Received for publication August 29, 2008.
Revised October 29, 2008.
Accepted for publication October 30, 2008.

FXR Deficiency in Mice Leads to Increased Intestinal Epithelial Cell Proliferation and Tumor Development

Abstract

Increased dietary fat consumption is associated with colon cancer development. The exact mechanism by which fat induces colon cancer is not clear, however, increased bile-acid excretion in response to high-fat diet may promote colon carcinogenesis. The farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily and bile acids are endogenous ligands of FXR. FXR is highly expressed in the intestine and liver where FXR is essential for maintaining bile-acid homeostasis. The role of FXR in intestine cancer development is not known. The current study evaluated the effects of FXR deficiency in mice on intestinal cell proliferation and cancer development. The results showed that FXR deficiency resulted in increased colon cell proliferation, which was accompanied by an up-regulation in the expression of genes involved in cell-cycle progression and inflammation, including cyclin D1 and IL-6. Most importantly, FXR deficiency led to an increase in the size of small intestine adenocarcinomas in adenomatous polypsosis coli mutant (APC^min) mice. Furthermore, following treatment with a colon carcinogen, azoxymethane (AOM), FXR deficiency increased the adenocarcinoma multiplicity and size in colon and rectum of C57BL/6 mice. Loss of FXR function also increased the intestinal lymphoid nodule numbers in the intestine. Taken together, the current study is the first to show that FXR deficiency promotes cell proliferation, inflammation and tumorigenesis in the intestine, suggesting that activation of FXR by non-bile-acid ligands may protect against intestinal carcinogenesis.

Key words: APCmin mice, azoxymethane, bile acids, colon cancer, farnesoid x receptor, nuclear receptor