Shp expression. Finally, we report that ERα interacts with FXR in an estradiol-dependent manner and represses its function in vitro.


CONCLUSIONS
Ligand-activated ERα may inhibit FXR function during pregnancy and result in procholestatic gene expression and raised hepatic bile acid levels. We propose that this could cause intrahepatic cholestasis of pregnancy in genetically predisposed individuals.
Milona
Alexandra
A
Department of Surgery and Cancer, Institute of Reproductive and Developmental Biology, London, United Kingdom.
Owen
Bryn M
BM
Cobbold
Jeremy F L
JF
Willemsen
Ellen C L
EC
Cox
Isobel J
IJ
Boudjelal
Mohamed
M
Cairns
William
W
Schoonjans
Kristina
K
Taylor-Robinson
Simon D
SD
Klomp
Leo W J
LW
Parker
Malcolm G
MG
White
Roger
R
van Mil
Saskia W C
SW
Williamson
Catherine
C
D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors / Q000378:metabolism; D005260:Female; D000077267:Fulvestrant; D020869:Gene Expression Profiling; D006801:Humans; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000097:blood / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis / Q000502:physiology*; D000099150:Receptor, Farnesoid X-Activated
D001647:Bile Acids and Salts; D004958:Estradiol; D047628:Estrogen Receptor alpha; D000077267:Fulvestrant; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated; C099713:nuclear receptor subfamily 0, group B, member 2