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

Abstract

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.

• Authors: Donato F Romagnolo, Micah G Donovan, Tom C Doetschman, Ornella I Selmin
• Journal: Nutrients (Nutrients) Vol. 11 Issue 1 (Jan 15 2019) ISSN: 2072-6643 [Electronic] Switzerland
• PMID: 30650553 (Publication Type: Journal Article)

Chemical References

• APC protein, human
• Adenomatous Polyposis Coli Protein
• Bile Acids and Salts
• CCND1 protein, human
• Dietary Fats
• FXR1 protein, human
• RNA-Binding Proteins
• Cyclin D1
• Linoleic Acid
• Cyclooxygenase 2
• PTGS2 protein, human

Topics

• Adenomatous Polyposis Coli Protein (genetics, metabolism)
• Animals
• Bile Acids and Salts (metabolism)
• Cells, Cultured
• Colitis (etiology, genetics, metabolism)
• Colon (drug effects, metabolism, pathology)
• Colonic Neoplasms (etiology, genetics, metabolism)
• Cyclin D1 (genetics, metabolism)
• Cyclooxygenase 2 (genetics, metabolism)
• DNA Methylation (drug effects)
• Diet, High-Fat (adverse effects)
• Dietary Fats (administration & dosage, adverse effects)
• Epigenesis, Genetic
• Fetal Research
• Genes, jun
• Humans
• Inflammation (etiology, genetics, metabolism)
• Intestinal Mucosa (drug effects, metabolism, pathology)
• Linoleic Acid (adverse effects, pharmacology)
• Mice, Inbred C57BL
• RNA-Binding Proteins (genetics, metabolism)