Oleate regulates genes controlled by signaling pathways of mitogen-activated protein kinase, insulin, and hypoxia

Oleate (C18:1) is, besides palmitate (C16:0), the most abundant fatty acid in the human diet, and its involvement in the development of insulin resistance is broadly discussed. Because its influence on gene expression is poorly defined in mammalian cells, we performed whole genome expression profiling and quantitative real-time polymerase chain reaction in the human hepatocyte cell line HepG2 to identify oleate-regulated genes. In this respect, HepG2 cells were exposed for 24 hours to a physiologic concentration of oleate coupled to bovine serum albumin (BSA) (200 μmol/L) or BSA alone. Subsequent microarray analysis revealed 14 genes that were significantly (single-sided permutational t test, P < .05) regulated after oleate treatment. To decipher the functional and regulatory connections of these genes, a text mining approach combined with transcription factor binding site analysis was performed using Genomatix BiblioSphere (Munich, Germany) and MatInspector (Munich, Germany). The oleate-inducible genes encoding early growth response 1, c-fos, S-phase kinase-associated protein 2, and splicing factor 2 are mapped into a network, which is controlled by signaling pathways of mitogen-activated protein kinase, insulin, or hypoxia. Comparative in silico promoter analysis revealed putative regulation of oleate-sensitive genes through v-ets erythroblastosis virus E26 oncogene homolog 1 and retinoid X receptor family. In sum, a physiologic oleate concentration modulates genes expression in a very sensitive way as 14 genes were regulated.