title: Transcriptional dynamics of bile salt export pump during pregnancy: mechanisms and implications in intrahepatic cholestasis of pregnancy.
abstract: Bile salt export pump (BSEP) is responsible for biliary secretion of bile acids, a rate-limiting step in the enterohepatic circulation of bile acids and transactivated by nuclear receptor farnesoid X receptor (FXR). Intrahepatic cholestasis of pregnancy (ICP) is the most prevalent disorder among diseases unique to pregnancy and primarily occurs in the third trimester of pregnancy, with a hallmark of elevated serum bile acids. Currently, the transcriptional regulation of BSEP during pregnancy and its underlying mechanisms and involvement in ICP are not fully understood. In this study the dynamics of BSEP transcription in vivo in the same group of pregnant mice before, during, and after gestation were established with an in vivo imaging system (IVIS). BSEP transcription was markedly repressed in the later stages of pregnancy and immediately recovered after parturition, resembling the clinical course of ICP in human. The transcriptional dynamics of BSEP was inversely correlated with serum 17β-estradiol (E2) levels before, during, and after gestation. Further studies showed that E2 repressed BSEP expression in human primary hepatocytes, Huh 7 cells, and in vivo in mice. Such transrepression of BSEP by E2 in vitro and in vivo required estrogen receptor α (ERα). Mechanistic studies with chromatin immunoprecipitation (ChIP), protein coimmunoprecipitation (Co-IP), and bimolecular fluorescence complementation (BiFC) assays demonstrated that ERα directly interacted with FXR in living cells and in vivo in mice.
  
  
  CONCLUSIONS
  BSEP expression was repressed by E2 in the late stages of pregnancy through a nonclassical E2/ERα transrepressive pathway, directly interacting with FXR. E2-mediated repression of BSEP expression represents an etiological contributing factor to ICP and therapies targeting the ERα/FXR interaction may be developed for prevention and treatment of ICP.
authors.affiliation: Department of Biomedical and Pharmaceutical Sciences, Center for Pharmacogenomics and Molecular Therapy, College of Pharmacy, University of Rhode Island, Kingston, RI.
authors.forename: Xiulong
authors.initials: X
authors.lastname: Song
authors.forename: Alexander
authors.initials: A
authors.lastname: Vasilenko
authors.forename: Yuan
authors.initials: Y
authors.lastname: Chen
authors.forename: Leila
authors.initials: L
authors.lastname: Valanejad
authors.forename: Ruchi
authors.initials: R
authors.lastname: Verma
authors.forename: Bingfang
authors.initials: B
authors.lastname: Yan
authors.forename: Ruitang
authors.initials: R
authors.lastname: Deng
mesh_terms: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D002780:Cholestasis, Intrahepatic / Q000378:metabolism*; D004958:Estradiol / Q000097:blood; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008099:Liver / Q000378:metabolism; D051379:Mice; D011247:Pregnancy; D011248:Pregnancy Complications / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; D004958:Estradiol; D047628:Estrogen Receptor alpha; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated; C093491:ABCB11 protein, human; C490549:Abcb11 protein, mouse
references.citation: Annu Rev Physiol. 2002;64:635-61
references.pmid: 11826283
references.citation: Ethn Health. 1999 Feb-May;4(1-2):35-7
references.pmid: 10887460
references.citation: Ann Intern Med. 1978 Apr;88(4):487-93
references.pmid: 637428
references.citation: Lancet. 2010 Feb 13;375(9714):594-605
references.pmid: 20159293
references.citation: Gastroenterology. 2007 Aug;133(2):507-16
references.pmid: 17681172
references.citation: Obstet Gynecol. 2000 Mar;95(3):372-6
references.pmid: 10711547
references.citation: J Biol Chem. 2001 Aug 3;276(31):28857-65
references.pmid: 11387316
references.citation: Expert Opin Drug Metab Toxicol. 2011 Apr;7(4):411-25
references.pmid: 21320040
references.citation: Hepatology. 2009 Nov;50(5):1588-96
references.pmid: 19821532
references.citation: J Lipid Res. 2008 May;49(5):973-84
references.pmid: 18270374
references.citation: Hepatology. 2004 Aug;40(2):467-74
references.pmid: 15368452
references.citation: Breast Cancer Res Treat. 2008 Jan;107(1):49-61
references.pmid: 17333335
references.citation: Annu Rev Biophys. 2008;37:465-87
references.pmid: 18573091
references.citation: Physiol Rev. 2001 Oct;81(4):1535-65
references.pmid: 11581496
references.citation: J Biol Chem. 2006 Jun 16;281(24):16625-31
references.pmid: 16606610
references.citation: J Mol Endocrinol. 2008 Nov;41(5):263-75
references.pmid: 18772268
references.citation: Eur J Clin Nutr. 2000 Mar;54 Suppl 1:S47-51
references.pmid: 10805038
references.citation: Trends Endocrinol Metab. 2011 Nov;22(11):458-66
references.pmid: 21862343
references.citation: Acta Gastroenterol Belg. 2012 Dec;75(4):389-98
references.pmid: 23402081
references.citation: Hepatology. 2013 Feb;57(2):716-26
references.pmid: 22961653
references.citation: Gastroenterology. 2004 Jan;126(1):322-42
references.pmid: 14699511
references.citation: Semin Liver Dis. 2010 May;30(2):125-33
references.pmid: 20422495
references.citation: Hepatology. 2002 Mar;35(3):589-96
references.pmid: 11870371
references.citation: Clin Chim Acta. 1983 May 30;130(2):171-6
references.pmid: 6872255
references.citation: J Lipid Res. 2009 Oct;50(10):1955-66
references.pmid: 19346330
references.citation: J Pharmacol Exp Ther. 2007 Mar;320(3):1153-62
references.pmid: 17135343
references.citation: Gastroenterology. 2000 Feb;118(2):422-30
references.pmid: 10648470
references.citation: World J Gastroenterol. 2009 May 7;15(17):2049-66
references.pmid: 19418576
references.citation: Br J Obstet Gynaecol. 1981 Mar;88(3):240-5
references.pmid: 7470414
references.citation: PLoS One. 2012;7(3):e28343
references.pmid: 22403605
references.citation: Hepatology. 2013 Apr;57(4):1530-41
references.pmid: 23213087
references.citation: Mol Cell Endocrinol. 2013 Apr 10;368(1-2):120-8
references.pmid: 23159988
references.citation: Dig Dis. 2010;28(1):220-4
references.pmid: 20460915
references.citation: Hepatology. 2010 Oct;52(4):1341-9
references.pmid: 20842631
references.citation: J Lipid Res. 2013 Nov;54(11):3030-44
references.pmid: 24002920
references.citation: J Pharmacol Exp Ther. 2006 Apr;317(1):317-25
references.pmid: 16371446
references.citation: Toxicol Sci. 2012 Dec;130(2):257-68
references.pmid: 22903823
references.citation: Hepatology. 2008 Mar;47(3):1067-76
references.pmid: 18265410
references.citation: Clin Lab. 2007;53(3-4):173-7
references.pmid: 17447654
references.citation: Gastroenterology. 1986 Oct;91(4):825-9
references.pmid: 3743960