Abstract

Several studies have suggested an important role of miR-291b-3p in the development of embryonic stem cells. In previous study, we found that the expression of miR-291b-3p was significantly upregulated in the liver of db/db mice. However, the role of miR-291b-3p in glucose metabolism and its underlying mechanisms remain unknown. In the present study, we demonstrated that miR-291b-3p was abundantly expressed in the liver. Of note, hepatic miR-291b-3p expression was upregulated in HFD-fed mice and induced by fasting in C57BL/6 J normal mice. Importantly, hepatic inhibition miR-291b-3p expression ameliorated hyperglycemia and insulin resistance in HFD-fed mice, whereas hepatic overexpression of miR-291b-3p led to hyperglycemia and insulin resistance in C57BL/6 J normal mice. Further study revealed that miR-291b-3p suppressed insulin-stimulated AKT/GSK signaling and increased the expression of gluconeogenic genes in hepatocytes. Moreover, we identified that p65, a subunit of nuclear factor-κB (NF-κB), is a target of miR-291b-3p by bioinformatics analysis and luciferase reporter assay. Silencing of p65 significantly augmented the expression of PTEN and impaired AKT activation. In conclusion, we found novel evidence suggesting that hepatic miR-291b-3p mediated glycogen synthesis and gluconeogenesis through targeting p65 to regulate PTEN expression. Our findings indicate the therapeutic potential of miR-291b-3p inhibitor in hyperglycemia and insulin resistance.

Highlights

  • Several studies have suggested an important role of miR-291b-3p in the development of embryonic stem cells

  • Our findings indicate the therapeutic potential of miR-291b-3p inhibitor in hyperglycemia and insulin resistance

  • We demonstrated that the expression level of miR-291b-3p was increased in the liver of db/db mice and HFD-fed mice

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Summary

Introduction

Several studies have suggested an important role of miR-291b-3p in the development of embryonic stem cells. Further study revealed that miR-291b-3p suppressed insulin-stimulated AKT/GSK signaling and increased the expression of gluconeogenic genes in hepatocytes. Numerous studies revealed that overexpression of PTEN could suppress insulin-induced PtdIns (3,4) P2/PtdIns (3,4,5) P3 PIP3 production, thereby inhibiting AKT activation, GLUT4 translocation and glucose uptake[12,13,14]. Example, p38 mitogen-activated protein kinases (MAPK) was found to increase the protein expression of PTEN in human aortic vascular endothelial cells and transforming growth factor (TGF)-βwas demonstrated to suppress PTEN transcription in pancreatic cancer cells[15,16]. In a panel of cancer cells, p65, a subunit of nuclear factor-κB (NF-κB), could repress the expression of PTEN, thereby prompting tumor growth through the PI3K/AKT pathway[18,19]. Dysregulation of PTEN expression represents a potential therapeutic for many diseases, including cancer and metabolic syndrome

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