| Raised hepatic bile acid concentrations during pregnancy in mice are associated with reduced farnesoid X receptor function. | |
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MedLine Citation:
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PMID: 20842631 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Alexandra Milona; Bryn M Owen; Jeremy F L Cobbold; Ellen C L Willemsen; Isobel J Cox; Mohamed Boudjelal; William Cairns; Kristina Schoonjans; Simon D Taylor-Robinson; Leo W J Klomp; Malcolm G Parker; Roger White; Saskia W C van Mil; Catherine Williamson |
Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Hepatology (Baltimore, Md.) Volume: 52 ISSN: 1527-3350 ISO Abbreviation: Hepatology Publication Date: 2010 Oct |
Date Detail:
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Created Date: 2010-09-29 Completed Date: 2010-10-18 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 8302946 Medline TA: Hepatology Country: United States |
Other Details:
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Languages: eng Pagination: 1341-9 Citation Subset: IM |
Affiliation:
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Department of Surgery and Cancer, Institute of Reproductive and Developmental Biology, London, United Kingdom. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Bile Acids and Salts / metabolism* Estradiol / analogs & derivatives, pharmacology Estrogen Receptor alpha / antagonists & inhibitors, metabolism Female Gene Expression Profiling Humans Liver / metabolism* Mice Mice, Inbred C57BL Pregnancy Pregnancy, Animal / blood, physiology* RNA, Messenger / metabolism Receptors, Cytoplasmic and Nuclear / biosynthesis, physiology* |
| Grant Support | |
ID/Acronym/Agency:
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//Biotechnology and Biological Sciences Research Council |
| Chemical | |
Reg. No./Substance:
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0/Bile Acids and Salts; 0/Estrogen Receptor alpha; 0/RNA, Messenger; 0/Receptors, Cytoplasmic and Nuclear; 0/farnesoid X-activated receptor; 0/nuclear receptor subfamily 0, group B, member 2; 129453-61-8/fulvestrant; 50-28-2/Estradiol |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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