-6 Linoleic Acid Induces Epigenetics Alterations Associated with Colonic Inflammation and Cancer.

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, -6 linoleic acid (LA) is the most commonly used dietary vegetable fat. Metabolism of -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 (-6HFD) on CpG methylation of and prostaglandin-endoperoxide synthase-2 () genes, and the impact on the expression of tumor suppressor adenomatous polyposis Coli () and proliferative cyclin D1 () genes. Weaned C57BL/6J male mice were fed for 6 weeks either an -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 -6HFD had reduced (60%) promoter CpG methylation and increased ( 50%) mRNA. The expression of FXR-target ileal bile acid-binding protein (), small heterodimer protein (), and anti-inflammatory peroxisome proliferator-activated-γ1 genes was increased. The -6HFD reduced CpG methylation, increased the expression of , and increased CpG methylation in colonic mucosa. Accordingly, reduced expression of was coupled to accumulation of c-JUN and respectively cofactor and gene targets for the β-catenin/Wnt signaling pathway. Finally, the -6HFD reduced the expression of histone deacetylase-1 while favoring the accumulation of acetylated histone 3. We conclude that an -6HFD epigenetically modifies , leading to the activation of downstream factors that participate in BA homeostasis. However, epigenetic activation of coupled with silencing of and accumulation of C-JUN and may increase the risk of inflammation and cancer of the colon.