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Leptin enhances α1(I) collagen gene expression in LX‐2 human hepatic stellate cells through JAK‐mediated H 2 O 2 ‐dependent MAPK pathways
Author(s) -
Cao Qi,
Mak Ki M.,
Lieber Charles S.
Publication year - 2005
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.20622
Subject(s) - hepatic stellate cell , janus kinase , p38 mitogen activated protein kinases , janus kinase 2 , microbiology and biotechnology , leptin , signal transduction , chemistry , oxidative stress , kinase , mapk/erk pathway , endocrinology , biology , medicine , obesity
Leptin, a liver profibrogenic cytokine, induces oxidative stress in hepatic stellate cells (HSCs), with increased formation of the oxidant H 2 O 2 , which signals through p38 and extracellular signal‐regulated kinase 1/2 (ERK1/2) pathways, stimulating tissue inhibitor of metalloproteinase‐1 production. Since oxidative stress is a pathogenic mechanism of liver fibrosis and activation of collagen gene is a marker of fibrogenesis, we evaluated the effects of leptin on collagen I expression. We report here that, in LX‐2 human HSCs, leptin enhances the levels of α1(I) collagen mRNA, promoter activity and protein. Janus kinase (JAK)1 and JAK2 were activated. H 2 O 2 formation was increased; this was prevented by the JAK inhibitor AG490, suggesting a JAK‐mediated process. ERK1/2 and p38 were activated, and the activation was blocked by catalase, consistent with an H 2 O 2 ‐dependent mechanism. AG490 and catalase also prevented leptin‐stimulated α1(I) collagen mRNA expression. PD098059, an ERK1/2 inhibitor, abrogated ERK1/2 activation and suppressed α1(I) collagen promoter activity, resulting in mRNA down‐regulation. The p38 inhibitor SB203580 and overexpression of dominant negative p38 mutants abrogated p38 activation and down‐regulated the mRNA. While SB203580 had no effect on the promoter activity, it reduced the mRNA half‐life from 24 to 4 h, contributing to the decreased mRNA level. We conclude that leptin stimulates collagen production through the H 2 O 2 ‐dependent and ERK1/2 and p38 pathways via activated JAK1 and JAK2. ERK1/2 stimulates α1(I) collagen promoter activity, whereas p38 stabilizes its mRNA. Accordingly, interference with leptin‐induced oxidative stress by antioxidants provides an opportunity for the prevention of liver fibrosis. J. Cell. Biochem. © 2005 Wiley‐Liss, Inc.