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

点击翻译按钮获取中文摘要

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.