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. 2009 Feb;328(2):469-77.
doi: 10.1124/jpet.108.145409. Epub 2008 Nov 3.

Farnesoid X receptor deficiency in mice leads to increased intestinal epithelial cell proliferation and tumor development

Rengasamy R M Maran  1 , Ann Thomas, Megan Roth, Zhonghua Sheng, Noriko Esterly, David Pinson, Xin Gao, Yawei Zhang, Vadivel Ganapathy, Frank J Gonzalez, Grace L Guo
Affiliations

Farnesoid X receptor deficiency in mice leads to increased intestinal epithelial cell proliferation and tumor development

Rengasamy R M Maran et al. J Pharmacol Exp Ther. 2009 Feb.

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 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.

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Figures

Fig. 1.
Fig. 1.
Localization of FXR protein in the colon and effect of FXR deficiency on colon histomorphology. A, localization of FXR protein in the colon of WT mice (1, negative control; 2, cross-section of crypts, 20×; 3, cross-section of crypts, 40×; and 4, longitudinal section of crypts, 40×). B, H&E staining of colons from 2- and 12-month-old male WT and FXR KO mice (40×). Arrows, goblet cells and minimized pictures at the bottom show loci of lymphoid cells in the colon of FXR KO mice. C-1, quantification of average crypt height in the colons of these mice. C-2, quantification of the number of colon goblet cells per mouse per 40× macroscopic field gathered from 10 random fields. n = 6 per genotype per age. *, P < 0.05.
Fig. 2.
Fig. 2.
Colon cell proliferation determined by BrdU labeling index and apoptosis evaluated by TUNEL staining. All pictures are in 40× magnification. A, BrdU staining in the colon, a BrdU-positive cell is a cell with nuclei stained brown. B, TUNEL staining of the colon. C, quantification of the percentage of BrdU positively stained cell (LI). D, quantification of the percentage of TUNEL positively stained cells. *, P < 0.05.
Fig. 3.
Fig. 3.
The effects of FXR deficiency on intestinal carcinogenesis in APCmin mice. A, small intestinal polyp stained with 0.5% methylene blue for 2 min (left) and a cross-section view of a small intestinal polyp (right; 10×). B1, adenoma multiplicity expressed as number of adenoma polyps per mouse. B2, average size of adenoma polyps. B3, adenocarcinoma multiplicity. B4, average size of adenocarcinoma polyps. n = 15 (male and female APCmin mice) and n = 20 (male and female APCmin/FXR KO mice). *, P < 0.05.
Fig. 4.
Fig. 4.
Effects of FXR deficiency on adenocarcinoma development in AOM-treated mice. A, left, picture of a colon polyp stained with 0.5% methylene blue for 2 min. Right, cross-section view of a colon adenocarcinoma (10×). B1, adenocarcinoma prevalence (percentage of animals with adenocarcinomas) in male and female WT and FXR KO mice after AOM treatment. B2, average size of adenocarcinomas in male and female WT and FXR KO mice with AOM treatment. *, P < 0.05.
Fig. 5.
Fig. 5.
Effects of FXR deficiency on average number of intestinal lymphoid nodules per mouse. A, left, picture of a lymphoid nodule in the small intestine with 0.5% methylene blue staining for 2 min. Right, cross-section view of the same lymphoid nodule (10×). B, average number of small intestine lymphoid nodules per mouse in male and female WT, FXR KO, with treatment of vehicle or AOM, and in APCmin and FXR KO/APCmin mice. C, average number of colon/rectum lymphoid nodules per mouse in male and female WT, FXR KO, with treatment of vehicle or AOM, and in APCmin and FXR KO/APCmin mice. n = 15 per genotype per treatment per gender except for n = 20 for FXR KO/APCmin mice. *, P < 0.05.
Fig. 6.
Fig. 6.
Expression of genes involved in cell proliferation, tumor suppression, and inflammation in the colons of 2- and 12-month-old male WT and FXR KO mice. A, mRNA levels of genes in 2-month-old male mice. B, mRNA levels of genes in 12-month-old male mice. n = 6/genotype/time point. *, P < 0.05. C, Western blot analysis of cyclin D1, c-Myc, β-catenin, and APC protein in the colon of 2- and 12-month-old WT and FXR KO male mice, with n = 6 per group. D, immunohistochemistry staining of β-catenin in the colon of 2- and 12-month-old WT and FXR KO male mice.
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