HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 280, Issue 24, 23232-23242, June 17, 2005

This Article Full Text Full Text (PDF) All Versions of this Article: 280/24/23232    most recent M411520200v2 M411520200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by McCarthy, T. C. Articles by Sinal, C. J. Search for Related Content PubMed PubMed Citation Articles by McCarthy, T. C. Articles by Sinal, C. J. Social Bookmarking                      What's this?

Vitamin D Receptor-dependent Regulation of Colon Multidrug Resistance-associated Protein 3 Gene Expression by Bile Acids^*

Tanya C. McCarthy, Xiufeng Li, and Christopher J. Sinal

From the Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia B3H 1X5, Canada

The multidrug resistance-associated protein 3 (MRP3) is a multispecific anion transporter that is capable of transporting a number of conjugated and unconjugated bile acids. Expression of the MRP3 gene is increased during pathological states associated with elevated bile acid concentrations indicating a role for this transporter in adaptive and homeostatic bile acid metabolism. Analysis of Mrp3 mRNA levels in various mouse tissues with known relevance and/or exposure to bile acids revealed the highest levels of basal expression in the colon followed in order by the liver, duodenum, jejunum, ileum, and kidney. Functional analysis of a murine Mrp3 promoter reporter construct revealed vitamin D receptor (VDR)-dependent activation by 1,25-dihydroxyvitamin D₃ (VD3), 9-cis-retinoic acid (RA), and the cholestatic secondary bile acid, lithocholic acid (LCA). Using a series of deletion constructs combined with sequence analysis, a candidate VDR response element (VDRE) was identified between -1028 and -1014 bp of the Mrp3 promoter. Activation of the Mrp3 promoter in response to VD3, RA, or LCA, as well as binding of VDR/RXR heterodimers, was attenuated substantially by mutation of this VDRE. Treatment of mice with VD3 or LCA demonstrated in vivo modulation of the Mrp3 gene in colon but not in the liver. Reduction of endogenous VDR expression in colon adenocarcinoma MCA-38 cells by siRNA transfection was associated with reduced constitutive and inducible expression of the Mrp3 gene. These data support a regulatory role for the VDR in the protection of colon cells from bile acid toxicity through regulation of the Mrp3 expression.

Received for publication, October 8, 2004 , and in revised form, March 10, 2005.

^* This work was supported by a grant from the Canadian Institutes for Health Research. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Pharmacology, Dalhousie University, 5850 College St., Halifax, Nova Scotia B3H 1X5, Canada. Tel.: 902-494-2347; Fax: 902-494-1388; E-mail: csinal{at}dal.ca.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				X. Chen, F. Chen, S. Liu, H. Glaeser, P. A. Dawson, A. F. Hofmann, R. B. Kim, B. L. Shneider, and K. S. Pang Transactivation of Rat Apical Sodium-Dependent Bile Acid Transporter and Increased Bile Acid Transport by 1{alpha},25-Dihydroxyvitamin D3 via the Vitamin D Receptor Mol. Pharmacol., June 1, 2006; 69(6): 1913 - 1923. [Abstract] [Full Text] [PDF]

				E. A. Hanniman, G. Lambert, T. C. McCarthy, and C. J. Sinal Loss of functional farnesoid X receptor increases atherosclerotic lesions in apolipoprotein E-deficient mice J. Lipid Res., December 1, 2005; 46(12): 2595 - 2604. [Abstract] [Full Text] [PDF]