Western Diet Deregulates Bile Acid Homeostasis, Cell Proliferation, and Tumorigenesis in Colon

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...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2017-06, Vol.77 (12), p.3352-3363
Main Authors: Dermadi, Denis, Valo, Satu, Ollila, Saara, Soliymani, Rabah, Sipari, Nina, Pussila, Marjaana, Sarantaus, Laura, Linden, Jere, Baumann, Marc, Nyström, Minna
Format: Article
Language:English
Subjects:
Acids
Animals
Bile
Bile Acids and Salts - metabolism
Blotting, Western
Cell activation
Cell growth
Cell Proliferation
Cell Transformation, Neoplastic - pathology
Chromatography, Liquid
Colon
Colon - pathology
Colon cancer
Colorectal cancer
Colorectal carcinoma
Deoxycholic acid
Deregulation
Diet
Diet, Western - adverse effects
Disease Models, Animal
Electrophoresis, Gel, Two-Dimensional
Female
Health risks
High fat diet
High-Throughput Screening Assays
Homeostasis
Homeostasis - physiology
Inactivation
Intestinal Mucosa - metabolism
Intestinal Mucosa - pathology
Male
Mass Spectrometry
Mice
Mice, Inbred C57BL
Mucosa
Polymerase Chain Reaction
Proteomics
Random Allocation
Receptors, Cytoplasmic and Nuclear
Tumorigenesis
Vitamin D
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Summary: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 increased crypt depth and colon cell proliferation. Despite increased luminal BA, colonocytes from WD-fed mice exhibited decreased expression of the BA transporters FABP6, OSTβ, 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. .
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.can-16-2860