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Journal of Lipid Research, Vol. 47, 201-214, January 2006
Copyright © 2006 by American Society for Biochemistry and Molecular Biology

FXR regulates organic solute transporters and ß in the adrenal gland, kidney, and intestine

Hans Lee^*, Yanqiao Zhang^*, Florence Y. Lee^*, Stanley F. Nelson, Frank J. Gonzalez and Peter A. Edwards^1,*,**

^* Department of Biological Chemistry and Medicine, University of California, Los Angeles, Los Angeles, CA 90095
Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA 90095
^** Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095
Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892

Published, JLR Papers in Press, October 26, 2005.

¹ To whom correspondence should be addressed. e-mail: pedwards{at}mednet.ucla.edu

Expression of the farnesoid X receptor (FXR; NR1H4) is limited to the liver, intestine, kidney, and adrenal gland. However, the role of FXR in the latter two organs is unknown. In the current study, we performed microarray analysis using RNA from H295R cells infected with constitutively active FXR. Several putative FXR target genes were identified, including the organic solute transporters and ß (OST and OSTß). Electromobility shift assays and promoter-reporter studies identified functional farnesoid X receptor response elements (FXREs) in the promoters of both human genes. These FXREs are conserved in both mouse genes. Treatment of wild-type mice with 3-(2,6-dichlorophenyl)-4-(3'-carboxy-2-chloro-stilben-4-yl)-oxymethyl-5-isopropyl-isoxazole (GW4064), a synthetic FXR agonist, induced OST and OSTß mRNAs in the intestine and kidney. Both mRNAs were also induced when wild-type, but not FXR-deficient (FXR^–/–), adrenals were cultured in the presence of GW4064. OST and OSTß mRNA levels were also induced in the adrenals and kidneys of wild-type, but not FXR^–/–, mice after the increase of plasma bile acids in response to the hepatotoxin -naphthylisothiocyanate. Finally, overexpression of human OST and OSTß facilitated the uptake of conjugated chenodeoxycholate and the activation of FXR target genes. These results demonstrate that OST and OSTß are novel FXR target genes that are expressed in the adrenal gland, kidney, and intestine.—Lee, H., Y. Zhang, F. Y. Lee, S. F. Nelson, F. J. Gonzalez, and P. A. Edwards. FXR regulates organic solute transporters and ß in the adrenal gland, kidney, and intestine.

Supplementary key words farnesoid X receptor • chenodeoxycholic acid • 3-(2,6-dichlorophenyl)-4-(3'carboxy-2-chloro-stilben-4-yl)-oxymethyl-5-isopropyl-isoxazole

Abbreviations: ANIT, -naphthylisothiocyanate; ASBT, apical sodium-dependent bile acid transporter; BSEP, bile salt export pump; CDCA, chenodeoxycholic acid; FGF-19, fibroblast growth factor 19; FXR, farnesoid X receptor; FXRE, farnesoid X receptor response element; GFP, green fluorescent protein; GW4064, 3-(2,6-dichlorophenyl)-4-(3'-carboxy-2-chloro-stilben-4-yl)-oxymethyl-5-isopropyl-isoxazole; I-BABP, ileal bile acid binding protein; MRP2, multidrug resistance-related protein 2; OST and OSTß, organic solute transporters and ß; PLTP, phospholipid transfer protein; RXR, 9-cis retinoic acid receptor ; SHP, small heterodimer partner

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