title: High-fat diet alters gene expression in the liver and colon: links to increased development of aberrant crypt foci.
abstract: 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.
  
  
  OBJECTIVE
  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.affiliation: Rowett Institute of Nutrition and Health, University of Aberdeen, Aberdeen, Scotland, UK.
authors.forename: Sara
authors.initials: S
authors.lastname: Padidar
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Farquharson
authors.forename: Lynda M
authors.initials: LM
authors.lastname: Williams
authors.forename: Rebecca
authors.initials: R
authors.lastname: Kearney
authors.forename: John R
authors.initials: JR
authors.lastname: Arthur
authors.forename: Janice E
authors.initials: JE
authors.lastname: Drew
mesh_terms: D058739:Aberrant Crypt Foci / Q000453:epidemiology / Q000209:etiology* / Q000473:pathology; D000818:Animals; D001823:Body Composition / Q000187:drug effects / Q000502:physiology; D003106:Colon / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D015179:Colorectal Neoplasms / Q000453:epidemiology / Q000209:etiology* / Q000473:pathology; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D059305:Diet, High-Fat; D004041:Dietary Fats / Q000009:adverse effects* / Q000494:pharmacology*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000502:physiology; D015994:Incidence; D020738:Leptin / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D054411:Receptors, Leptin / Q000235:genetics / Q000378:metabolism
chemical_list: D016207:Cytokines; D004041:Dietary Fats; D020738:Leptin; C493597:Lgr5 protein, mouse; D043562:Receptors, G-Protein-Coupled; D054411:Receptors, Leptin; D019392:Cytochrome P-450 CYP2E1