出版社：American Society for Biochemistry and Molecular Biology
摘要：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 α and β (OSTα and OSTβ). 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 OSTα and OSTβ 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. OSTα and OSTβ 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 α-naphthylisothiocyanate. Finally, overexpression of human OSTα and OSTβ facilitated the uptake of conjugated chenodeoxycholate and the activation of FXR target genes. These results demonstrate that OSTα and OSTβ 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 α and β in the adrenal gland, kidney, and intestine.
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