Fxr-activating Ligands Inhibit Rabbit Asbt Expression Via Fxr-shp-ftf Cascade

Title

Fxr-activating Ligands Inhibit Rabbit Asbt Expression Via Fxr-shp-ftf Cascade

Creator

Li H; Chen F; Shang Q; Pan L X; Shneider B L; Chiang J Y L; Forman B M; Ananthanarayanan M; Tint G S; Salen G; Xu G R

Publisher

American Journal of Physiology-Gastrointestinal and Liver Physiology

Date

2005
2005-01

Description

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.

Subject

bile-acid transporter; cloning; down-regulation; Gastroenterology & Hepatology; identification; ileal; messenger-rna; negative feedback-regulation; nuclear receptor; Physiology; rats; real-time

Format

Journal Article or Conference Abstract Publication

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Rights

Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).

Pages

G60-G66

Issue

1

Volume

288

Citation

Li H; Chen F; Shang Q; Pan L X; Shneider B L; Chiang J Y L; Forman B M; Ananthanarayanan M; Tint G S; Salen G; Xu G R, “Fxr-activating Ligands Inhibit Rabbit Asbt Expression Via Fxr-shp-ftf Cascade,” NEOMED Bibliography Database, accessed August 5, 2021, https://neomed.omeka.net/items/show/10723.

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