title: Raised hepatic bile acid concentrations during pregnancy in mice are associated with reduced farnesoid X receptor function.
abstract: 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.
authors.affiliation: Department of Surgery and Cancer, Institute of Reproductive and Developmental Biology, London, United Kingdom.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Milona
authors.forename: Bryn M
authors.initials: BM
authors.lastname: Owen
authors.forename: Jeremy F L
authors.initials: JF
authors.lastname: Cobbold
authors.forename: Ellen C L
authors.initials: EC
authors.lastname: Willemsen
authors.forename: Isobel J
authors.initials: IJ
authors.lastname: Cox
authors.forename: Mohamed
authors.initials: M
authors.lastname: Boudjelal
authors.forename: William
authors.initials: W
authors.lastname: Cairns
authors.forename: Kristina
authors.initials: K
authors.lastname: Schoonjans
authors.forename: Simon D
authors.initials: SD
authors.lastname: Taylor-Robinson
authors.forename: Leo W J
authors.initials: LW
authors.lastname: Klomp
authors.forename: Malcolm G
authors.initials: MG
authors.lastname: Parker
authors.forename: Roger
authors.initials: R
authors.lastname: White
authors.forename: Saskia W C
authors.initials: SW
authors.lastname: van Mil
authors.forename: Catherine
authors.initials: C
authors.lastname: Williamson
mesh_terms: 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
chemical_list: 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