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Intestine-Specific Mttp Deletion Increases the Severity of Experimental Colitis and Leads to Greater Tumor Burden in a Model of Colitis Associated Cancer
BACKGROUND: Gut derived lipid factors have been implicated in systemic injury and inflammation but the precise pathways involved are unknown. In addition, dietary fat intake and obesity are independent risk factors for the development of colorectal cancer. Here we studied the severity of experimenta...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3689718/ https://www.ncbi.nlm.nih.gov/pubmed/23805328 http://dx.doi.org/10.1371/journal.pone.0067819 |
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author | Xie, Yan Matsumoto, Hitoshi Nalbantoglu, ILKe Kerr, Thomas A. Luo, Jianyang Rubin, Deborah C. Kennedy, Susan Davidson, Nicholas O. |
author_facet | Xie, Yan Matsumoto, Hitoshi Nalbantoglu, ILKe Kerr, Thomas A. Luo, Jianyang Rubin, Deborah C. Kennedy, Susan Davidson, Nicholas O. |
author_sort | Xie, Yan |
collection | PubMed |
description | BACKGROUND: Gut derived lipid factors have been implicated in systemic injury and inflammation but the precise pathways involved are unknown. In addition, dietary fat intake and obesity are independent risk factors for the development of colorectal cancer. Here we studied the severity of experimental colitis and the development of colitis associated cancer (CAC) in mice with an inducible block in chylomicron secretion and fat malabsorption, following intestine-specific deletion of microsomal triglyceride transfer protein (Mttp-IKO). METHODOLOGY/PRINCIPAL FINDINGS: Mttp-IKO mice exhibited more severe injury with ∼90% mortality following dextran sodium sulfate (DSS) induced colitis, compared to <20% in controls. Intestinal permeability was increased in Mttp-IKO mice compared to controls, both at baseline and after DSS administration, in association with increased circulating levels of TNFα. DSS treatment increased colonic mRNA expression of IL-1β and IL-17A as well as inflammasome expression in both genotypes, but the abundance of TNFα was selectively increased in DSS treated Mttp-IKO mice. There was a 2-fold increase in colonic tumor burden in Mttp-IKO mice following azoxymethane/DSS treatment, which was associated with increased colonic inflammation as well as alterations in cytokine expression. To examine the pathways by which alterations in fatty acid abundance might interact with cytokine signaling to regulate colonic epithelial growth, we used primary murine myofibroblasts to demonstrate that palmitate induced expression of amphiregulin and epiregulin and augmented the increase in both of these growth mediators when added to IL-1βor to TNFα. CONCLUSIONS: These studies demonstrate that Mttp-IKO mice, despite absorbing virtually no dietary fat, exhibit augmented fatty acid dependent signaling that in turn exacerbates colonic injury and increases tumor formation. |
format | Online Article Text |
id | pubmed-3689718 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-36897182013-06-26 Intestine-Specific Mttp Deletion Increases the Severity of Experimental Colitis and Leads to Greater Tumor Burden in a Model of Colitis Associated Cancer Xie, Yan Matsumoto, Hitoshi Nalbantoglu, ILKe Kerr, Thomas A. Luo, Jianyang Rubin, Deborah C. Kennedy, Susan Davidson, Nicholas O. PLoS One Research Article BACKGROUND: Gut derived lipid factors have been implicated in systemic injury and inflammation but the precise pathways involved are unknown. In addition, dietary fat intake and obesity are independent risk factors for the development of colorectal cancer. Here we studied the severity of experimental colitis and the development of colitis associated cancer (CAC) in mice with an inducible block in chylomicron secretion and fat malabsorption, following intestine-specific deletion of microsomal triglyceride transfer protein (Mttp-IKO). METHODOLOGY/PRINCIPAL FINDINGS: Mttp-IKO mice exhibited more severe injury with ∼90% mortality following dextran sodium sulfate (DSS) induced colitis, compared to <20% in controls. Intestinal permeability was increased in Mttp-IKO mice compared to controls, both at baseline and after DSS administration, in association with increased circulating levels of TNFα. DSS treatment increased colonic mRNA expression of IL-1β and IL-17A as well as inflammasome expression in both genotypes, but the abundance of TNFα was selectively increased in DSS treated Mttp-IKO mice. There was a 2-fold increase in colonic tumor burden in Mttp-IKO mice following azoxymethane/DSS treatment, which was associated with increased colonic inflammation as well as alterations in cytokine expression. To examine the pathways by which alterations in fatty acid abundance might interact with cytokine signaling to regulate colonic epithelial growth, we used primary murine myofibroblasts to demonstrate that palmitate induced expression of amphiregulin and epiregulin and augmented the increase in both of these growth mediators when added to IL-1βor to TNFα. CONCLUSIONS: These studies demonstrate that Mttp-IKO mice, despite absorbing virtually no dietary fat, exhibit augmented fatty acid dependent signaling that in turn exacerbates colonic injury and increases tumor formation. Public Library of Science 2013-06-21 /pmc/articles/PMC3689718/ /pubmed/23805328 http://dx.doi.org/10.1371/journal.pone.0067819 Text en © 2013 Xie et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Xie, Yan Matsumoto, Hitoshi Nalbantoglu, ILKe Kerr, Thomas A. Luo, Jianyang Rubin, Deborah C. Kennedy, Susan Davidson, Nicholas O. Intestine-Specific Mttp Deletion Increases the Severity of Experimental Colitis and Leads to Greater Tumor Burden in a Model of Colitis Associated Cancer |
title | Intestine-Specific Mttp Deletion Increases the Severity of Experimental Colitis and Leads to Greater Tumor Burden in a Model of Colitis Associated Cancer |
title_full | Intestine-Specific Mttp Deletion Increases the Severity of Experimental Colitis and Leads to Greater Tumor Burden in a Model of Colitis Associated Cancer |
title_fullStr | Intestine-Specific Mttp Deletion Increases the Severity of Experimental Colitis and Leads to Greater Tumor Burden in a Model of Colitis Associated Cancer |
title_full_unstemmed | Intestine-Specific Mttp Deletion Increases the Severity of Experimental Colitis and Leads to Greater Tumor Burden in a Model of Colitis Associated Cancer |
title_short | Intestine-Specific Mttp Deletion Increases the Severity of Experimental Colitis and Leads to Greater Tumor Burden in a Model of Colitis Associated Cancer |
title_sort | intestine-specific mttp deletion increases the severity of experimental colitis and leads to greater tumor burden in a model of colitis associated cancer |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3689718/ https://www.ncbi.nlm.nih.gov/pubmed/23805328 http://dx.doi.org/10.1371/journal.pone.0067819 |
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