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首页> 外文期刊>World Journal of Gastroenterology >Lithocholic acid induction of the FGF19 promoter in intestinal cells is mediated by PXR
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Lithocholic acid induction of the FGF19 promoter in intestinal cells is mediated by PXR

机译：PXR介导肠细胞中对FGF19启动子的石胆酸诱导

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摘要

AIM: To study the effect of the toxic secondary bile acid lithocholic acid (LCA) on the expression of fibroblast growth factor 19 (FGF19) in intestinal cells and to characterize the pregnane-X-receptor (PXR) response of the FGF19 promoter region. METHODS: The intestinal cell line LS174T was stimulated with various concentrations of chenodeoxy-cholic acid and lithocholic acid for several time points. FGF19 mRNA levels were determined with quantitative realtime RT-PCR. FGF19 deletion promoter constructs were generated and the LCA response was analzyed in reporter assays. Co-transfections with PXR and RXR were carried out to study FGF19 regulation by these factors. RESULTS: LCA and CDCA strongly up-regulate FGF19 mRNA expression in LS174T cells in a time and dose dependent manner. Using reporter gene assays with several deletion constructs we found that the LCA responsive element in the human FGF19 promoter maps to the proximal regulatory region containing two potential binding sites for PXR. Overexpression of PXR and its dimerization partner retinoid X receptor (RXR) and stimulation with LCA or the potent PXR ligand rifampicin leads to a significant induction of FGF19 promoter activity in intestinal cells. CONCLUSION: LCA induced feedback inhibition of bile acid synthesis in the liver is likely to be regulated by PXR inducing intestinal FGF19 expression.
机译：目的：研究有毒的胆汁酸胆石酸（LCA）对肠道细胞中成纤维细胞生长因子19（FGF19）表达的影响，并表征FGF19启动子区域的孕烷-X受体（PXR）反应。方法：用不同浓度的鹅去氧胆酸和石胆酸刺激肠道细胞系LS174T几个时间点。用定量实时RT-PCR测定FGF19 mRNA水平。生成了FGF19缺失启动子构建体，并在报道基因分析中分析了LCA应答。进行了与PXR和RXR的共转染，以研究这些因素对FGF19的调控。结果：LCA和CDCA以时间和剂量依赖性方式强烈上调了LS174T细胞中FGF19 mRNA的表达。使用带有几种缺失构建体的报道基因检测，我们发现人FGF19启动子中的LCA响应元件映射到包含两个潜在的PXR结合位点的近端调节区域。 PXR及其二聚体类视黄醇X受体（RXR）的过表达以及LCA或强效PXR配体利福平的刺激导致肠道细胞中FGF19启动子活性的显着诱导。结论：LCA诱导的肝脏胆汁酸合成的反馈抑制可能是由PXR诱导肠道FGF19表达所调节。

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