FXR regulates organic solute transporters α and β in the adrenal gland, kidney, and intestine
FXR regulates organic solute transporters α and β in the adrenal gland, kidney, and intestine
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DOI：
10.1194/jlr.m500417-jlr200
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发表时间：
2006-01-01
影响因子：
6.5
通讯作者：
Edwards, PA
中科院分区：
文献类型：
--
作者：
Lee, H;Zhang, YQ;Edwards, PA
法尼类X受体(FXR；NR1H4)的表达仅限于肝、肠、肾和肾上腺。然而，FXR在后两个器官中的作用尚不清楚。在目前的研究中，我们使用感染了成分活性FXR的H295R细胞的RNA进行了微阵列分析。已确定了几个可能的FXR靶基因，包括有机溶质转运蛋白α和β(OSTα和OSTβ)。电迁移率改变分析和启动子-报告研究发现，在这两个人类基因的启动子中都存在功能性法尼类X受体反应元件(FXREs)。这些FXRE在两个小鼠基因中都是保守的。用合成的FXR激动剂3-(2，6-dichlorophenyl)-4-(3‘-carboxy-2-chloro-stilben-4-yl)oxymethyl-)5-异丙基异恶唑(GW4064)处理野生型小鼠，可诱导肠和肾脏中OSTα和OSTβ的mRNAs表达。野生型而非FXR缺陷型(FXR-/-)肾上腺在GW4064存在下培养时，这两种mRNAs也被诱导。在野生型小鼠的肾上腺和肾脏中，OSTα和OSTβ的mRNA水平也被诱导，但FXR-/-小鼠在对肝毒素α-异硫氰酸酯的反应中血浆胆汁酸增加后，OSTα和OSTβmRNA的表达没有变化。最后，人OSTα和OSTβ的过表达促进了结合的鹅去氧胆酸的摄取和FXR靶基因的激活。这些结果表明，OSTα和OSTβ是在肾上腺、肾脏和肠中表达的新的FXR靶基因。
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 (OST alpha and OST beta). 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 alpha and OST beta 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 alpha and OST beta 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 OST alpha and OST beta facilitated the uptake of conjugated chenodeoxycholate and the activation of FXR target genes. These results demonstrate that OST alpha and OST beta are novel FXR target genes that are expressed in the adrenal gland, kidney, and intestine.