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J. Biol. Chem., Vol. 282, Issue 30, 21653-21661, July 27, 2007

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Regulation of the Sodium/Sulfate Co-transporter by Farnesoid X Receptor ^*

Hans Lee, Melissa L. Hubbert, Timothy F. Osborne^¶, Katherine Woodford^||, Noa Zerangue^||, and Peter A. Edwards^**1

From the Departments of Biological Chemistry and Medicine, David Geffen School of Medicine, and the ^**Molecular Biology Institute at UCLA, UCLA, Los Angeles, California 90095, the ^¶Department of Molecular Biology and Biochemistry at UCI, University of California, Irvine, California 92697, and ^||XenoPort, Inc., Santa Clara, California 95051

Fxr is known to regulate a variety of metabolic processes, including bile acid, cholesterol, and carbohydrate metabolism. In this study, we show direct evidence that Fxr is a key player in maintaining sulfate homeostasis. We identified and characterized the sodium/sulfate co-transporter (NaS-1; Slc13a1) as an Fxr target gene expressed in the kidney and intestine. Electromobility shift assays, chromatin immunoprecipitation, and promoter reporter studies identified a single functional Fxr response element in the second intron of the mouse Slc13a1 gene. Treatment of wild-type mice with GW4064, a synthetic Fxr agonist, induced Slc13a1 mRNA in the intestine and kidney. Slc13a1 mRNA was also induced in the kidney and intestine of wild-type, but not Fxr^–/– mice, after treatment with the hepatotoxin -naphthylisothiocyanate, which is known to result in elevated blood bile acid levels. Finally, we observed a decrease in Slc13a1 mRNA in the kidney and intestine of Fxr^–/– mice and a corresponding increase in urinary excretion of free sulfates as compared with wild-type mice. These results demonstrate that mouse Slc13a1 is a novel Fxr target gene expressed in the kidney and intestine and that in the absence of Fxr, mice waste sulfate into the urine. Thus, Fxr is necessary for normal sulfate homeostasis in vivo.

Received for publication, January 31, 2007 , and in revised form, May 31, 2007.

^* This work was supported by National Institutes of Health Grants HL-68445 and HL-30568 (to P. A. E.) and a grant from the Laubisch Fund (to P. A. E.). 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.

¹ To whom correspondence should be addressed: Dept. of Biological Chemistry, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave., 33-257 CHS, Los Angeles, CA 90095. Tel.: 310-206-3717; Fax: 310-794-7345; E-mail: pedwards{at}mednet.ucla.edu.

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