Simvastatin activates Keap1/Nrf2 signaling in rat liver

J Mol Med (Berl). 2008 Nov;86(11):1279-85. doi: 10.1007/s00109-008-0393-4. Epub 2008 Sep 2.


Some of the statins' pleiotropic actions have been attributed to their antioxidant activity. The Nrf2 transcription factor controls the expression of a number of protective genes in response to oxidative stress. In the present study, wistar rats, primary hepatocytes as well as ST2 cells, were employed to explore the potential role of Nrf2 in mediating the reported antioxidant effects of statins. Simvastatin triggered nuclear translocation of Nrf2 in rat liver and in primary rat hepatocytes in a mevalonate-dependent and cholesterol-independent way. In liver, nuclear extracts from simvastatin-treated rats, the DNA-binding activity of Nrf2, was significantly increased and the mRNA of two known targets of Nrf2 (HO-1 and GPX2) was induced. In ST2 cells stably transfected with constructs bearing Nrf2-binding site (antioxidant responsive element), simvastatin enhanced Nrf2-mediated transcriptional activity in a mevalonate-dependent and cholesterol-independent fashion. In conclusion, activation of Keap1/Nrf2 signaling pathway by simvastatin might provide effective protection of the cell from the deleterious effects of oxidative stress.

MeSH terms

  • Animals
  • Antioxidants / pharmacology*
  • Cell Nucleus / metabolism
  • Cells, Cultured
  • Cholesterol / physiology
  • DNA / genetics
  • Glutathione Peroxidase / genetics
  • Glutathione Peroxidase / metabolism
  • Heme Oxygenase-1 / genetics
  • Heme Oxygenase-1 / metabolism
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology*
  • Intracellular Signaling Peptides and Proteins
  • Kelch-Like ECH-Associated Protein 1
  • Liver / drug effects*
  • Liver / metabolism
  • Mevalonic Acid / metabolism
  • NF-E2-Related Factor 2 / physiology*
  • Protein Transport
  • Proteins / physiology*
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Wistar
  • Response Elements
  • Signal Transduction
  • Simvastatin / pharmacology*


  • Antioxidants
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Intracellular Signaling Peptides and Proteins
  • KEAP1 protein, rat
  • Kelch-Like ECH-Associated Protein 1
  • NF-E2-Related Factor 2
  • Nfe2l2 protein, rat
  • Proteins
  • RNA, Messenger
  • DNA
  • Cholesterol
  • Simvastatin
  • Glutathione Peroxidase
  • glutathione peroxidase 2, rat
  • Heme Oxygenase-1
  • Mevalonic Acid