Liver fatty acid-binding protein (L-Fabp) modifies intestinal fatty acid composition and adenoma formation in ApcMin/+ mice

Sekhar Dharmarajan, Elizabeth P. Newberry, Grace Montenegro, ILKe Nalbantoglu, Victoria R. Davis, Michael J. Clanahan, Valerie Blanc, Yan Xie, Jianyang Luo, James W. Fleshman, Susan Kennedy, Nicholas O. Davidson

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

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-/- ApcMin/+ 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 ApcMin/+ controls, reflecting a significant shift in distribution toward smaller polyps. Adenomas from L-Fabp-/- ApcMin/+ 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-/- ApcMin/+ mice also showed corresponding changes in mRNA expression of enzymes involved in fatty acid elongation and desaturation. Furthermore, adenomas from L-Fabp-/- ApcMin/+ 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.

Original languageEnglish
Pages (from-to)1026-1037
Number of pages12
JournalCancer Prevention Research
Volume6
Issue number10
DOIs
StatePublished - Oct 1 2013

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