Bile Acids and Nuclear Receptors: Their Roles in Nutrition and Cancer
Schmidt, Daniel R.
MetadataShow full item record
The bile acid receptor, also known as farnesoid X receptor (FXR), is essential for feedback regulation of bile acid synthesis. Bile acids are required for the proper absorption of dietary lipids, including fat-soluble vitamins; however, some bacterial metabolites of bile acids have been shown to promote intestinal tumorigenesis in rodent models. Since high fat diet is considered a major risk factor for colorectal cancer (CRC), and is associated with increased bile acid concentrations in the colon, it has been proposed that bile acids contribute to the pathogenesis of CRC. This study was undertaken to investigate the mechanism of tumor promotion by bile acids and determine whether FXR is involved in this process. The effects of bile acids and FXR on intestinal tumorigenesis were studied in mouse models of CRC and in colon cancer cell lines. In addition, the effects of FXR on bile acid-induced intestinal proliferation were investigated. To gain insight into the function of FXR in the large intestine, transcriptional profiling experiments were performed in mouse colon treated with natural and synthetic FXR agonists. Finally, a variety of mouse models were used to understand how fat-soluble vitamins affect bile acid synthesis at a molecular level. These studies found that FXR plays a role in protecting against colorectal cancer. Akr1b7 was identified as a novel FXR target gene and was shown to detoxify bacterial bile acid metabolites, suggesting that FXR may play a role in protecting intestinal mucosa by inducing bile acid detoxification. The proliferative effects of bile acids in vivo were found to be independent of FXR, and instead involved activation of PI3K/AKT signaling. Finally, vitamins A and D were found to activate nuclear receptors in the intestine and repress bile acid synthesis. These results underscore the role of nuclear receptors and their ligands in maintaining intestinal homeostasis and in protecting against the tumor- promoting effects of bile acids.