Regulation of the expression and functions of the bile acid receptor FXR in the intestinal epithelium

胆汁酸是肝脏合成的清洁剂，释放到小肠中，促进膳食脂质的吸收。胆汁酸在小肠末端被吸收，然后返回肝脏循环。在细胞中，胆汁酸与FXR结合，FXR是一种调节与胆汁酸的产生、排泄和吸收有关的许多基因表达的蛋白质。越来越多的证据表明，FXR还调节肠道内层细胞的各种典型功能。我们的初步研究结果表明，FXR可以调节消化道对磷酸盐的吸收。预计FXR不是单独作用，而是与其他关键因子共同作用，通过影响基因表达水平调节肠细胞功能。事实上，这些其他因素也可以控制肠道细胞中更丰富的FXR形式的表达。这项研究计划的长期目标是了解FXR如何通过调节基因表达来调节肠道的基本过程。首先，我们将进一步评估合成配体激活FXR对肠细胞中磷酸盐运输的调节作用。此外，我们将在细胞模型和FXR基因缺陷小鼠中确定抑制FXR表达对肠道磷酸盐转运相关蛋白表达的影响。其次，我们将在基因组水平上研究哪些信号被肠细胞接收，并导致它们表达特定形式的FXR。第三，我们将研究FXR如何调节一个参与磷酸盐吸收的基因的表达，以及其他在肠道中表达良好的因子如何参与这种调节。我们相信我们的研究项目将大大提高我们对胆汁酸受体FXR在维持肠道细胞活性方面所起关键作用的认识。

Bile acids are detergents synthesized in the liver and released into the small intestine to facilitate the absorption of dietary lipids. Bile acids are absorbed at the end of the small intestine to return to the liver to be recycled. In cells, bile acids bind to FXR, a protein that modulates the expression of a number of genes involved in the production, excretion and absorption of bile acids. There are growing evidences that FXR also regulates various functions typical of the cells lining the inner layer of the gut. Our preliminary results revealed that FXR could regulate alimentary phosphate absorption. It is expected that FXR does not act alone but rather with other key factors that regulate the functions of intestinal cells by affecting the level of gene expression. In fact, these other factors could also control the expression of forms of FXR more abundant in intestinal cells. The long-term objective of this research program is to understand how FXR regulates fundamental processes of the intestine through the modulation of gene expression.Firstly, we will further evaluate the effects of FXR activation by a synthetic ligand on the regulation of phosphate transport in intestinal cells. In addition, we will determine the consequence of inhibiting the expression of FXR on the expression of proteins involved in intestinal phosphate transport in cellular models and in mice genetically deficient for FXR. Secondly, we will study at the genomic level which signals are received by the intestinal cells and that causes them to express a specific form of FXR. Thirdly, we will investigate how FXR regulates the expression of a gene involved in phosphate absorption and how other factors well expressed in the intestine contribute to this regulation. We believe that our research program will greatly improve our knowledge of the key roles played by the bile acid receptor FXR to maintain competent intestinal cells.