n-6 Linoleic Acid Induces Epigenetics Alterations Associated with Colonic Inflammation and Cancer
AbstractThe 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. View Full-Text
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Romagnolo, D.F.; Donovan, M.G.; Doetschman, T.C.; Selmin, O.I. n-6 Linoleic Acid Induces Epigenetics Alterations Associated with Colonic Inflammation and Cancer. Nutrients 2019, 11, 171.
Romagnolo DF, Donovan MG, Doetschman TC, Selmin OI. n-6 Linoleic Acid Induces Epigenetics Alterations Associated with Colonic Inflammation and Cancer. Nutrients. 2019; 11(1):171.Chicago/Turabian Style
Romagnolo, Donato F.; Donovan, Micah G.; Doetschman, Tom C.; Selmin, Ornella I. 2019. "n-6 Linoleic Acid Induces Epigenetics Alterations Associated with Colonic Inflammation and Cancer." Nutrients 11, no. 1: 171.
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