Abstract
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.
Highlights
From the Alcohol Research and Treatment Center, Bronx Veterans Affairs Medical Center and Mount Sinai School of Medicine, Bronx, New York 10468
Leptin treatment for 24 h elicited a dose-dependent increase in tissue inhibitor of metalloproteinase (TIMP)-1 mRNA, reaching a maximal level of 3.6-fold at 75 ng/ml leptin
This study demonstrates that leptin has the capacity to stimulate TIMP-1 gene expression and to increase TIMP-1
Summary
From the Alcohol Research and Treatment Center, Bronx Veterans Affairs Medical Center and Mount Sinai School of Medicine, Bronx, New York 10468. 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. Recent laboratory studies showed that hepatic fibrosis induced by chemical toxins and by Schistosoma mansoni was markedly decreased in leptin-deficient ob/ob mice [15,16,17], in ob/ob mice during the progression of experimental steatohepatitis [18] and in Zucker rats (fa/fa) [19], which lack a functional leptin receptor (compared with corresponding lean littermates) These findings implicated leptin as a mediator in the development of liver fibrosis but did not elucidate the mechanisms and cell types involved. ERK1/2, extracellular signal-regulated kinase1/2; FCS, fetal calf serum; GSH, reduced glutathione; HSC, hepatic stellate cells; JAK, Janus kinase; MAPK, mitogen-activated protein kinase; STAT, signal transducer and activator of transcription; TGF-1, transforming growth factor-1; TIMP-1, tissue inhibitor of metalloproteinase-1
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