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First published on February 15, 2006; DOI: 10.1124/mol.105.020792

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Received for publication November 14, 2005.
Revised February 15, 2006.
Accepted for publication February 15, 2006.

TRANSACTIVATION OF RAT ASBT AND INCREASED BILE ACID TRANSPORT BY 1{alpha},25-DIHYDROXYVITAMIN D3 VIA THE VITAMIN D RECEPTOR (VDR)

Xianghai Chen 1, Frank Chen 2, Shanjun Liu 3, Hartmut Glaeser 4, Paul A. Dawson 5, Alan F. Hofmann 6, Richard B Kim 4, Benjamin L. Shneider 7, K. Sandy Pang 8*

1 Department of Pharmacology, Faculty of Medicine, University of Toronto, Toronto, Canada 2 Department of Pediatrics, Mount Sinai School of Medicine, New York 3 Leslie Dan Faculty of Pharmacy, Univeristy of Toronto, Toronto, Canada 4 Division of Clinical Pharmacology, School of Medicine, Vanderbilt University, Nashville, TN 5 Wake Forest University School of Medicine, Winston-Salem, NC 6 Division of Gastroenterology, School of Medicine, University of California at San Diego, La Jolla 7 Division of Pediatric Hepatology, Department of Pediatrics, Mount Sinai School of Medicine, New York 8 Leslie Dan Faculty of Pharmacy, and Department of Pharmacology, University of Toronto

* Address correspondence to: E-mail: ks.pang{at}utoronto.ca

Abstract

Transactivation of the rat ASBT (apical sodium-dependent bile acid transporter, Slc10a2) by 1{alpha},25- dihydroxyvitamin D3, 1,25(OH) 2D3, via the vitamin D receptor (VDR), was studied. Levels of ASBT protein and mRNA were low in the duodenum and high in the ileum, and both were induced by 1,25(OH)2D3. The nuclear receptor protein, VDR, was present uniformly in the duodenum, jejunum, and ileum of the rat small intestine. The physiologic relevance of ASBT induction by 1,25(OH)2D3 was assessed by measuring absorption of cholylsarcosine, a non- metabolized synthetic bile acid analog, from duodenal or ileal closed-loops of the perfused rat small intestine preparation. Absorption of cholylsarcosine was much greater from the ileal segment (28-fold that of the duodenum under control conditions), and was enhanced with 1,25(OH)2D3 treatment. Transient transfection analysis of the rat ASBT promoter in Caco-2 cells revealed concentration-dependent enhancement of luciferase reporter activity after treatment with 1,25(OH)2D3. The activation by 1,25(OH)2D3 was abrogated after site-directed mutagenesis or deletion of the vitamin D response element (VDRE) in the ASBT promoter. Gel-shift mobility assays of nuclear extracts from rat ileum showed that both rat RXR and VDR were bound to the VDRE. The results indicate that rat ASBT gene expression is activated by 1,25(OH) 2D3 by specific binding to the VDRE, and that such activation enhances ileal bile acid transport. Human ABST mRNA and promoter activity were also increased in Caco-2 cells treated with 1,25(OH) 2D3, suggesting a physiological role of VDR in human ileal bile acid homeostasis.


Key words: Vitamin D, Regulation - transcriptional


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