FXR regulates organic solute transporters alpha and beta 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 alpha and beta (OSTalpha and OSTbeta). 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 OSTalpha and OSTbeta 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. OSTalpha and OSTbeta 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 alpha-naphthylisothiocyanate. Finally, overexpression of human OSTalpha and OSTbeta facilitated the uptake of conjugated chenodeoxycholate and the activation of FXR target genes. These results demonstrate that OSTalpha and OSTbeta are novel FXR target genes that are expressed in the adrenal gland, kidney, and intestine.
Lee
Hans
H
Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Zhang
Yanqiao
Y
Lee
Florence Y
FY
Nelson
Stanley F
SF
Gonzalez
Frank J
FJ
Edwards
Peter A
PA
D000311:Adrenal Glands / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D001647:Bile Acids and Salts / Q000494:pharmacology; D002460:Cell Line; D017124:Conserved Sequence; D004268:DNA-Binding Proteins / Q000819:agonists / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D017930:Genes, Reporter; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D007555:Isoxazoles / Q000494:pharmacology; D007668:Kidney / Q000378:metabolism; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors / Q000819:agonists / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D000099150:Receptor, Farnesoid X-Activated
D001647:Bile Acids and Salts; D004268:DNA-Binding Proteins; D007555:Isoxazoles; D026901:Membrane Transport Proteins; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated; C476575:organic solute transporter alpha, human; C476576:organic solute transporter alpha, mouse; C476577:SLC51B protein, human; C476578:organic solute transporter beta, mouse; C412815:GW 4064