Regulation of the sodium/sulfate co-transporter by farnesoid X receptor α

Fxrα is known to regulate a variety of metabolic processes, including bile acid, cholesterol, and carbohydrate metabolism. In this study, we show direct evidence that Fxrα is a key player in maintaining sulfate homeostasis. We identified and characterized the sodium/sulfate co-transporter (NaS-1; Slc13a1) as an Fxrα target gene expressed in the kidney and intestine. Electromobility shift assays, chromatin immunoprecipitation, and promoter reporter studies identified a single functional Fxrα response element in the second intron of the mouse Slc13a1 gene. Treatment of wild-type mice with GW4064, a synthetic Fxrα agonist, induced Slc13a1 mRNA in the intestine and kidney. Slc13a1mRNAwas also induced in the kidney and intestine of wild-type, but not Fxrα^-/- mice, after treatment with the hepatotoxin α-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 Fxrα^-/- 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 Fxrα target gene expressed in the kidney and intestine and that in the absence of Fxrα, mice waste sulfate into the urine. Thus, Fxrα is necessary for normal sulfate homeostasis in vivo.