Abstract
Abstract Bile acids (BAs) not recycled through the enterohepatic system can be modified in the colon into cancer-promoting secondary BAs such as deoxycholic acid (DCA). The farnesoid-X-receptor (FXR) regulates hepatic and intestinal BA homeostasis. However, in intestinal cells carrying defective adenomatous polyposis coli (Apc) gene the expression of FXR is reduced through yet unknown mechanisms. To investigate if Western high-fat diet (HFD) and Apc status influence epigenetic regulation of the Fxr in colonic mucosa. Weaned C57BL/6J male mice were fed a HFD (22% safflower oil = SO) or control low fat diet (LFD; 5% SO) for 6 wks. We examined the effects on CpG pmethylation of Fxr, and expression of FXR, peroxisome-proliferator activated receptor-gamma (PPARγ), and cyclooxygenase-2 (COX-2) mRNA. Also, we studied the influence of APC status on CpG methylation of the Fxr gene, and expression of FXR, ileal bile acid-binding protein (IBABP), small heterodimer partner (SHP), and COX-2 mRNA in normal colonic mucosa and colon tumors from APCMin/+ mice. Mice fed the HFD had reduced (60%) Fxr promoter methylation and increased (2∼3-fold) FXR, COX-2, and PPARγ mRNA levels. Conversely, APC-deficiency was associated with constitutive hypermethylation of the Fxr gene, elevation of COX-2, and reduced (60-90%) baseline FXR, IBABP, and SHP mRNA. In human HCT-116 colon cells, siRNA knock-down of APC reduced (50%) basal FXR mRNA expression, which was further reduced to 80% by DCA. We conclude that APC deficiency leads to constitutive epigenetic silencing of Fxr increasing the risk of inflammation and colon cancer associated with a Western HFD. Note: This abstract was not presented at the meeting. Citation Format: Ornella I. Selmin, Adam M. Lyon, Changming Fang, Tom C. Doetschman, Patricia A. Thompson, Jesse D. Martinez, Jeffrey Smith, Peter M. Lance, Donato F. Romagnolo. Influence of high fat diet and APC status on epigenetic regulation of FXR in colon cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 905. doi:10.1158/1538-7445.AM2015-905
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