title: Intrahepatic cholestasis of pregnancy levels of sulfated progesterone metabolites inhibit farnesoid X receptor resulting in a cholestatic phenotype.
abstract: 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 3α-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 3β-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, coadministration 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 cofactor recruitment assays, we show that epiallopregnanolone sulfate competitively inhibits bile acid-mediated recruitment of cofactor motifs to the FXR-ligand binding domain.
  
  
  CONCLUSIONS
  Our results reveal a novel molecular interaction between ICP-associated levels of the 3β-sulfated progesterone metabolite epiallopregnanolone sulfate and FXR that couples the endocrine component of pregnancy in ICP to abnormal bile acid homeostasis.
authors.affiliation: Institute of Reproductive and Developmental Biology, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, UK.
authors.forename: Shadi
authors.initials: S
authors.lastname: Abu-Hayyeh
authors.forename: Georgia
authors.initials: G
authors.lastname: Papacleovoulou
authors.forename: Anita
authors.initials: A
authors.lastname: Lövgren-Sandblom
authors.forename: Mehreen
authors.initials: M
authors.lastname: Tahir
authors.forename: Olayiwola
authors.initials: O
authors.lastname: Oduwole
authors.forename: Nurul Akmal
authors.initials: NA
authors.lastname: Jamaludin
authors.forename: Sabiha
authors.initials: S
authors.lastname: Ravat
authors.forename: Vanya
authors.initials: V
authors.lastname: Nikolova
authors.forename: Jenny
authors.initials: J
authors.lastname: Chambers
authors.forename: Clare
authors.initials: C
authors.lastname: Selden
authors.forename: Myrddin
authors.initials: M
authors.lastname: Rees
authors.forename: Hanns-Ulrich
authors.initials: HU
authors.lastname: Marschall
authors.forename: Malcolm G
authors.initials: MG
authors.lastname: Parker
authors.forename: Catherine
authors.initials: C
authors.lastname: Williamson
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D002779:Cholestasis / Q000139:chemically induced; D002780:Cholestasis, Intrahepatic / Q000378:metabolism*; D019826:Cholic Acid; D005260:Female; D006706:Homeostasis; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D010641:Phenotype; D011247:Pregnancy; D011248:Pregnancy Complications / Q000378:metabolism*; D011280:Pregnanolone / Q000031:analogs & derivatives* / Q000097:blood; D011374:Progesterone / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000037:antagonists & inhibitors*; D013463:Sulfuric Acid Esters / Q000097:blood*; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D001647:Bile Acids and Salts; D019826:Cholic Acid; D011280:Pregnanolone; D011374:Progesterone; D018160:Receptors, Cytoplasmic and Nuclear; D013463:Sulfuric Acid Esters; D000099150:Receptor, Farnesoid X-Activated; C579439:epiallopregnanolone sulfate