Farnesoid X receptor and bile salts are involved in transcriptional regulation of the gene encoding the human bile salt export pump

Jacqueline R M Plass, Olaf Mol, Janette Heegsma, Mariska Geuken, Klaas Nico Faber, Peter L M Jansen, Michael Müller

Research output: Contribution to journalArticle

203 Citations (Scopus)

Abstract

The bile salt export pump (BSEP or ABCB11) mediates the adenosine triphosphate-dependent transport of bile salts across the canalicular membrane of the hepatocyte. Mutations in the corresponding ABCB11 gene cause progressive familial intrahepatic cholestasis type 2. The aim of this study was to investigate the regulation of human ABCB11 gene transcription by bile salts. First, a 1.7-kilobase human ABCB11 promoter region was cloned. Sequence analysis for possible regulatory elements showed a farnesoid X receptor responsive element (FXRE) at position minus sign180. The farnesoid X receptor (FXR) functions as a heterodimer with the retinoid X receptor alpha (RXRalpha) and can be activated by the bile salt chenodeoxycholic acid (CDCA). Luciferase reporter gene assays showed that the ABCB11 promoter is positively controlled by FXR, RXRalpha, and bile salts in a concentration-dependent manner. Mutation of the FXRE strongly represses the FXR-dependent induction. Second, endogenous ABCB11 transcription regulation was studied in HepG2 cells, stably expressing the rat sodium-dependent taurocholate transporter (rNtcp) cells. ABCB11 expression was induced by adding bile salts to the culture medium, and this effect was maximized by combining it with cotransfection of rFxr and hRXRalpha. Reducing endogenous FXR levels using RNA interference fully repressed the bile salt-induced ABCB11 expression. In conclusion, these results show that FXR is required for the bile salt-dependent transcriptional control of the human ABCB11 gene and that the cellular amount of FXR is critical for the level of activation of ABCB11 transcription.
Original languageEnglish
Pages (from-to)589-96
Number of pages8
JournalHepatology
Volume35
Issue number3
DOIs
Publication statusPublished - Mar 2002

Keywords

  • ATP-Binding Cassette Transporters
  • Base Sequence
  • Chenodeoxycholic Acid
  • Cloning, Molecular
  • DNA-Binding Proteins
  • Humans
  • Molecular Sequence Data
  • Promoter Regions, Genetic
  • RNA, Messenger
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Retinoic Acid
  • Response Elements
  • Retinoid X Receptors
  • Transcription Factors
  • Transcription, Genetic
  • Tumor Cells, Cultured

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