MicroRNA-200a controls Nrf2 activation by target Keap1 in hepatic stellate cell proliferation and fibrosis

Cell Signal. 2014 Nov;26(11):2381-9. doi: 10.1016/j.cellsig.2014.07.016. Epub 2014 Jul 15.


Hepatic fibrosis is a common final pathological process in the progression of liver disease, which is primarily due to oxidative stress. Nrf2 is known to coordinate induction of genes that encode antioxidant enzymes. Moreover, Nrf2 expression is largely regulated through the association of Nrf2 with Keap1, which results in cytoplasmic Nrf2 degradation. Conversely, little is known concerning the regulation of Keap1 expression. Although the function of miRNA-200a controls Keap1 gene expression has been discussed in many cancers and fibrotic diseases, its role in hepatic fibrosis is still poorly understood. By using miRNA mimic, we observed miRNA-200a silencing in activated hepatic stellate cell and demonstrated that upon re-expression, miRNA-200a targets the Keap1, and leading to Keap1 mRNA degradation. We find that treatment with miRNA-200a mimics, restored miRNA-200a expression and reduced Keap1 levels. This reduction in Keap1 levels corresponded with Nrf2 nuclear translocation and activation of Nrf2-dependent NQO1 gene transcription. Moreover, we found that Nrf2 activation inhibited the TGF-β1-independent growth of hepatic stellate cell. Finally, our study demonstrates that miRNA-200a regulates the Keap1/Nrf2 pathway in hepatic stellate cell and fibrosis, and we find that epigenetic therapy can restore miRNA-200a regulation of Keap1 expression, therefore reactivating the Nrf2-dependent antioxidant pathway in liver fibrosis.

Keywords: Hepatic fibrosis; Hepatic stellate cells; Kelch-like ECH-associated protein 1; MicroRNA-200a; Nuclear factor-erythroid-2-related factor 2; α-SMA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus / genetics
  • Animals
  • Cell Nucleus / genetics
  • Cell Nucleus / metabolism*
  • Cell Nucleus / pathology
  • Cell Proliferation*
  • Gene Expression Regulation / genetics
  • Hepatic Stellate Cells / metabolism*
  • Hepatic Stellate Cells / pathology
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Kelch-Like ECH-Associated Protein 1
  • Liver Cirrhosis / genetics
  • Liver Cirrhosis / metabolism*
  • Liver Cirrhosis / pathology
  • Male
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • NF-E2-Related Factor 2 / genetics
  • NF-E2-Related Factor 2 / metabolism*
  • RNA Stability / genetics
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction / genetics


  • Intracellular Signaling Peptides and Proteins
  • KEAP1 protein, rat
  • Kelch-Like ECH-Associated Protein 1
  • MIRN200 microRNA, rat
  • MicroRNAs
  • NF-E2-Related Factor 2
  • Nfe2l2 protein, rat
  • RNA, Messenger