Dietary Stearic Acid Accelerates Intestinal Tumorigenesis via Fatty Acid-binding Protein 5 Without Promoting Obesity

Dietary fat increases the risk of intestinal cancer, but the effect of the fatty acid composition on tumorigenesis is unclear. The aim of this study is to investigate the impact of diets with different fatty acids on carcinogenesis in the intestine.

Mice were fed a linoleic acid (LA)-rich or stearic acid (SA)-rich high-fat diet (HFD) from the age of 4 weeks. The Apc^Min/+ mice and an azoxymethane- and a dextran sulfate sodium-induced colorectal cancer (CRC) mouse model were used to examine the effects of different dietary fatty acids on CRC development. Fatty acid-binding protein 5 (FABP5) knockout mice and SBFI-26, an inhibitor of FABP5, were used to assess its contribution.

We found that an SA-rich HFD more strongly accelerated tumorigenesis in murine CRC models than an LA-rich HFD, with fewer obesity phenotypes compared with LA-rich HFD-fed mice. Dietary SA more strongly promoted epithelial cell proliferation and Paneth cell differentiation than LA, whereas no differences in the numbers of leucine-rich repeat-containing G protein-coupled receptor 5⁺ and B lymphoma Mo-MLV insertion region 1 homolog⁺ intestinal stem cells were detected between the groups. In murine and human intestinal organoids, SA promoted crypt formation. We found that FABP5 was expressed in a small population of Ki67⁺ proliferative cells in crypts, and the number of Ki67⁺ FABP5⁺ cells was increased by SA-rich HFD feeding. FABP5 inhibition suppressed SA-induced epithelial cell proliferation, Paneth cell differentiation, and tumorigenesis.

Dietary SA can promote CRC via FABP5 without promoting obesity.