FXR regulates organic solute transporters α and β in the adrenal gland, kidney, and intestine
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. 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. Farnesoid X receptor (FXR; NR1H4) is a ligand-activated transcription factor that contains a number of domains, including the ligand-independent activation function (activation function 1) at the N terminus, a DNA binding domain, a hinge region, a dimerization interface, a ligand binding domain, and a ligand-dependent activation function (activation function 2) at the C terminus (1Glass C.K. Differential recognition of target genes by nuclear receptor monomers, dimers, and heterodimers.Endocr. 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Scholar). of RNA from cultured cells with using of and of were for and of for and for using the in and to in mRNA expression were for expression were from The for are in for bile farnesoid X bile acid binding OSTα and organic solute transporters α and heterodimer in a bile farnesoid X bile acid binding OSTα and organic solute transporters α and heterodimer RNA for microarray H295R cells in were for with at a of of The infected cells were with for RNA using and for using the to and analysis were performed at the of and FXREs in the promoters of and were identified using the is a nucleotide from functional shift assays were performed (5Laffitte B.A. Kast H.R. Nguyen C.M. Zavacki A.M. Moore D.D. Edwards P.A. Identification of the DNA binding specificity and potential target genes for the farnesoid X-activated receptor.J. Biol. Chem. 2000; 275: 10638-10647Google Scholar). 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H295R cells of the with cells of the adrenal shown that overexpression of FXR to in FXR target genes the specificity in the of FXR (6Anisfeld A.M. Kast-Woelbern H.R. Meyer M.E. Jones S.A. Zhang Y. Williams K.J. Willson T. Edwards P.A. Syndecan-1 expression is regulated in an isoform-specific manner by the farnesoid-X receptor.J. Biol. Chem. Scholar). of the cells with FXR target gene expression (6Anisfeld A.M. Kast-Woelbern H.R. Meyer M.E. Jones S.A. Zhang Y. Williams K.J. Willson T. Edwards P.A. Syndecan-1 expression is regulated in an isoform-specific manner by the farnesoid-X receptor.J. Biol. Chem. Scholar). that and the two that the with to target gene activation and also activate target genes to levels (6Anisfeld A.M. Kast-Woelbern H.R. Meyer M.E. Jones S.A. Zhang Y. Williams K.J. Willson T. Edwards P.A. Syndecan-1 expression is regulated in an isoform-specific manner by the farnesoid-X receptor.J. Biol. Chem. Scholar, Y. Kast-Woelbern H.R. 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However, to the expression and of the of by FXR in adrenal cells has not been organic transporters α and β and were for studies the microarray that both genes were induced by analysis FXR target genes in H295R and FXR cells were infected with the RNA and using expression the of genes is in a H295R cells were infected with the RNA and using expression the of genes is to the from the microarray H295R cells were infected with human that and the cells were for with and RNA that both and synthetic FXR in a increase in and mRNAs activation in a of the FXR The mRNA levels of and were also induced by the FXR agonist, after of the cells with is that the the specificity for has been in studies with cells that FXR with an promoter-reporter gene Y. Kast-Woelbern H.R. Edwards P.A. variants of the nuclear receptor farnesoid X receptor Biol. Chem. Scholar). with the microarray both and were to ligand-activated with The results from demonstrate that and are induced in human adrenal cells by a that is the activation of FXR. both and mRNAs were regulated after the activation of the promoters of both and for potential FXREs using the identified putative and and two putative and in the promoters of the and in and and in shift assays to the FXR/RXR heterodimer bind to putative The in that both and bind to and and and and but not to to not to a but not to a to and and and a from the Moore D.D. The farnesoid X-activated receptor bile acid activation of gene Biol. Chem. 2000; 275: a assays were also performed to the of FXR/RXR for the and and the the sequence in the presence of of DNA the The results demonstrate that the wild-type and and for the binding of heterodimers and and the of the by the presence of the DNA the and and assays shown were performed with in and results were using not The in that and and are functional we genes the of the promoters the wild-type H295R cells in the presence of and and the cells were for with the FXR of with and to and in after the of and in were after the of to cells with and of to and in after the of and to and in after the of to cells and that the putative elements in the promoters are functional we gene both and also the that of the in response to ligand-activated FXR by when when the in both and elements of the in the gene activation in response to the FXR These demonstrate that the in the of and the two FXREs and in the of are for the activation in response to FXR. The results demonstrate that FXR the transcription of human OSTα and OSTβ mRNAs in the of the nucleotide of the promoters of the and human OSTα and OSTβ genes that the functional human FXREs are conserved in the genes we wild-type and mice to two genes induced in in response to FXR The in demonstrate that both OSTα and OSTβ mRNAs are induced in the intestine of wild-type mice in response to of GW4064. the FXR target J. of expression by the bile acid receptor Biol. Chem. and J. Jones S.A. S.A. Willson T. P. Identification of a bile in the human bile of the farnesoid X acid receptor Biol. Chem. Scholar, J. P. of the bile an to its 2002; are also induced to in the intestine in response to that OSTα and OSTβ are also induced in the kidneys of the wild-type mice in response to GW4064. mRNAs and two FXR target were also induced in the kidneys of mice expression in the has not been the mRNA expression induced in response to GW4064. to that of in mice FXR in the intestine and kidney. In and mRNA levels were by in the of the a of and mRNA levels in the not These latter that and are not expressed in in we were to demonstrate in the mRNA levels of genes in the adrenal of mice in response to of not is that not in adrenal in in to activate FXR. we an to increase the of FXR of to a of and bile and induced by and Rev. Scholar). The is a in bile and an increase in bile acid levels in the plasma induced by and Rev. Scholar). that with of plasma bile acids to levels to activate FXR in the adrenal and The in that of in a increase in mRNA levels of both OSTα and OSTβ in the kidneys of wild-type In OSTα and OSTβ mRNA levels were after the of to mice also mRNA levels in the kidneys of wild-type, but not FXR−/−, mice the of the expression of in the that of results in plasma bile acids that activate FXR in the and the transcription of FXR target genes. and mRNA levels were induced in the adrenal of wild-type, but not FXR−/−, mice In the expression of two genes and that are expressed in the adrenals not in response to of wild-type mice and not that plasma bile acids in mice to levels that to the activation of FXR target genes in both the and adrenal with the of the synthetic FXR to the adrenal in we an were from wild-type and mice and for in GW4064. the wild-type adrenal were to for a the FXR in a of and mRNA In genes were not when the adrenal were from mice The by FXR ligand and a that OSTα and OSTβ are expressed in the adrenal gland, kidney, and intestine and that genes are induced after the activation of FXR. the liver, intestine, and kidney, are not to in bile acid FXR is expressed in the adrenal the role of FXR in is an P.A. M. J. The organic solute is an bile acid Biol. Chem. that OSTα and OSTβ of and bile In studies that of with mRNAs for OSTα and OSTβ to uptake of a number of including and D.J. a novel and an organic solute Biol. Chem. Scholar, D.J. Expression of two genes that organic solute and in the of a Scholar). These studies are with OSTα and OSTβ a that in the we that when plasma bile acid levels are in induced by and Rev. Scholar, Y. J. S. G. B. S.A. B. by the farnesoid X receptor in of and OSTα and OSTβ function to bile acids the adrenal activate FXR in a and of bile acids are to cells in the of a functional bile acid D.J. G. S.A. Willson Zavacki A.M. Moore D.D. for an orphan nuclear Scholar). human OSTα and OSTβ the uptake of conjugated bile acids activate and target we H295R cells with expression that and with a the of the The latter contains a functional M. M. D.J. bile is by the farnesoid X acid receptor.J. Biol. Chem. Scholar). The cells were in the presence of conjugated bile The in demonstrate that the to of the gene by is by the of OSTα and These latter results are and are both to cells of In the induced to by conjugated and in the of OSTα and OSTβ However, of the gene in cells with OSTα and OSTβ the of conjugated not when the cells were with OSTα OSTβ the results from the we human cells with human OSTα and OSTβ and mRNA levels after of the cells with conjugated bile These cells were FXR and FXR target genes in response to shown in overexpression of both OSTα and OSTβ in an increase in the mRNA levels of in response to conjugated bile In of mRNA levels by by the overexpression of OSTα and OSTβ These results demonstrate that OSTα and when the uptake of conjugated bile acids the activation of FXR target genes. In the studies that identified the FXR J. D.J. T. D.J. T. Identification of a nuclear receptor that is by 1995; Scholar, Moore D.D. of that with the X two novel orphan 1995; FXR shown to expressed in the liver, intestine, adrenal and of the kidney. studies shown that the FXR are expressed in a manner R.M. K. B. A. F. of the of 2002; Scholar, Y. Kast-Woelbern H.R. Edwards P.A. variants of the nuclear receptor farnesoid X receptor Biol. Chem. Scholar). In studies that FXR target genes in bile acid and lipid (6Anisfeld A.M. Kast-Woelbern H.R. Meyer M.E. Jones S.A. Zhang Y. Williams K.J. Willson T. Edwards P.A. Syndecan-1 expression is regulated in an isoform-specific manner by the farnesoid-X receptor.J. Biol. Chem. Scholar, Moore D.D. The farnesoid X-activated receptor bile acid activation of gene Biol. Chem. 2000; 275: Scholar, H.R. Nguyen C.M. Jones S.A. B.A. K. Willson Edwards P.A. Farnesoid X-activated receptor a plasma levels to bile 15: Scholar, M. M. D.J. bile is by the farnesoid X acid receptor.J. Biol. Chem. Scholar, B. Jones S.A. 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The that OSTα and OSTβ mRNA levels increase in an and FXR ligand-dependent manner in cultured adrenal and in and that the promoters of both human genes functional demonstrate that OSTα and OSTβ are direct FXR target genes. OSTα and OSTβ were identified in the of D.J. a novel and an organic solute Biol. Chem. Scholar, D.J. Expression of two genes that organic solute and in the of a their function in is unknown. In a study, OSTα and OSTβ were shown to in the of it function to bile acids the P.A. M. J. The organic solute is an bile acid Biol. Chem. Scholar). we that OSTα and OSTβ are expressed in the and adrenal gland, in to the intestine, and we demonstrate that both genes are induced in after activation of the nuclear receptor FXR. studies also demonstrate that OSTα and OSTβ the uptake of conjugated bile acids cultured cells and activate FXR target genes. the current we that when the levels of bile acids in the are in after OSTα and OSTβ the uptake of conjugated bile acids the adrenals and that results in a activation of OSTα and OSTβ by FXR. However, OSTα and OSTβ a heterodimer also from the adrenal gland. expression of OSTα and OSTβ in shown to the of from cells P.A. a bile acid and in human and Scholar). the human adrenal and of that OSTα and OSTβ also function to conjugated from the adrenals the it is not adrenal FXR is not after the uptake of bile acids but also a of of a novel a from adrenal to activate FXR D.J. of and of the farnesoid X-activated nuclear 2000; Scholar). However, activation of a promoter-reporter gene by of it are of FXR. The of FXR target genes in the adrenal the role of nuclear receptor in The is a that the of the by to studies by J. D.J. T. D.J. T. Identification of a nuclear receptor that is by 1995; that FXR is expressed in the of the kidney, a for the and of the of of bile acids are the expression of and FXR in the that FXR function in bile acid the function of OSTα and OSTβ in the adrenal gland, kidney, and intestine the of OSTα OSTβ In OSTα and OSTβ novel FXR target genes that are expressed in the adrenal gland, kidney, and intestine. that OSTα and OSTβ are transporters that the uptake of bile acids from the the adrenal in bile acid levels are and the of conjugated from the The B. Zhang for in the microarray and for by of and a from the an and and were the of and bile acid bile acid factor farnesoid X receptor farnesoid X receptor response 3-(2,6-dichlorophenyl)-4-(3′-carboxy-2-chloro-stilben-4-yl)-oxymethyl-5-isopropyl-isoxazole bile acid binding organic solute transporters α and β 9-cis retinoic acid receptor α heterodimer partner