Western-style diets (WD) high in fat and scarce in fiber and vitamin D increase risks of colorectal cancer (CRC). Here we performed a long-term diet study in mice to follow tumorigenesis and characterize structural and metabolic changes in colon mucosa associated with WD and predisposition to CRC. WD increased colon tumor numbers and mucosa proteomic analysis indicated severe deregulation of intracellular bile acid (BA) homeostasis and activation of cell proliferation. WD also increased crypt depth and colon cell proliferation. Despite increased luminal BA, colonocytes from WD-fed mice exhibited decreased expression of the BA transporters FABP6, OSTβ and ASBT and decreased concentrations of secondary BA deoxycholic acid and lithocholic acid, indicating reduced activity of the nuclear BA receptor FXR. Overall, our results suggest that WD increases cancer risk by FXR inactivation leading to BA deregulation and increased colon cell proliferation.
- Received October 24, 2016.
- Revision received April 7, 2017.
- Accepted April 10, 2017.
- Copyright ©2017, American Association for Cancer Research.