title: FXR-activating ligands inhibit rabbit ASBT expression via FXR-SHP-FTF cascade.
abstract: The regulation of the rabbit apical sodium-dependent bile acid transporter (ASBT) was studied both in vivo and in vitro. New Zealand White rabbits were fed 0.5% deoxycholic acid (DCA) or SC-435, a competitive ASBT inhibitor, for 1 wk. In DCA-fed rabbits, ASBT expression was repressed, associated with activated FXR, and evidenced by increased ileal short heterodimer partner (SHP) mRNA. Feeding SC-435 to the rabbits blocked bile acid absorption, decreased SHP mRNA, and increased ASBT expression. A 1.9-kb rabbit ASBT 5'-flanking region (promoter) was cloned, and a cis-acting element for alpha-fetoprotein transcription factor (FTF) was identified (-1166/-1158). The effects of transcriptional factors and different bile acids on the rabbit ASBT promoter were studied in Caco-2 cells. FTF stimulated the rabbit ASBT promoter activity fourfold but not after the FTF binding site was deleted from the promoter. Increasing the SHP protein notably inhibited FTF-dependent trans-activation of rabbit ASBT. Adding hydrophobic bile acids deoxycholic acid, chenodeoxycholic acid, and cholic acid, activating ligands for FXR, inhibited rabbit ASBT promoter activity in Caco-2 cells, but this inhibitory effect was abolished after the FTF binding site was deleted. Ursodeoxycholic acid and ursocholic acid, nonactivating ligands for FXR, did not repress ASBT promoter activity. Thus the rabbit ASBT promoter is negative-feedback regulated by bile acids via a functional FTF binding site. Only FXR-activating ligands can downregulate rabbit ASBT expression through the regulatory cascade FXR-SHP-FTF.
authors.affiliation: Department of Medicine, University fo Medicine and Dentistry of New Jersey, Newark, New Jersey, USA.
authors.forename: Hai
authors.initials: H
authors.lastname: Li
authors.forename: Frank
authors.initials: F
authors.lastname: Chen
authors.forename: Quan
authors.initials: Q
authors.lastname: Shang
authors.forename: Luxing
authors.initials: L
authors.lastname: Pan
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Shneider
authors.forename: John Y L
authors.initials: JY
authors.lastname: Chiang
authors.forename: Barry M
authors.initials: BM
authors.lastname: Forman
authors.forename: M
authors.initials: M
authors.lastname: Ananthanarayanan
authors.forename: G Stephen
authors.initials: GS
authors.lastname: Tint
authors.forename: Gerald
authors.initials: G
authors.lastname: Salen
authors.forename: Guorong
authors.initials: G
authors.lastname: Xu
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000494:pharmacology; D018938:Caco-2 Cells; D002352:Carrier Proteins / Q000096:biosynthesis* / Q000235:genetics* / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000494:pharmacology*; D003840:Deoxycholic Acid / Q000494:pharmacology; D015536:Down-Regulation; D006801:Humans; D008024:Ligands; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis* / Q000235:genetics* / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D011817:Rabbits; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology; D014157:Transcription Factors / Q000494:pharmacology*; D000509:alpha-Fetoproteins; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D001647:Bile Acids and Salts; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D003840:Deoxycholic Acid; D008024:Ligands; D008562:Membrane Glycoproteins; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D000509:alpha-Fetoproteins; D000099150:Receptor, Farnesoid X-Activated; C037643:bile acid binding proteins; C099713:nuclear receptor subfamily 0, group B, member 2