Saturated fatty acids regulate retinoic acid signaling and suppress tumorigenesis by targeting fatty acid-binding protein 5

Long chain fatty acids (LCFA) serve as energy sources, components of cell membranes, and precursors for signalling molecules. Here we show that these important biological compounds also regulate gene expression by controlling the transcriptional activities of the retinoic acid (RA)-activated nuclear receptors RAR and PPARβ/δ. Our data indicates that these activities of LCFA are mediated by FABP5, a protein that delivers ligands from the cytosol to nuclear PPARβ/δ. Both saturated and unsaturated LCFA (SLCFA, ULCFA) tightly bind to FABP5, thereby displacing RA and diverting it to RAR. However, while SLCFA inhibit, ULCFA activate the FABP5/PPARβ/δ pathway. By concomitantly promoting the activation of RAR and inhibiting the activity of PPARβ/δ, SLCFA suppress the growth and oncogenic properties of FABP5-expressing carcinoma cells both in cultured cells and in vivo. Mammary carcinoma line NaF was used to to examine the whole-genome effect of RAR and PPARd ligands on gene expression.