Western Diet Deregulates Bile Acid Homeostasis, Cell Proliferation, and Tumorigenesis in Colon
Western Diet Deregulates Bile Acid Homeostasis, Cell Proliferation, and Tumorigenesis in Colon
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DOI：
10.1158/0008-5472.can-16-2860
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发表时间：
2017-06-15
期刊：
影响因子：
11.2
通讯作者：
Nystrom, Minna
中科院分区：
文献类型：
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作者：
Dermadi, Denis;Valo, Satu;Nystrom, Minna
西式饮食 (WD) 脂肪含量高、纤维和维生素 D 缺乏，会增加患结直肠癌的风险。在这里，我们对小鼠进行了一项长期饮食研究，以跟踪肿瘤发生并表征与 WD 和结直肠癌易感性相关的结肠粘膜的结构和代谢变化。 WD 增加了结肠肿瘤数量，粘膜蛋白质组分析表明细胞内胆汁酸 (BA) 稳态严重失调并激活了细胞增殖。 WD 还增加了隐窝深度和结肠细胞增殖。尽管管腔 BA 增加，但 WD 喂养小鼠的结肠细胞表现出 BA 转运蛋白 FABP6、OST β 和 ASBT 表达降低，次级 BA 脱氧胆酸和石胆酸浓度降低，表明核 BA 受体 FXR 活性降低。总体而言，我们的结果表明，WD 通过 FXR 失活增加癌症风险，导致 BA 失调并增加结肠细胞增殖。 (C) 2017 年 AACR。
Western-style diets (WD) high in fat and scarce in fiber and vitamin D increase risks of colorectal cancer. Here, we performed a long-term diet study in mice to follow tumorigenesis and characterize structural and metabolic changes in colon mucosa associated with WD and predisposition to colorectal cancer. WD increased colon tumor numbers, and mucosa proteomic analysis indicated severe deregulation of intracellular bile acid (BA) homeostasis and activation of cell proliferation. WD also in-creased crypt depth and colon cell proliferation. Despite increased luminal BA, colonocytes from WD-fed mice exhibited decreased expression of the BA transporters FABP6, OST beta, and ASBT and decreased concentrations of secondary BA deoxycholic acid and lithocholic acid, indicating reduced activity of the nuclear BA receptor FXR. Overall, our results suggest that WD increases cancer risk by FXR inactivation, leading to BA deregulation and increased colon cell proliferation. (C) 2017 AACR.