Effects of high-fat diet and intestinal aryl hydrocarbon receptor deletion on colon carcinogenesis

• Published in: American journal of physiology: Gastrointestinal and liver physiology 2020-03, Vol.318 (3), p.G451-G463
• Main Authors: Garcia-Villatoro, Erika L, DeLuca, Jennifer A A, Callaway, Evelyn S, Allred, Kimberly F, Davidson, Laurie A, Hensel, Martha E, Menon, Rani, Ivanov, Ivan, Safe, Stephen H, Jayaraman, Arul, Chapkin, Robert S, Allred, Clinton D
• Format: Article
• Language: English
• Subjects: Animals; Azoxymethane; Basic Helix-Loop-Helix Transcription Factors - deficiency; Basic Helix-Loop-Helix Transcription Factors - genetics; beta Catenin - genetics; beta Catenin - metabolism; Carcinogenesis; Cecum; Cell Proliferation; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Cell Transformation, Neoplastic - pathology; Colon - metabolism; Colon - pathology; Colon cancer; Colonic Neoplasms - chemically induced; Colonic Neoplasms - genetics; Colonic Neoplasms - metabolism; Colonic Neoplasms - pathology; Colorectal cancer; Colorectal carcinoma; Diet; Diet, High-Fat; Disease Models, Animal; DNA Damage; Epithelial cells; Epithelial Cells - metabolism; Epithelial Cells - pathology; Gene Deletion; Gene Expression Regulation, Neoplastic; High fat diet; Homeostasis; Hydrocarbons; Intestinal Mucosa - metabolism; Intestinal Mucosa - pathology; Intestine; Lesions; Localization; Mice, Inbred C57BL; Mice, Knockout; Precancerous Conditions - chemically induced; Precancerous Conditions - genetics; Precancerous Conditions - metabolism; Precancerous Conditions - pathology; Receptors, Aryl Hydrocarbon - deficiency; Receptors, Aryl Hydrocarbon - genetics; Signal Transduction; Tumors; β-Catenin
• ISSN: 0193-1857; 1522-1547
• DOI: 10.1152/ajpgi.00268.2019

Consumption of a high-fat diet has been associated with an increased risk of developing colorectal cancer (CRC). However, the effects of the interaction between dietary fat content and the aryl hydrocarbon receptor (AhR) on colorectal carcinogenesis remain unclear. Mainly known for its role in xenobiotic metabolism, AhR has been identified as an important regulator for maintaining intestinal epithelial homeostasis. Although previous research using whole body AhR knockout mice has revealed an increased incidence of colon and cecal tumors, the unique role of AhR activity in intestinal epithelial cells (IECs) and modifying effects of fat content in the diet at different stages of sporadic CRC development are yet to be elucidated. In the present study, we have examined the effects of a high-fat diet on IEC-specific AhR knockout mice in a model of sporadic CRC. Although loss of AhR activity in IECs significantly induced the development of premalignant lesions, in a separate experiment, no significant changes in colon mass incidence were observed. Moreover, consumption of a high-fat diet promoted cell proliferation in crypts at the premalignant colon cancer lesion stage and colon mass multiplicity as well as β-catenin expression and nuclear localization in actively proliferating cells in colon masses. Our data demonstrate the modifying effects of high-fat diet and AhR deletion in IECs on tumor initiation and progression. Through the use of an intestinal-specific aryl hydrocarbon receptor (AhR) knockout mouse model, this study demonstrates that the expression of AhR in intestinal epithelial cells is required to reduce the formation of premalignant colon cancer lesions. Furthermore, consumption of a high-fat diet and the loss of AhR in intestinal epithelial cells influences the development of colorectal cancer at various stages.