Open Access

lncRNA MEG3 promotes hepatic insulin resistance by serving as a competing endogenous RNA of miR-214 to regulate ATF4 expression

  • Authors:
    • Xiang Zhu
    • Hongqi Li
    • Yuanbo Wu
    • Jian Zhou
    • Guangwei Yang
    • Weidong Wang
  • View Affiliations

  • Published online on: November 5, 2018     https://doi.org/10.3892/ijmm.2018.3975
  • Pages: 345-357
  • Copyright: © Zhu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

MicroRNA (miR)‑214 has been demonstrated to suppress gluconeogenesis by targeting activating transcription factor 4 (ATF4), which regulates gluconeogenesis by affecting the transcriptional activity of forkhead box protein O1 (FoxO1). Our previous study revealed that the upregulation of maternally expressed gene 3 (MEG3), a long noncoding RNA, enhanced hepatic insulin resistance via increased FoxO1 expression. The present study aimed to explore whether miR‑214 and ATF4 were involved in the MEG3‑mediated increase of FoxO1 expression. MEG3, miR‑214 and ATF4 expression were examined by reverse transcription quantitative polymerase chain reaction and western blot analysis. The interaction among MEG3, miR‑214 and ATF4 was analysed using the luciferase reporter assay. MEG3‑targeting small interference RNAs were injected into high‑fat diet (HFD)‑fed mice to verify the role of MEG3 in hepatic insulin resistance in vivo. MEG‑3 and ATF4 were demonstrated to be upregulated and miR‑214 was indicated to be downregulated in the livers of HFD‑fed and ob/ob mice. In mouse primary hepatocytes, palmitate time‑dependently increased MEG3 and ATF4 but decreased miR‑214 expression levels. Furthermore, MEG3 served as a competing endogenous RNA (ceRNA) for miR‑214 to facilitate ATF4 expression, while miR‑214 inhibition and ATF4 overexpression reversed the MEG3 knockdown‑mediated decrease in the expression of FoxO1 and FoxO1‑downstream targets phosphoenolpyruvate carboxykinase and glucose‑6‑phosphatase catalytic subunit. In HFD‑fed mice, MEG3 knockdown substantially improved impaired glucose and insulin tolerance, while downregulating HFD‑induced ATF4 expression and upregulating HFD‑suppressed miR‑214 expression. In conclusion, MEG3 promoted hepatic insulin resistance by serving as a ceRNA of miR‑214 to facilitate ATF4 expression. These data provide insight into the molecular mechanism of MEG3 involvement in the development of type 2 diabetes mellitus.
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January 2019
Volume 43 Issue 1

Print ISSN: 1107-3756
Online ISSN:1791-244X

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APA
Zhu, X., Li, H., Wu, Y., Zhou, J., Yang, G., & Wang, W. (2019). lncRNA MEG3 promotes hepatic insulin resistance by serving as a competing endogenous RNA of miR-214 to regulate ATF4 expression. International Journal of Molecular Medicine, 43, 345-357. https://doi.org/10.3892/ijmm.2018.3975
MLA
Zhu, X., Li, H., Wu, Y., Zhou, J., Yang, G., Wang, W."lncRNA MEG3 promotes hepatic insulin resistance by serving as a competing endogenous RNA of miR-214 to regulate ATF4 expression". International Journal of Molecular Medicine 43.1 (2019): 345-357.
Chicago
Zhu, X., Li, H., Wu, Y., Zhou, J., Yang, G., Wang, W."lncRNA MEG3 promotes hepatic insulin resistance by serving as a competing endogenous RNA of miR-214 to regulate ATF4 expression". International Journal of Molecular Medicine 43, no. 1 (2019): 345-357. https://doi.org/10.3892/ijmm.2018.3975