| First Author | Xie Y | Year | 2013 |
| Journal | PLoS One | Volume | 8 |
| Issue | 6 | Pages | e67819 |
| PubMed ID | 23805328 | Mgi Jnum | J:204352 |
| Mgi Id | MGI:5532279 | Doi | 10.1371/journal.pone.0067819 |
| Citation | Xie Y, et al. (2013) Intestine-Specific Mttp Deletion Increases the Severity of Experimental Colitis and Leads to Greater Tumor Burden in a Model of Colitis Associated Cancer. PLoS One 8(6):e67819 |
| abstractText | 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 approximately 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 TNFalpha. DSS treatment increased colonic mRNA expression of IL-1beta and IL-17A as well as inflammasome expression in both genotypes, but the abundance of TNFalpha 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-1betaor to TNFalpha. 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. |
