Dietary saturated fatty acids (SFA) in excess not only induce hepatic insulin resistance, but also result in type 2 diabetes (T2DM). Although microRNAs (miRNAs) participate widely in the pathogenesis of a range of diseases through the suppression of target gene expression at the post-transcriptional level, the implications of SFA-induced miRNAs in the dysregulation of metabolism, particularly in the development of insulin resistance, are largely unclear. SFA palmitate provoked an impairment of insulin signaling in HepG2 cells via a reduction in the expression of INSR and IRS-1 protein. The significant upregulation of miR-1271, which was presumed to target INSR and IRS-1 3'UTRs, was observed in the palmitate-treated HepG2 cells. Using a reporter gene assay, miR-1271 authentically targeted the 3'UTRs of INSR and IRS-1. Furthermore, the overexpression of miR-1271 caused a substantial decrease in INSR and IRS-1 expression, which led to an impairment in insulin signaling and glycogen metabolism. Therefore, these findings suggest that the induction of miR-1271 by SFA palmitate promotes the development of insulin resistance by targeting INSR and IRS-1 in hepatocytes. (C) 2016 Elsevier Inc. All rights reserved.