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

Donato Romagnolo,Micah Donovan,Ornella Selmin,Tom Doetschman

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.

Highlights

A diet high in n-6 fatty acids (n-6HFD) is a recognized risk factor for inflammatory bowel diseases (IBDs) [1,2]
Epigenetic activation of prostaglandin-endoperoxide synthase-2 (Ptsg-2) coupled with silencing of adenomatous polyposis Coli (Apc) and accumulation of C-JUN and cyclin D1 (Ccnd1) may increase the risk of inflammation and cancer of the colon
We investigated in a mouse model the effects of an n-6HFD rich in linoleic acid (LA) on CpG methylation of Fxr, prostaglandin-endoperoxide synthase-2 (Ptsg-2), and Apc genes, and the expression of factors involved in bile acids (BA) homeostasis (Ibabp and small heterodimer protein (Shp)), proliferation (Ccnd1), and oncogenic transformation (c-JUN)

Summary

Introduction

A diet high in n-6 fatty acids (n-6HFD) is a recognized risk factor for inflammatory bowel diseases (IBDs) [1,2]. Individuals with diets high in linoleic acid (LA), an n-6 fatty acid found predominantly in plant oils (e.g., soybean, corn, safflower), are at increased risk for one common form of IBD, ulcerative colitis [3,4]. A causative relationship exists between colon cancer development and a high concentration of rectal BA in preclinical models [8] and human patients [9,10,11,12]. Because colon rectal cancer (CRC) is a leading cause of death and its incidence in early onset patients (

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