Department of Food and Environmental Sciences, Division of Nutrition, P.O. Box 66 (Agnes Sjöbergin katu 2), FIN-00014 University of Helsinki, Finland.
J Nutr Biochem. 2013 Jan;24(1):343-52. doi: 10.1016/j.jnutbio.2012.07.002. Epub 2012 Sep 13.
The rate of APC mutations in the intestine increases in middle-age. At the same period of life, plant sterol and stanol enriched functional foods are introduced to diet to lower blood cholesterol. This study examined the effect of plant stanol enriched diet on intestinal adenoma formation in the Apc(Min) mouse. Apc(Min) mice were fed 0.8% plant stanol diet or control diet for nine weeks. Cholesterol, plant sterols and plant stanols were analyzed from the caecum content and the intestinal mucosa. Levels of β-catenin, cyclin D1, epidermal growth factor receptor (EGFR) and extracellular signal-regulated kinase 1/2 (ERK1/2) were measured from the intestinal mucosa by Western blotting. Gene expression was determined from the intestinal mucosa using Affymetrix and the data were analyzed for enriched categories and pathways. Plant stanols induced adenoma formation in the small intestine, however, the adenoma size was not affected. We saw increased levels of nuclear β-catenin, phosphorylated β-catenin (Ser675 and Ser552), nuclear cyclin D1, total and phosphorylated EGFR and phosphorylated ERK1/2 in the intestinal mucosa after plant stanol feeding. The Affymetrix data demonstrate that several enzymes of cholesterol synthesis pathway were up-regulated, although the cholesterol level in the intestinal mucosa was not altered. We show that plant stanols induce adenoma formation by activating Wnt and EGFR signaling. EGFR signaling seems to have promoted β-catenin phosphorylation and its translocation into the nucleus, where the expression of cyclin D1 was increased. Up-regulated cholesterol synthesis may partly explain the increased EGFR signaling in the plant stanol-fed mice.
肠道中 APC 突变的速度在中年时期增加。在同一生命时期，富含植物固醇和甾烷醇的功能性食品被引入饮食中以降低血液胆固醇。本研究检查了富含植物甾烷醇的饮食对 Apc(Min)小鼠肠道腺瘤形成的影响。Apc(Min)小鼠喂食 0.8%植物甾烷醇饮食或对照饮食 9 周。从盲肠内容物和肠黏膜中分析胆固醇、植物固醇和植物甾烷醇。通过 Western blot 从肠黏膜中测量β-连环蛋白、细胞周期蛋白 D1、表皮生长因子受体 (EGFR) 和细胞外信号调节激酶 1/2 (ERK1/2) 的水平。使用 Affymetrix 从肠黏膜中确定基因表达，并对富集类别和途径进行数据分析。植物甾烷醇在小肠中诱导腺瘤形成，但腺瘤大小不受影响。我们在植物甾烷醇喂养后观察到肠黏膜中核β-连环蛋白、磷酸化β-连环蛋白 (Ser675 和 Ser552)、核细胞周期蛋白 D1、总和磷酸化 EGFR 和磷酸化 ERK1/2 水平增加。Affymetrix 数据表明，尽管肠黏膜中的胆固醇水平没有改变，但几种胆固醇合成途径的酶被上调。我们表明，植物甾烷醇通过激活 Wnt 和 EGFR 信号转导诱导腺瘤形成。EGFR 信号似乎促进了β-连环蛋白的磷酸化及其向细胞核的易位，从而增加了细胞周期蛋白 D1 的表达。上调的胆固醇合成可能部分解释了植物甾烷醇喂养小鼠中 EGFR 信号的增加。
