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 ß-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 ß 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.