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DLPC and SAMe combined prevent leptin‐stimulated TIMP‐1 production in LX‐2 human hepatic stellate cells by inhibiting H 2 O 2 ‐mediated signal transduction
Author(s) -
Cao Qi,
Mak Ki M.,
Lieber Charles S.
Publication year - 2006
Publication title -
liver international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.873
H-Index - 110
eISSN - 1478-3231
pISSN - 1478-3223
DOI - 10.1111/j.1478-3231.2005.01204.x
Subject(s) - hepatic stellate cell , leptin , signal transduction , chemistry , p38 mitogen activated protein kinases , phosphorylation , antioxidant , endocrinology , medicine , pharmacology , protein kinase a , biochemistry , obesity
Background/Aims: Both dilinoleoylphosphatidylcholine (DLPC) and S‐adenosylmethionine (SAMe) have antioxidant properties and antifibrogenic actions. Because H 2 O 2 mediates signal transduction‐stimulating liver fibrogenesis, we investigated whether DLPC and SAMe attenuate the production of tissue inhibitor of metalloproteinase (TIMP)‐1 by inhibiting H 2 O 2 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. H 2 O 2 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, whereas phosphorylation of ERK1/2 and p38 was blocked by DLPC+SAMe or catalase, suggesting an H 2 O 2 ‐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 ERK1/2 inhibitor, suppressed TIMP‐1 promoter activity, whereas SB203580, a p38 inhibitor, decreased TIMP‐1 message stability; both resulted 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 H 2 O 2 ‐mediated signaling and the resulting fibrosis.