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Hepatic miR-181b-5p Contributes to Glycogen Synthesis Through Targeting EGR1

Abstract

Background/Aim

The miR-181 family plays an important role in the regulation of various cellular functions. However, whether miR-181b-5p mediates hepatic insulin resistance remains unknown. In this study, we investigated the effect of miR-181b-5p on the regulation of hepatic glycogen synthesis.

Methods

The miR-181b-5p levels in the livers of diabetic mice were detected by real-time PCR. The glycogen levels and AKT/GSK pathway activation were examined in human hepatic L02 cells and HepG2 cells transfected with miR-181b-5p mimic or inhibitor. The potential target genes of miR-181b-5p were evaluated using a luciferase reporter assay and Western blot analysis. EGR1-specific siRNA and pCMV-EGR1 were used to further determine the role of miR-181b-5p in hepatic glycogen synthesis in vitro. Hepatic inhibition of miR-181b-5p in mice was performed using adeno-associated virus 8 (AAV8) vectors by tail intravenous injection.

Results

The miR-181b-5p levels were significantly decreased in the serum and livers of diabetic mice as well as the serum of type 2 diabetes patients. Importantly, inhibition of miR-181b-5p expression impaired the AKT/GSK pathway and reduced glycogenesis in hepatocytes. Moreover, upregulation of miR-181b-5p reversed high-glucose-induced suppression of glycogenesis. Further analysis revealed that early growth response 1 (EGR1) was a downstream target of miR-181b-5p. Silencing of EGR1 expression rescued miR-181b-5p inhibition-reduced AKT/GSK pathway activation and glycogenesis in hepatocytes. Hepatic inhibition of miR-181b-5p led to insulin resistance in C57BL/6 J mice.

Conclusion

We demonstrated that miR-181b-5p contributes to glycogen synthesis by targeting EGR1, thereby regulating PTEN expression to mediate hepatic insulin resistance.

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Acknowledgments

This work was supported by grants from the National Natural Science Foundation of China (81700709 and 81502284), the Research Foundation of Jilin Provincial Science & Technology Development (20180520105JH and 20170414028GH), the Fundamental Research Funds for the Central Universities (2412017DQ015), and the Changchun Science and Technology Bureau (17YJ003-1).

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Correspondence to Yuxin Li, Luguo Sun or Huiying Zhao.

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The authors of this study declare that no conflicts of interest exist.

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Cite this article

Wang, S., Liang, C., Ai, H. et al. Hepatic miR-181b-5p Contributes to Glycogen Synthesis Through Targeting EGR1. Dig Dis Sci 64, 1548–1559 (2019). https://doi.org/10.1007/s10620-018-5442-4

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  • DOI: https://doi.org/10.1007/s10620-018-5442-4

Keywords

  • Hepatic glycogenesis
  • miR-181b-5p
  • EGR1
  • PTEN