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Dig Dis Sci. 2019 Jun;64(6):1548-1559. doi: 10.1007/s10620-018-5442-4. Epub 2019 Jan 9.

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

Author information

1
National Engineering Laboratory for Druggable Gene and Protein Screening, School of Life Sciences, Northeast Normal University, No. 5268, Renmin Road, Changchun, 130024, China.
2
Research Center of Agriculture and Medicine Gene Engineering of Ministry of Education, Northeast Normal University, Changchun, 130024, China.
3
National Engineering Laboratory for Druggable Gene and Protein Screening, School of Life Sciences, Northeast Normal University, No. 5268, Renmin Road, Changchun, 130024, China. liyx486@nenu.edu.cn.
4
Research Center of Agriculture and Medicine Gene Engineering of Ministry of Education, Northeast Normal University, Changchun, 130024, China. liyx486@nenu.edu.cn.
5
Research Center of Agriculture and Medicine Gene Engineering of Ministry of Education, Northeast Normal University, Changchun, 130024, China. sunlg388@nenu.edu.cn.
6
Department of Geriatrics, The First Hospital of Jilin University, Changchun, 130021, China. zhaohuiying163@163.com.

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.

KEYWORDS:

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

PMID:
30627917
DOI:
10.1007/s10620-018-5442-4

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