title: Plant sterol feeding induces tumor formation and alters sterol metabolism in the intestine of Apc(Min) mice.
abstract: Dietary plant sterols reduce the absorption of cholesterol and therefore increase intraluminal cholesterol concentration. We examined how plant sterol esters from functional foods affect intestinal tumorigenesis in tumor-prone adenomatous polyposis coli (Apc)(Min) mice. Feeding plant sterols at 0.8% increased the number of intestinal adenomas, and the effect was significant in female mice. The concentration of mucosal free sitosterol increased by eightfold in plant sterol males and by threefold in plant sterol females when compared with respective controls. The concentration of mucosal free cholesterol was significantly lower in plant sterol males than in control males, and the decrease in free cholesterol was accompanied with a significant increase in nuclear sterol regulatory element binding protein-2. No difference was found in the levels of β-catenin, cyclin D1, epidermal growth factor receptor, extracellular signal-regulated kinase 1/2, or caveolin-1 in either gender after plant sterol feeding. Among all measured parameters, higher levels of estrogen receptor β and free cholesterol in the mucosa were among the strongest predictors of increased intestinal tumorigenesis. In addition, gene expression data showed significant enrichment of up-regulated genes of cell cycle control and cholesterol biosynthesis in plant sterol females. The results indicate that high intake of plant sterols accelerates intestinal tumorigenesis in female Apc (Min)mice; however, the mechanism behind the adverse effect remains to be discovered.
authors.affiliation: a Department of Food and Environmental Sciences, Division of Nutrition , University of Helsinki , Helsinki , Finland.
authors.forename: Maija
authors.initials: M
authors.lastname: Marttinen
authors.forename: Anne-Maria
authors.initials: AM
authors.lastname: Pajari
authors.forename: Essi
authors.initials: E
authors.lastname: Päivärinta
authors.forename: Markus
authors.initials: M
authors.lastname: Storvik
authors.forename: Pekka
authors.initials: P
authors.lastname: Marttinen
authors.forename: Tanja
authors.initials: T
authors.lastname: Nurmi
authors.forename: Mikael
authors.initials: M
authors.lastname: Niku
authors.forename: Vieno
authors.initials: V
authors.lastname: Piironen
authors.forename: Marja
authors.initials: M
authors.lastname: Mutanen
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000139:chemically induced / Q000473:pathology*; D000818:Animals; D051242:Caveolin 1 / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D019938:Cyclin D1 / Q000378:metabolism; D004032:Diet; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D007408:Intestinal Absorption / Q000187:drug effects; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism; D007422:Intestines / Q000187:drug effects* / Q000473:pathology; D050356:Lipid Metabolism / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010840:Phytosterols / Q000008:administration & dosage* / Q000009:adverse effects*; D012855:Sitosterols / Q000378:metabolism; D051782:Sterol Regulatory Element Binding Protein 2 / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
chemical_list: C495267:CTNNB1 protein, mouse; C495541:Cav1 protein, mouse; D051242:Caveolin 1; C530105:Ccnd1 protein, mouse; D010840:Phytosterols; D012855:Sitosterols; C497391:Srebf2 protein, mouse; D051782:Sterol Regulatory Element Binding Protein 2; D051176:beta Catenin; D019938:Cyclin D1; C025473:gamma-sitosterol; D002784:Cholesterol; C541485:EGFR protein, mouse; D066246:ErbB Receptors; D048052:Mitogen-Activated Protein Kinase 3