n-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, n-6 linolei...
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doaj-a6e56d749ed94093a18eb8e3a32fdb522020-11-24T22:16:24ZengMDPI AGNutrients2072-66432019-01-0111117110.3390/nu11010171nu11010171n-6 Linoleic Acid Induces Epigenetics Alterations Associated with Colonic Inflammation and CancerDonato F. Romagnolo0Micah G. Donovan1Tom C. Doetschman2Ornella I. Selmin3The University of Arizona Cancer Center, Tucson, AZ 85724, USAInterdisciplinary Cancer Biology Graduate Program, University of Arizona, Tucson, AZ 85724, USADepartment of Cellular & Molecular Medicine, University of Arizona, Tucson, AZ 85724, USAThe University of Arizona Cancer Center, Tucson, AZ 85724, USAThe 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.http://www.mdpi.com/2072-6643/11/1/171n-6 linoleic acidhigh-fat diet (HFD)bile acidsepigeneticsfarnesoid-X-receptor (FXR)cyclooxygenase-2 (COX-2)Apccolon cancer |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Donato F. Romagnolo Micah G. Donovan Tom C. Doetschman Ornella I. Selmin |
spellingShingle |
Donato F. Romagnolo Micah G. Donovan Tom C. Doetschman Ornella I. Selmin n-6 Linoleic Acid Induces Epigenetics Alterations Associated with Colonic Inflammation and Cancer Nutrients n-6 linoleic acid high-fat diet (HFD) bile acids epigenetics farnesoid-X-receptor (FXR) cyclooxygenase-2 (COX-2) Apc colon cancer |
author_facet |
Donato F. Romagnolo Micah G. Donovan Tom C. Doetschman Ornella I. Selmin |
author_sort |
Donato F. Romagnolo |
title |
n-6 Linoleic Acid Induces Epigenetics Alterations Associated with Colonic Inflammation and Cancer |
title_short |
n-6 Linoleic Acid Induces Epigenetics Alterations Associated with Colonic Inflammation and Cancer |
title_full |
n-6 Linoleic Acid Induces Epigenetics Alterations Associated with Colonic Inflammation and Cancer |
title_fullStr |
n-6 Linoleic Acid Induces Epigenetics Alterations Associated with Colonic Inflammation and Cancer |
title_full_unstemmed |
n-6 Linoleic Acid Induces Epigenetics Alterations Associated with Colonic Inflammation and Cancer |
title_sort |
n-6 linoleic acid induces epigenetics alterations associated with colonic inflammation and cancer |
publisher |
MDPI AG |
series |
Nutrients |
issn |
2072-6643 |
publishDate |
2019-01-01 |
description |
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. |
topic |
n-6 linoleic acid high-fat diet (HFD) bile acids epigenetics farnesoid-X-receptor (FXR) cyclooxygenase-2 (COX-2) Apc colon cancer |
url |
http://www.mdpi.com/2072-6643/11/1/171 |
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