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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 / Copyright

    Affiliations: Department of Gerontology, The First Affiliated Hospital of University of Science and Technology of China, Hefei, Anhui 230001, P.R. China, Department of Neurology, The First Affiliated Hospital of University of Science and Technology of China, Hefei, Anhui 230001, P.R. China, Department of Endocrinology, The First Affiliated Hospital of University of Science and Technology of China, Hefei, Anhui 230001, P.R. China
    Copyright: © Zhu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Pages: 345-357
    |
    Published online on: November 5, 2018
       https://doi.org/10.3892/ijmm.2018.3975
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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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Copy and paste a formatted citation
Spandidos Publications style
Zhu X, Li H, Wu Y, Zhou J, Yang G and Wang W: lncRNA MEG3 promotes hepatic insulin resistance by serving as a competing endogenous RNA of miR-214 to regulate ATF4 expression. Int J Mol Med 43: 345-357, 2019.
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
Copy and paste a formatted citation
x
Spandidos Publications style
Zhu X, Li H, Wu Y, Zhou J, Yang G and Wang W: lncRNA MEG3 promotes hepatic insulin resistance by serving as a competing endogenous RNA of miR-214 to regulate ATF4 expression. Int J Mol Med 43: 345-357, 2019.
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
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