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

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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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Author notes

  1. Yuxin Li

    Present address: National Engineering Laboratory for Druggable Gene and Protein Screening, School of Life Sciences, Northeast Normal University, No. 5268, Renmin Road, Changchun, 130024, China

Authors and Affiliations

  1. National Engineering Laboratory for Druggable Gene and Protein Screening, School of Life Sciences, Northeast Normal University, No. 5268, Renmin Road, Changchun, 130024, China

    Shuyue Wang, Chen Liang, Huihan Ai, Meiting Yang, Lei Liu, Zhenbo Song & Yongli Bao

  2. Research Center of Agriculture and Medicine Gene Engineering of Ministry of Education, Northeast Normal University, Changchun, 130024, China

    Shuyue Wang, Jingwen Yi, Yuxin Li & Luguo Sun

  3. Department of Geriatrics, The First Hospital of Jilin University, Changchun, 130021, China

    Huiying Zhao

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  1. Shuyue Wang
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Correspondence to Yuxin Li, Luguo Sun or Huiying Zhao.

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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

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