Liver fatty acid-binding protein (L-Fabp) modifies intestinal fatty acid composition and adenoma formation in ApcMin/+ mice.
Evidence suggests a relationship between dietary fat intake, obesity, and colorectal cancer, implying a role for fatty acid metabolism in intestinal tumorigenesis that is incompletely understood. Liver fatty acid-binding protein (L-Fabp), a dominant intestinal fatty acid-binding protein, regulates intestinal fatty acid trafficking and metabolism, and L-Fabp deletion attenuates diet-induced obesity. Here, we examined whether changes in intestinal fatty acid metabolism following L-Fabp deletion modify adenoma development in Apc(Min)(/+) mice. Compound L-Fabp(-/-)Apc(Min)(/+) mice were generated and fed a 10% fat diet balanced equally between saturated, monounsaturated, and polyunsaturated fat. L-Fabp(-/-)Apc(Min)(/+) mice displayed significant reductions in adenoma number and total polyp area compared with Apc(Min)(/+)controls, reflecting a significant shift in distribution toward smaller polyps. Adenomas from L-Fabp(-/-)Apc(Min)(/+) mice exhibited reductions in cellular proliferation, high-grade dysplasia, and nuclear β-catenin translocation. Intestinal fatty acid content was increased in L-Fabp(-/-)Apc(Min)(/+) mice, and lipidomic profiling of intestinal mucosa revealed significant shifts to polyunsaturated fatty acid species with reduced saturated fatty acid species. L-Fabp(-/-)Apc(Min)(/+) mice also showed corresponding changes in mRNA expression of enzymes involved in fatty acid elongation and desaturation. Furthermore, adenomas from L-Fabp(-/-)Apc(Min)(/+) mice displayed significant reductions in mRNA abundance of nuclear hormone receptors involved in cellular proliferation and in enzymes involved in lipogenesis. These findings collectively implicate L-Fabp as an important genetic modifier of intestinal tumorigenesis, and identify fatty acid trafficking and metabolic compartmentalization as an important pathway linking dietary fat intake, obesity, and intestinal tumor formation.
Washington University, Campus Box 8124, 660 South Euclid Avenue, St. Louis, MO 63110. nod@wustl.edu.
Sekhar
S
Dharmarajan
Elizabeth P
EP
Newberry
Grace
G
Montenegro
Ilke
I
Nalbantoglu
Victoria R
VR
Davis
Michael J
MJ
Clanahan
Valerie
V
Blanc
Yan
Y
Xie
Jianyang
J
Luo
James W
JW
Fleshman
Susan
S
Kennedy
Nicholas O
NO
Davidson
D000236:Adenoma / Q000378:metabolism*; D000818:Animals; D049109:Cell Proliferation; D004041:Dietary Fats; D015232:Dinoprostone / Q000378:metabolism; D050556:Fatty Acid-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism*; D005260:Female; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D005838:Genotype; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000378:metabolism*; D008055:Lipids / Q000737:chemistry; D051379:Mice; D008822:Mice, Transgenic; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors
D004041:Dietary Fats; C493320:Fabp1 protein, mouse; D050556:Fatty Acid-Binding Proteins; D005227:Fatty Acids; D008055:Lipids; D012333:RNA, Messenger; D015232:Dinoprostone