Suppression of intestinal inflammation and inflammation-driven colon cancer in mice by dietary sphingomyelin: Importance of peroxisome proliferator-activated receptor γ expression

dc.contributor.authorMazzei, Joseph Cayetanoen
dc.contributor.committeechairSchmelz, Eva M.en
dc.contributor.committeememberRoberts, Paul C.en
dc.contributor.committeememberGrange, Robert W.en
dc.contributor.departmentHuman Nutrition, Foods, and Exerciseen
dc.date.accessioned2014-03-14T21:40:34Zen
dc.date.adate2012-08-14en
dc.date.available2014-03-14T21:40:34Zen
dc.date.issued2012-07-06en
dc.date.rdate2012-08-14en
dc.date.sdate2012-07-20en
dc.description.abstractSphingolipid metabolites play a role in the initiation and perpetuation of inflammatory responses. Since intestinal inflammation is a driving force in the development of colon cancer, in the present study, we investigated the suppression of dextran sodium sulfate (DSS)-induced colitis by dietary sphingomyelin in mice that lack functional peroxisome proliferator-activated receptor γ (PPAR-γ) in intestinal epithelial and immune cells. Dietary spingomyelin decreased colonic inflammation in mice of both genotypes but more efficiently in mice expressing PPAR-γ. Using a real-time polymerase chain reaction array, we detected an up-regulation in genes involved in Th1 (interferon γ) and Th17 (interleukin [IL]-17 and IL-23) responses despite the reduced inflammation. However, the genes involved in Th2 (IL-4, IL-13 and IL-13ra2) and Treg (IL-10rb) anti-inflammatory responses were up-regulated in a PPAR-γ-dependent manner. In order to direct mechanistic studies of how PPAR-γ expression is involved in SM-induced suppression of DSS colitis, we investigated the effect of dietary SM in DSS-treated mice that lack PPAR-γ in the CD4+ T-cells. While the pathogenesis of colitis was independent of PPAR-γ expression in CD4+ T-cells, dietary SM decreased disease activity and colonic inflammation in mice of both genotypes but more efficiently in mice expressing PPAR-γ, indicating both PPAR-γ dependent and independent signaling pathways. In conclusion, in contrast to endogenous sphingolipid metabolites, dietary SM modulated both pro- and anti-inflammatory responses at the early stages of the disease in a partially PPAR-γ dependent manner resulting in a suppression of inflammation that may be critical for the suppression of inflammation-driven colon cancer.en
dc.description.degreeMaster of Scienceen
dc.identifier.otheretd-07202012-111447en
dc.identifier.sourceurlhttp://scholar.lib.vt.edu/theses/available/etd-07202012-111447/en
dc.identifier.urihttp://hdl.handle.net/10919/43766en
dc.publisherVirginia Techen
dc.relation.haspartMazzei_Joey_C_T_2012.pdfen
dc.rightsIn Copyrighten
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/en
dc.subjectSphingomyelinen
dc.subjectInflammationen
dc.subjectCD4+ T cellsen
dc.subjectColon Canceren
dc.titleSuppression of intestinal inflammation and inflammation-driven colon cancer in mice by dietary sphingomyelin: Importance of peroxisome proliferator-activated receptor γ expressionen
dc.typeThesisen
thesis.degree.disciplineHuman Nutrition, Foods, and Exerciseen
thesis.degree.grantorVirginia Polytechnic Institute and State Universityen
thesis.degree.levelmastersen
thesis.degree.nameMaster of Scienceen
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