BACKGROUND: Obesity is associated with an increased risk of colon cancer. High-fat diets that lead to obesity may be a contributing factor, but the mechanisms are unknown. AIMS: This study examines susceptibility to azoxymethane (AOM)-induced precancerous lesions in mice in response to consumption of either a low or a high-fat diet and associated molecular changes in the liver and colon. METHODS: Gene markers of xenobiotic metabolism, leptin-regulated inflammatory cytokines and proliferation were assessed in liver and colon in response to high-fat feeding to determine links with increased sensitivity to AOM. RESULTS: High-fat feeding increased development of AOM-induced precancerous lesions and was associated with increased CYP2E1 gene expression in the liver, but not the colon. Leptin receptors and the colon stem cell marker (Lgr5) were down-regulated in the proximal colon, with a corresponding up-regulation of the inflammatory cytokine (IL6) in response to high-fat feeding. Notably in the distal colon, where aberrant crypt foci develop in response to AOM, the proliferative stem cell marker, Lgr5, was significantly up-regulated with high-fat feeding. CONCLUSIONS: The current study provides evidence that high-fat diets can alter regulation of molecular markers of xenobiotic metabolism that may expose the colon to carcinogens, in parallel with activation of β-catenin-regulated targets regulating colon epithelial cells. High-fat diets associated with obesity may alter multiple molecular factors that act synergistically to increase the risk of colon cancer associated with obesity.
BACKGROUND:Obesity is associated with an increased risk of colon cancer. High-fat diets that lead to obesity may be a contributing factor, but the mechanisms are unknown. AIMS: This study examines susceptibility to azoxymethane (AOM)-induced precancerous lesions in mice in response to consumption of either a low or a high-fat diet and associated molecular changes in the liver and colon. METHODS: Gene markers of xenobiotic metabolism, leptin-regulated inflammatory cytokines and proliferation were assessed in liver and colon in response to high-fat feeding to determine links with increased sensitivity to AOM. RESULTS: High-fat feeding increased development of AOM-induced precancerous lesions and was associated with increased CYP2E1 gene expression in the liver, but not the colon. Leptin receptors and the colon stem cell marker (Lgr5) were down-regulated in the proximal colon, with a corresponding up-regulation of the inflammatory cytokine (IL6) in response to high-fat feeding. Notably in the distal colon, where aberrant crypt foci develop in response to AOM, the proliferative stem cell marker, Lgr5, was significantly up-regulated with high-fat feeding. CONCLUSIONS: The current study provides evidence that high-fat diets can alter regulation of molecular markers of xenobiotic metabolism that may expose the colon to carcinogens, in parallel with activation of β-catenin-regulated targets regulating colon epithelial cells. High-fat diets associated with obesity may alter multiple molecular factors that act synergistically to increase the risk of colon cancer associated with obesity.
Authors: Sara Padidar; Andrew J Farquharson; Lynda M Williams; Nigel Hoggard; Martin D Reid; Gary J Duncan; Janice E Drew Journal: Dig Dis Sci Date: 2010-09-08 Impact factor: 3.199
Authors: Jenifer I Fenton; Norman G Hord; Jackie A Lavigne; Susan N Perkins; Stephen D Hursting Journal: Cancer Epidemiol Biomarkers Prev Date: 2005-07 Impact factor: 4.254
Authors: D J Harriss; G Atkinson; K George; N Tim Cable; T Reilly; N Haboubi; M Zwahlen; M Egger; A G Renehan Journal: Colorectal Dis Date: 2009-01-17 Impact factor: 3.788
Authors: Kandy T Velázquez; Reilly T Enos; Meredith S Carson; Taryn L Cranford; Jackie E Bader; Ioulia Chatzistamou; Udai P Singh; Prakash S Nagarkatti; Mitzi Nagarkatti; J Mark Davis; James A Carson; E Angela Murphy Journal: Am J Physiol Gastrointest Liver Physiol Date: 2016-09-08 Impact factor: 4.052
Authors: Stani D Day; Reilly T Enos; Jamie L McClellan; J L Steiner; Kandy T Velázquez; E A Murphy Journal: Cytokine Date: 2013-06-02 Impact factor: 3.861
Authors: 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 Journal: Am J Physiol Gastrointest Liver Physiol Date: 2020-01-06 Impact factor: 4.052