Abstract
Excessive saturated fatty acids (SFA) uptake is known to be a primary cause of obesity, a widely acknowledged risk factor of insulin resistance and type 2 diabetes. Although specific microRNAs (miRNAs) targeting insulin signaling intermediates are dysregulated by SFA, their effects on insulin signaling and sensitivity are largely unknown. Here, we investigated the role of SFA-induced miR-183-5p in the regulation of proximal insulin signaling molecules and the development of hepatic insulin resistance. HepG2 hepatocytes treated with palmitate and the livers of high-fat diet (HFD)-fed mice exhibited impaired insulin signaling resulting from dramatic reductions in the protein expressions of insulin receptor (INSR) and insulin receptor substrate-1 (IRS-1). Differential expression analysis showed the level of miR-183-5p, which tentatively targets the 3′UTR of IRS-1, was significantly elevated in palmitate-treated HepG2 hepatocytes and the livers of HFD-fed mice. Dual-luciferase analysis showed miR-183-5p bound directly to the 3′UTR of IRS-1 and reduced IRS-1 expression at the post-transcriptional stage. Moreover, transfection of HepG2 hepatocytes with miR-183-5p mimic significantly inhibited IRS-1 expression and hindered insulin signaling, consequently inhibiting insulin-stimulated glycogen synthesis. Collectively, this study reveals a novel mechanism whereby miR-183-5p induction by SFA impairs insulin signaling and suggests miR-183-5p plays a crucial role in the pathogenesis of hepatic insulin resistance in the background of obesity.
Highlights
This study reveals the crucial role of miR-183-5p in the insulin signaling pathway by targeting insulin receptor substrate-1 (IRS-1) and suggests a novel mechanism for hepatic insulin resistance in obesity
saturated fatty acids (SFA) has been shown to downregulate the expressions of insulin receptor (INSR) and insulin receptor substrate (IRS)-1 via multiple mechanisms, this study demonstrates that SFA-inducible miR-183-5p contributes to IRS-1 reduction in hepatocytes and suggests that induction of miR-183-5p contributes toward hepatic insulin resistance in a background of obesity
MiR-183-5p was induced by SFA palmitate and suppressed IRS-1 expression by targeting the 30 untranslated regions (30 UTRs) of IRS-1, and the ectopic expression of miR-183-5p mimic suppressed IRS-1 expression, inhibiting proximal insulin signaling and insulin-stimulated glycogen synthesis in HepG2 hepatocytes
Summary
Excessive consumption of dietary saturated fatty acids (SFA) is closely associated with obesity and the ectopic accumulation of lipids, which can provoke lipotoxicity, metabolic dysfunction, and apoptosis in tissues [1,2]. As the liver is a vital organ in whole-body metabolic homeostasis, lipid burden in hepatocytes reduces insulin sensitivity and can lead to metabolic diseases, such as hepatic insulin resistance and type 2 diabetes (T2DM) [3]. The insulin signaling pathway is triggered when insulin binds to cell surface insulin receptor (INSR), and this interaction is followed by the phosphorylations of various proximal signaling intermediates, including insulin receptor substrate (IRS) and v-akt murine thymoma viral oncogene (Akt), and subsequently modulates various metabolic functions [4,5]. Hepatic insulin resistance is characterized by insufficient insulin sensitivity or impaired insulin signaling in the liver, which increases inappropriate gluconeogenesis and glucose output, developing hyperglycemia and impeding whole-body energy utilization [6]
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