The farnesoid-X-receptor (FXR) protects against inflammation and cancer of the colon through maintenance of intestinal bile acid (BA) homeostasis. Conversely, higher levels of BA and cyclooxygenase-2 (COX-2) are risk factors for inflammation and cancer of the colon. In the United States,
n-6 linoleic acid (LA) is the most commonly used dietary vegetable fat. Metabolism of
n-6 fatty acids has been linked to a higher risk of intestinal cancer. The objectives of this study were to investigate in colonic mucosa the effects of a high-fat diet rich in LA (
n-6HFD) on CpG methylation of
Fxr and prostaglandin-endoperoxide synthase-2 (
Ptsg-2) genes, and the impact on the expression of tumor suppressor adenomatous polyposis Coli (
Apc) and proliferative cyclin D1 (
Ccnd1) genes. Weaned C57BL/6J male mice were fed for 6 weeks either an
n-6HFD containing 44% energy (44%E) from 22% safflower oil (SO, 76% LA by weight) or a 13% energy (13%E) control diet (Control) from SO (5% by weight). Mice fed the
n-6HFD had reduced (60%)
Fxr promoter CpG methylation and increased (~50%)
Fxr mRNA. The expression of FXR-target ileal bile acid-binding protein (
Ibabp), small heterodimer protein (
Shp), and anti-inflammatory peroxisome proliferator-activated-γ1 genes was increased. The
n-6HFD reduced
Ptgs-2 CpG methylation, increased the expression of
Cox-2, and increased
Apc CpG methylation in colonic mucosa. Accordingly, reduced expression of
Apc was coupled to accumulation of c-JUN and
Ccnd1, respectively cofactor and gene targets for the β-catenin/Wnt signaling pathway. Finally, the
n-6HFD reduced the expression of histone deacetylase-1 while favoring the accumulation of acetylated histone 3. We conclude that an
n-6HFD epigenetically modifies
Fxr, leading to the activation of downstream factors that participate in BA homeostasis. However, epigenetic activation of
Ptsg-2 coupled with silencing of
Apc and accumulation of C-JUN and
Ccnd1 may increase the risk of inflammation and cancer of the colon.
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