DLPC and SAMe combined prevent leptin-stimulated TIMP-1 production in LX-2 human hepatic stellate cells by inhibiting H2O2-mediated signal transduction

Qi Cao, Ki M. Mak, Charles S. Lieber

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

Background/Aims: Both dilinoleoylphosphatidylcholine (DLPC) and s-adenosylmethionine (SAMe) have antioxidant properties and antifibrogenic actions. Because H2O2 mediates signal transduction-stimulating liver fibrogeneis, we investigated whether DLPC and SAMe attenuate the production of tissue inhibitor of metalloproteinase (TIMP)-1 by inhibiting H2O2 formation. Methods: LX-2 human hepatic stellate cells were treated with leptin with or without DLPC, SAMe or various inhibitors. Results: Leptin-stimulated TIMP-1 mRNA and its protein were diminished by DLPC or SAMe alone, and the response was fully prevented by the combination of DLPC and SAMe. H2O2 was increased while glutathione was decreased; these changes were prevented by AG490, suggesting a Janus kinases (JAK)-mediated process. Up-regulation of leptin receptor and activation of JAK1 and 2 were not affected by DLPC+SAMe, whrereas phosphorylation of ERK 1/2 and p38 was blocked by DLPC+SAMe or catalase, suggesting an H2O2 -dependent mechanism. These treatments also suppressed leptin-stimulated TIMP-1 promoter activity and decreased TIMP-1 mRNA stability, contributing to TIMP-1 mRNA down-regulation. PD098059, an ERK 1/2 inhibitor, suppressed TIMP-1 promoter activity, whrereas SB203580, a p38 inhibitor, decreased TIMP-1 message stability; both resulated in a partial reduction of TIMP-1 mRNA. Conclusion: As decreased TIMP-1 production may enhance collagen deposition, the combined administration of DLPC+SAMe should be considered for the prevention of H2O2-mediated signaling and the resulting fibrosis.

Original languageEnglish
Pages (from-to)221-231
Number of pages11
JournalLiver International
Volume26
Issue number2
DOIs
StatePublished - Mar 2006

Keywords

  • Catalase
  • ERK1/2
  • Janus kinases
  • Reduced glutathione
  • TIMP-1 mRNA stability
  • TIMP-1 promoter activity
  • p38

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