Western diet enhances intestinal tumorigenesis in Min/ plus mice, associating with mucosal metabolic and inflammatory stress and loss of Apc heterozygosity

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Niku , M , Pajari , A-M , Sarantaus , L , Päivärinta , E , Storvik , M , Heiman-Lindh , A , Suokas , S , Nyström , M & Mutanen , M 2017 , ' Western diet enhances intestinal tumorigenesis in Min / plus mice, associating with mucosal metabolic and inflammatory stress and loss of Apc heterozygosity ' , Journal of Nutritional Biochemistry , vol. 39 , pp. 126-133 . https://doi.org/10.1016/j.jnutbio.2016.09.016

Title: Western diet enhances intestinal tumorigenesis in Min/ plus mice, associating with mucosal metabolic and inflammatory stress and loss of Apc heterozygosity
Author: Niku, Mikael; Pajari, Anne-Maria; Sarantaus, Laura; Päivärinta, Essi; Storvik, Markus; Heiman-Lindh, Anu; Suokas, Santeri; Nyström, Minna; Mutanen, Marja
Contributor: University of Helsinki, Departments of Faculty of Veterinary Medicine
University of Helsinki, Department of Food and Nutrition
University of Helsinki, Biosciences
University of Helsinki, Department of Food and Nutrition
University of Helsinki, Biosciences
University of Helsinki, Department of Food and Nutrition
Date: 2017-01
Language: eng
Number of pages: 8
Belongs to series: Journal of Nutritional Biochemistry
ISSN: 0955-2863
URI: http://hdl.handle.net/10138/309229
Abstract: Western-type diet (WD) is a risk factor for colorectal cancer, but the underlying mechanisms are poorly understood. We investigated the interaction of WD and heterozygous mutation in the Apc gene on adenoma formation and metabolic and immunological changes in the histologically normal intestinal mucosa of Apc(Min/+) (Min/ +) mice. The diet used was high in saturated fat and low in calcium, vitamin D, fiber and folate. The number of adenomas was twofold higher in the WD mice compared to controls, but adenoma size, proliferation or apoptosis did not differ. The ratio of the MM to wild-type allele was higher in the WD mice, indicating accelerated loss of Apc heterozygosity (LOH). Densities of intraepithelial CD3 epsilon(+) T lymphocytes and of mucosal FoxP3(+) regulatory T cells were higher in the WD mice, implying inflammatory changes. Western blot analyses from the mucosa of the WD mice showed suppressed activation of the ERK and AKT pathways and a tendency for reduced activation of the mTOR pathway as measured in phosphoS6/S6 levels. The expression of pyruvate dehydrogenase kinase 4 was up-regulated in both mRNA and protein levels. Gene expression analyses showed changes in oxidation/reduction, fatty acid and monosaccharide metabolic pathways, tissue organization, cell fate and regulation of apoptosis. Together, our results suggest that the high-risk Western diet primes the intestine to tumorigenesis through synergistic effects in energy metabolism, inflammation and oxidative stress, which culminate in the acceleration of LOH of the Apc gene. (C) 2016 Elsevier Inc. All rights reserved.
Subject: High-risk Western-type diet
Intestinal cancer
Energy metabolism
Loss of heterozygosity
PDK4
ERK
Apc(min/+) mice
HIGH-FAT DIET
COLON-CANCER
APC(MIN/+) MICE
BETA-CATENIN
CELL-PROLIFERATION
INSULIN-RESISTANCE
TUMOR-FORMATION
DNA-DAMAGE
EXPRESSION
INHIBITOR
1182 Biochemistry, cell and molecular biology
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