Oleic acid inhibits hepatic insulin signaling through deregulation of STAT3 activation and C/EBPalpha expression.

Elevated free fatty acids (FFAs) are known to induce the impairment of insulin signaling. However, the insulin signaling components that are deregulated by FFAs in the liver remain unknown. Here, we examined the mechanisms of disruption of oleic acid on insulin signaling in hepatic cell lines. Oleic acid decreased the expression of insulin receptor substrate (IRS) 1 and augmented the expression of suppressor of cytokine signaling (SOCS) 3, which can induce the proteasome-mediated degradation of IRS. Moreover, oleic acid enhanced the phosphorylation of signal transducer and activator of transcription (STAT) 3 and induced the expression of CCAAT/enhancer-binding protein alpha (C/EBPalpha). The interaction between STAT3 and C/EBPalpha was increased by oleic acid; these proteins subsequently enhanced the promoter activity of SOCS3 in the presence of oleic acid. Finally, oleic acid impaired the insulin signaling cascades through inhibition of the alpha-associated signaling pathway.