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

Erika L. Garcia-Villatoro, Jennifer A.A. DeLuca, Evelyn S. Callaway, Kimberly F. Allred, Laurie A. Davidson, Martha E. Hensel, Rani Menon, Ivan Ivanov, Stephen H. Safe, Arul Jayaraman, Robert S. Chapkin, Clinton D. Allred

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

Abstract

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. NEW & NOTEWORTHY 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.

Original languageEnglish (US)
Pages (from-to)G451-G463
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume318
Issue number3
DOIs
StatePublished - Mar 1 2020

Keywords

  • Aberrant crypt foci
  • Aryl hydrocarbon receptor
  • Colorectal cancer
  • High-fat diet
  • Intestinal epithelial cell
  • Cell Proliferation
  • Gene Expression Regulation, Neoplastic
  • Precancerous Conditions/chemically induced
  • Azoxymethane
  • Colonic Neoplasms/chemically induced
  • Diet, High-Fat
  • Gene Deletion
  • beta Catenin/genetics
  • Disease Models, Animal
  • Epithelial Cells/metabolism
  • Signal Transduction
  • Mice, Inbred C57BL
  • Receptors, Aryl Hydrocarbon/deficiency
  • Cell Transformation, Neoplastic/genetics
  • Basic Helix-Loop-Helix Transcription Factors/deficiency
  • Colon/metabolism
  • Mice, Knockout
  • Animals
  • Intestinal Mucosa/metabolism
  • DNA Damage

ASJC Scopus subject areas

  • Gastroenterology
  • Physiology (medical)
  • Physiology
  • Hepatology

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