Premium
Raised hepatic bile acid concentrations during pregnancy in mice are associated with reduced farnesoid X receptor function
Author(s) -
Milona Alexandra,
Owen Bryn M.,
Cobbold Jeremy F. L.,
Willemsen Ellen C. L.,
Cox Isobel J.,
Boudjelal Mohamed,
Cairns William,
Schoonjans Kristina,
TaylorRobinson Simon D.,
Klomp Leo W. J.,
Parker Malcolm G.,
White Roger,
van Mil Saskia W. C.,
Williamson Catherine
Publication year - 2010
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.23849
Subject(s) - farnesoid x receptor , bile acid , pregnancy , medicine , endocrinology , hepatic function , chemistry , gastroenterology , nuclear receptor , biology , biochemistry , genetics , transcription factor , gene
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 . Conclusion: 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. H EPATOLOGY 2010