PT  - JOURNAL ARTICLE
AU  - Rengasamy R.M. Maran
AU  - Ann Thomas
AU  - Megan Roth
AU  - Zhonghua Sheng
AU  - Noriko Esterly
AU  - David Pinson
AU  - Xin Gao
AU  - Yawei Zhang
AU  - Vadivel Ganapathy
AU  - Frank J. Gonzalez
AU  - Grace L. Guo
TI  - Farnesoid X Receptor Deficiency in Mice Leads to Increased Intestinal Epithelial Cell Proliferation and Tumor Development
AID  - 10.1124/jpet.108.145409
DP  - 2009 Feb 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 469--477
VI  - 328
IP  - 2
4099  - http://jpet.aspetjournals.org/content/328/2/469.short
4100  - http://jpet.aspetjournals.org/content/328/2/469.full
SO  - J Pharmacol Exp Ther2009 Feb 01; 328
AB  - 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 interleukin-6. Most importantly, FXR deficiency led to an increase in the size of small intestine adenocarcinomas in adenomatous polyposis coli mutant mice. Furthermore, after treatment with a colon carcinogen, azoxymethane, 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 nonbile acid ligands may protect against intestinal carcinogenesis. U.S. Government work not protected by U.S. copyright