Lithium exacerbates hepatic ischemia/reperfusion injury by inhibiting GSK-3β/NF-κB-mediated protective signaling in mice

Eur J Pharmacol. 2012 Dec 15;697(1-3):117-25. doi: 10.1016/j.ejphar.2012.09.009. Epub 2012 Oct 7.


Lithium (an inhibitor of GSK-3β activity) has beneficial effects on ischemia/reperfusion (I/R) injury in the central nervous system, heart and kidney. However, the role of lithium in hepatic I/R injury is unknown. The aim of this study was to assess the effects of lithium on hepatic I/R injury in a mouse model of partial hepatic I/R. Previous studies showed that lithium chloride (LiCl) can phosphorylate residue Ser9, inhibit GSK-3β activity, and improve I/R injury in other organs. In the present study, mice were pretreated with either vehicle or LiCl, which had similar effects on GSK-3β activity. Surprisingly, treatment with LiCl significantly exacerbated hepatic I/R injury, which was determined by serological and histological analyses. Acute and chronic LiCl treatment caused serious damage in hepatic I/R injury, including increased apoptosis and oxidative stress. To gain insight into the mechanism involved in this damage, the activity of nuclear factor-κB (NF-κB) (GSK-3β can regulate the transcriptional complex of NF-κB) was analyzed, which revealed that LiCl treatment significantly down-regulated the activity of NF-κB. The NF-κB-mediated protective genes were then further evaluated, including anti-apoptotic genes (RAF2, cIAP 2, Bfl-1 and cFLIP) and the antioxidant gene MnSOD. The expression of these protective genes was obviously suppressed compared with the vehicle group. Taken together, these findings show that lithium exacerbates hepatic I/R injury by suppressing the expression of GSK-3β/NF-κB-mediated protective genes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • CASP8 and FADD-Like Apoptosis Regulating Protein / genetics
  • Caspase 3 / metabolism
  • Disease Models, Animal
  • Gene Expression Regulation
  • Glycogen Synthase Kinase 3 / antagonists & inhibitors*
  • Glycogen Synthase Kinase 3 / metabolism
  • Glycogen Synthase Kinase 3 beta
  • Inhibitor of Apoptosis Proteins / genetics
  • Lithium Chloride / toxicity*
  • Liver / blood supply*
  • Liver / drug effects*
  • Liver / enzymology
  • Liver / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Minor Histocompatibility Antigens
  • NF-kappa B / antagonists & inhibitors*
  • NF-kappa B / metabolism
  • Oxidative Stress / drug effects
  • Phosphorylation
  • Protein Kinase Inhibitors / toxicity*
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • RNA, Messenger / metabolism
  • Reactive Oxygen Species / metabolism
  • Reperfusion Injury / chemically induced*
  • Reperfusion Injury / enzymology
  • Reperfusion Injury / genetics
  • Reperfusion Injury / pathology
  • Serine
  • Signal Transduction / drug effects*
  • Superoxide Dismutase / genetics
  • TNF Receptor-Associated Factor 2 / genetics
  • Time Factors


  • BCL2-related protein A1
  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • Cflar protein, mouse
  • Inhibitor of Apoptosis Proteins
  • Minor Histocompatibility Antigens
  • NF-kappa B
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins c-bcl-2
  • RNA, Messenger
  • Reactive Oxygen Species
  • TNF Receptor-Associated Factor 2
  • Serine
  • Superoxide Dismutase
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, mouse
  • Glycogen Synthase Kinase 3
  • Casp3 protein, mouse
  • Caspase 3
  • Lithium Chloride