Liver Fatty Acid Binding Protein (L-Fabp): A Genetic Modifier of Murine Intestinal Polyposis
Ilke Nalbantoglu, Sekhar Dharmarajan, Elizabeth Newberry, Nicholas O Davidson. Washington University in St. Louis, St. Louis, MO
Background: Consumption of a high-fat diet is linked to an increased prevalence of colonic adenomas in the setting of obesity and insulin resistance. We examined the role of L-Fabp, a cytosolic transport protein that regulates trafficking of long chain fatty acids, bile acids, and cholesterol, as a genetic modifier(GM) of diet induced obesity. We predicted that L-Fabp is a potential GM linking obesity and dietary fat intake with adenoma susceptibility.
Design: L-Fabp -/- mice are protected against high fat diet-induced obesity. Apc min/+ mice carry a heterozygous deletion in the APC gene and develop intestinal adenomas with loss of heterozygosity. We crossed L-Fabp -/- mice into the Apc min/+ background to examine adenoma development and progression in L-Fabp -/-, Apc min/+ mice. Mice were fed a 10% fat diet, sacrificed at 100±4 days of age. Polyp number, regional distribution and histological characterization are undertaken to determine high grade dysplasia (HGD) for each genotype.
Results: The total number of polyps, and polyp area in proximal, mid and distal SI were significantly reduced in L-Fabp -/-, Apc min/+ compared to Apc min/+ mice, with a wild type L-Fabp allele. The average total polyp count was 52.3 ± 5.5 in Apc min/+ mice versus(vs) 35.5 ± 5.2 in L-Fabp -/-, Apc min/+ mice with protection against polyp development most significant in the proximal intestine.
The proportion of polyps with HGD was also reduced in L-Fabp-/-, Apc min/+ vs Apc min/+mice (p=0.04). Protection against development of HGD was most significant in distal SI (p=0.025).
Conclusions: L-Fabp -/- Apc min/+ mice are protected against intestinal polyposis, raising the possibility that alterations in the metabolism and/or trafficking of fatty acids, cholesterol or bile acids modulates adenoma growth.
Tuesday, March 20, 2012 9:30 AM
Poster Session III # 138, Tuesday Morning