出版社：American Society for Biochemistry and Molecular Biology
摘要：Expression of the farnesoid X receptor (FXR; NR1H4) is limitedto the liver, intestine, kidney, and adrenal gland. However,the role of FXR in the latter two organs is unknown. In thecurrent study, we performed microarray analysis using RNA fromH295R cells infected with constitutively active FXR. Severalputative FXR target genes were identified, including the organicsolute transporters and ß (OST and OSTß).Electromobility shift assays and promoter-reporter studies identifiedfunctional farnesoid X receptor response elements (FXREs) inthe promoters of both human genes. These FXREs are conservedin 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 OSTßmRNAs in the intestine and kidney. Both mRNAs were also inducedwhen wild-type, but not FXR-deficient (FXR–/–),adrenals were cultured in the presence of GW4064. OST and OSTßmRNA levels were also induced in the adrenals and kidneys ofwild-type, but not FXR–/–, mice after the increaseof plasma bile acids in response to the hepatotoxin -naphthylisothiocyanate.Finally, overexpression of human OST and OSTß facilitatedthe uptake of conjugated chenodeoxycholate and the activationof FXR target genes. These results demonstrate that OST andOSTß are novel FXR target genes that are expressedin 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 ßin 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
and ß (OST
