Open Access

Increased expression of sterol regulatory element binding protein‑2 alleviates autophagic dysfunction in NAFLD

  • Authors:
    • Chunwei Cheng
    • Xiaoling Deng
    • Keshu Xu
  • View Affiliations

  • Published online on: January 16, 2018     https://doi.org/10.3892/ijmm.2018.3389
  • Pages:1877-1886
  • Copyright: © Cheng et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Sterol regulatory element binding protein‑2 (SREBP‑2) is an important transcription factor in lipid homeostasis. A previous study showed that SREBP‑2 also activated autophagic genes during cell‑sterol depletion. Alterations in autophagy are reported to be involved in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). However, whether the regulation of SREBP‑2 restores dysfunctional autophagy in hepatocytes during NAFLD remains to be elucidated. In the present study, a steatosis model was established with palmitic acid (PA) treatment at the indicated times and concentrations. Autophagosomes in hepatocytes were visualized by confocal microscopy after transfection with a tandem GFP‑mCherry‑LC3 construct. Autophagy‑associated protein levels were analyzed by western blot analysis. Loss‑ and gain‑of‑function studies were performed to examine the role of SREBP‑2 in the regulation of hepatocyte autophagy. It was demonstrated that PA induced autophagy and enhanced autophagic flux at the early stage, whereas prolonged treatment with PA resulted in dysfunction of autophagy in the PA‑induced steatotic hepatocytes. In addition, different cellular models presented with differing dysfunctional autophagy in response to fatty acid overload. It was also confirmed that SREBP‑2 regulated autophagy‑related gene expression in hepatocytes, and it was shown that the overexpression of SREBP‑2 increased the expression of autophagy‑related genes, but did not affect the inhibition of the autophagic flux in lipid‑overloaded HL‑7702 cells. By contrast, increased SREBP‑2 partly restored the inhibited autophagic activity in lipid‑overloaded hepatoma HepG2 cells. Taken together, the present study demonstrated that autophagic function was impaired in lipid‑overloaded human hepatocytes, and the differential effect of PA on autophagy was associated with the duration of PA and the cell type. Under these conditions, the overexpression of SREBP‑2 alleviated the inhibited autophagic activity rather than the inhibition of autophagic flux. Consequently, the results indicated that restoration of autophagy dysfunction via the regulation of SREBP‑2 may be a potential therapeutic target for the treatment of NAFLD.

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April 2018
Volume 41 Issue 4

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

2016 Impact Factor: 2.341
Ranked #21/128 Medicine Research and Experimental
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APA
Cheng, C., Deng, X., & Xu, K. (2018). Increased expression of sterol regulatory element binding protein‑2 alleviates autophagic dysfunction in NAFLD. International Journal of Molecular Medicine, 41, 1877-1886. https://doi.org/10.3892/ijmm.2018.3389
MLA
Cheng, C., Deng, X., Xu, K."Increased expression of sterol regulatory element binding protein‑2 alleviates autophagic dysfunction in NAFLD". International Journal of Molecular Medicine 41.4 (2018): 1877-1886.
Chicago
Cheng, C., Deng, X., Xu, K."Increased expression of sterol regulatory element binding protein‑2 alleviates autophagic dysfunction in NAFLD". International Journal of Molecular Medicine 41, no. 4 (2018): 1877-1886. https://doi.org/10.3892/ijmm.2018.3389