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

Nutrients. 2019 Jan 15;11(1):171. doi: 10.3390/nu11010171.

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.

Keywords: Apc; bile acids; colon cancer; cyclooxygenase-2 (COX-2); epigenetics; farnesoid-X-receptor (FXR); high-fat diet (HFD); n-6 linoleic acid.

MeSH terms

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

Substances

  • 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