Dietary Heme-Mediated PPARα Activation Does Not Affect the Heme-Induced Epithelial Hyperproliferation and Hyperplasia in Mouse Colon 英文参考文献.docVIP

DietaryHeme-MediatedPPARaActivationDoesNot AffecttheHeme-InducedEpithelialHyperproliferation andHyperplasiainMouseColon NoortjeIJssennagger1,2*.,NicoledeWit1,3.,MichaelMu¨ller1,2,3,RoelofvanderMeer1,2 1TopInstituteFoodandNutrition,Wageningen,TheNetherlands,2Nutrition,MetabolismandGenomicsGroup,DivisionofHumanNutrition,WageningenUniversity, Wageningen,TheNetherlands,3NetherlandsNutrigenomicsCentre,Wageningen,TheNetherlands Abstract Red meat consumption is associated with an increased colon cancer risk. Heme, present in red meat, injures the colon surface epithelium by luminal cytotoxicity and reactive oxygen species. This surface injury is overcompensated by hyperproliferation and hyperplasia of crypt cells. Transcriptome analysis of mucosa of heme-fed mice showed, besides stress- and proliferation-related genes, many upregulated lipid metabolism-related PPARa target genes. The aim of this studywastoinvestigatetheroleofPPARainheme-inducedhyperproliferationandhyperplasia.MalePPARaKOandWT mice received a purified diet with or without heme. As PPARa is proposed to protect against oxidative stress and lipid peroxidation,wehypothesizedthattheabsenceofPPARaleadstomoresurfaceinjuryandcrypthyperproliferationinthe colon upon heme-feeding. Heme induced luminal cytotoxicity and lipid peroxidation and colonic hyperproliferation and hyperplasia to the same extent in WT and KO mice. Transcriptome analysis of colonic mucosa confirmed similar heme- inducedhyperproliferationinWTandKOmice.StainingsforalkalinephosphataseactivityandexpressionlevelsofVanin-1 andNrf2-targetsindicatedacompromisedantioxidantdefenseinheme-fedKOmice.Ourresultssuggestthattheprotective roleofPPARainantioxidantdefenseinvolvestheNrf2-inhibitorFosl1,whichisupregulatedbyhemeinPPARaKOmice.We concludethatPPARaplaysaprotectiveroleincolonagainstoxidativestress,butPPARadoesnotmediateheme-induced hyperproliferation. This implies that oxidative stress of surface cells is not the main determinant of heme-induced hyperpro