Leptin stimulates tissue inhibitor of metalloproteinase-1 in human hepatic stellate cells: respective roles of the JAK/STAT and JAK-mediated H2O2-dependant MAPK pathways.
Leptin is recognized as a profibrogenic hormone in the liver, but the mechanisms involved have not been clarified. The tissue inhibitor of metalloproteinase (TIMP)-1, which acts through inhibition of collagen degradation, is synthesized by activated hepatic stellate cells (HSC) in response to fibrogenic substances. The capacity of leptin to induce TIMP-1 and its signaling molecules were investigated in a human HSC cell line, LX-2. Leptin stimulated TIMP-1 protein, mRNA, and promoter activity. JAK1 and -2, as well as STAT3 and -5, were activated. After leptin, there was increased expression of tyrosine 1141-phosphorylated leptin receptor, which may contribute to STAT3 activation. AG 490, a JAK inhibitor, blocked JAK phosphorylation with concomitant inhibition of STAT activation, TIMP-1 mRNA expression, and promoter activity. Leptin also induced an oxidative stress, which was inhibited by AG 490, indicating a JAK mediation process. ERK1/2 MAPK and p38 were activated, which was prevented by catalase, indicating an H2O2-dependent mechanism. Catalase treatment resulted in total suppression of TIMP-1 mRNA expression and promoter activity. SB203580, a p38 inhibitor, prevented p38 activation and reduced TIMP-1 message half-life with down-regulation of TIMP-1 mRNA. These changes were reproduced by overexpression of the dominant negative p38alpha and p38beta mutants. PD098059, an ERK1/2 inhibitor, opposed ERK1/2 activation and TIMP-1 promoter activity, leading to TIMP-1 mRNA down-regulation. Thus, leptin has a direct action on liver fibrogenesis by stimulating TIMP-1 production in activated HSC. This process appears to be mediated by the JAK/STAT pathway via the leptin receptor long form and the H2O2-dependent p38 and ERK1/2 pathways via activated JAK.
Cao
Qi
Q
Alcohol Research and Treatment Center, Bronx Veterans Affairs Medical Center and Mount Sinai School of Medicine, Bronx, New York 10468, USA.
Mak
Ki M
KM
Ren
Chaoling
C
Lieber
Charles S
CS
D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D007700:Kinetics; D020738:Leptin / Q000378:metabolism / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008894:Milk Proteins; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D009154:Mutation; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases
D004268:DNA-Binding Proteins; D020738:Leptin; D008894:Milk Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D011994:Recombinant Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050799:STAT5 Transcription Factor; D019715:Tissue Inhibitor of Metalloproteinase-1; D015534:Trans-Activators; D006861:Hydrogen Peroxide; D011505:Protein-Tyrosine Kinases; C507904:JAK1 protein, human; C507924:JAK2 protein, human; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases