Western diet enhances intestinal tumorigenesis in Min/+ mice, associating with mucosal metabolic and inflammatory stress and loss of Apc heterozygosity.
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 ApcMin/+(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 Min to wild-type allele was higher in the WD mice, indicating accelerated loss of Apc heterozygosity (LOH). Densities of intraepithelial CD3ε+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.
Department of Food and Environmental Sciences, Division of Nutrition, University of Helsinki, P.O. Box 66, Agnes Sjöbergin katu 2, FI-00014 Helsinki, Finland; Faculty of Veterinary Medicine, Division of Veterinary Biosciences, University of Helsinki, P.O. Box 66, Agnes Sjöbergin katu 2, FI-00014 Helsinki, Finland.
Mikael
M
Niku
Department of Food and Environmental Sciences, Division of Nutrition, University of Helsinki, P.O. Box 66, Agnes Sjöbergin katu 2, FI-00014 Helsinki, Finland.
Anne-Maria
AM
Pajari
Department of Biosciences, Division of Genetics, P.O. Box 65, University of Helsinki, FI-00014 Helsinki, Finland.
Laura
L
Sarantaus
Department of Food and Environmental Sciences, Division of Nutrition, University of Helsinki, P.O. Box 66, Agnes Sjöbergin katu 2, FI-00014 Helsinki, Finland.
Essi
E
Päivärinta
School of Pharmacy, University of Eastern Finland, P.O. Box 1627, FI-70211, Kuopio, Finland.
Markus
M
Storvik
Department of Food and Environmental Sciences, Division of Nutrition, University of Helsinki, P.O. Box 66, Agnes Sjöbergin katu 2, FI-00014 Helsinki, Finland.
Anu
A
Heiman-Lindh
Faculty of Veterinary Medicine, Division of Veterinary Biosciences, University of Helsinki, P.O. Box 66, Agnes Sjöbergin katu 2, FI-00014 Helsinki, Finland.
Santeri
S
Suokas
Department of Biosciences, Division of Genetics, P.O. Box 65, University of Helsinki, FI-00014 Helsinki, Finland.
Minna
M
Nyström
Department of Food and Environmental Sciences, Division of Nutrition, University of Helsinki, P.O. Box 66, Agnes Sjöbergin katu 2, FI-00014 Helsinki, Finland. Electronic address: marja.mutanen@Helsinki.fi.
Marja
M
Mutanen
D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics / Q000378:metabolism; D000818:Animals; D063646:Carcinogenesis / Q000473:pathology*; D015179:Colorectal Neoplasms / Q000175:diagnosis / Q000473:pathology; D066273:Diet, Western / Q000009:adverse effects*; D004195:Disease Models, Animal; D005260:Female; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000473:pathology*; D019656:Loss of Heterozygosity; D020935:MAP Kinase Signaling System; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
D025601:Adenomatous Polyposis Coli Protein; C000631439:Pdk4 protein, mouse; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; C000613192:adenomatous polyposis coli protein, mouse; D051176:beta Catenin; D000076222:Mechanistic Target of Rapamycin Complex 1; D017346:Protein Serine-Threonine Kinases
Apc(Min/+) mice; ERK; Energy metabolism; High-risk Western-type diet; Intestinal cancer; Loss of heterozygosity; PDK4