Imperial College London
Dr Olayiwola Oduwole

DrOlayiwolaOduwole

Faculty of Medicine, Department of Metabolism, Digestion and Reproduction

Honorary Research Fellow
 
 
 
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Contact

 

+44 (0)20 7594 2173o.oduwole

 
 
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Location

 

Institute of Reproductive and Developmental BiologyHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Abu-Hayyeh:2012:10.1002/hep.26055,
author = {Abu-Hayyeh, S and Papacleovoulou, G and Lovgren-Sandblom, A and Tahir, M and Oduwole, O and Jamaludin, NA and Ravat, S and Nikolova, V and Chambers, J and Selden, C and Rees, M and Marschall, HU and Parker, MG and Williamson, C},
doi = {10.1002/hep.26055},
journal = {Hepatology},
title = {Intrahepatic cholestasis of pregnancy levels of sulfated progesterone metabolites inhibit FXR resulting in a pro-cholestatic phenotype},
url = {http://dx.doi.org/10.1002/hep.26055},
year = {2012}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - Intrahepatic cholestasis of pregnancy (ICP) is the most prevalent pregnancy-specific liver disease and is associated with an increased risk of adverse fetal outcomes, including preterm labor and intrauterine death. The endocrine signals that cause cholestasis are not known but 3alpha-sulfated progesterone metabolites have been shown to be elevated in ICP leading us to study the impact of sulfated progesterone metabolites on farnesoid x receptor (FXR) mediated bile acid homeostasis pathways. Here we report that the 3beta-sulfated progesterone metabolite epiallopregnanolone sulfate is supraphysiologically raised in the serum of ICP patients. Mice challenged with cholic acid developed hypercholanemia and a hepatic gene expression profile indicative of FXR activation. However, co-administration of epiallopregnanolone sulfate with cholic acid exacerbated the hypercholanemia and resulted in aberrant gene expression profiles for hepatic bile acid-responsive genes consistent with cholestasis. We demonstrate that levels of epiallopregnanolone sulfate found in ICP can function as a partial agonist for FXR,resulting in the aberrant expression of bile acid homeostasis genes in hepatoma cell lines and primary human hepatocytes. Furthermore, epiallopregnanolone sulfate inhibition of FXR results in reduced FXR-mediated bile acid efflux and secreted FGF19. Using co-factor recruitment assays, we show that epiallopregnanolone sulfate competitively inhibits bile acid-mediated recruitment of co-factor motifs to the FXR-ligand binding domain. Conclusion: Our results reveal a novel molecular interaction between ICP-associated levels of the 3beta-sulfated progesterone metabolite epiallopregnanolone sulfate and FXR that couples the endocrine component of pregnancy in ICP to abnormal bile acid homeostasis. (HEPATOLOGY 2012.)
AU  - Abu-Hayyeh,S
AU  - Papacleovoulou,G
AU  - Lovgren-Sandblom,A
AU  - Tahir,M
AU  - Oduwole,O
AU  - Jamaludin,NA
AU  - Ravat,S
AU  - Nikolova,V
AU  - Chambers,J
AU  - Selden,C
AU  - Rees,M
AU  - Marschall,HU
AU  - Parker,MG
AU  - Williamson,C
DO  - 10.1002/hep.26055
PY  - 2012///
TI  - Intrahepatic cholestasis of pregnancy levels of sulfated progesterone metabolites inhibit FXR resulting in a pro-cholestatic phenotype
T2  - Hepatology
UR  - http://dx.doi.org/10.1002/hep.26055
UR  - pm:22961653
ER  -
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