Leptin stimulates tissue inhibitor of metalloproteinase-1 in human hepatic stellate cells -: Respective roles of the JAK/STAT and JAK-mediated H2O2-dependent MAPK pathways
Leptin stimulates tissue inhibitor of metalloproteinase-1 in human hepatic stellate cells -: Respective roles of the JAK/STAT and JAK-mediated H2O2-dependent MAPK pathways
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DOI：
10.1074/jbc.m308351200
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发表时间：
2004-02-06
影响因子：
4.8
通讯作者：
Lieber, CS
中科院分区：
文献类型：
--
作者：
Cao, Q;Mak, KM;Lieber, CS
瘦素被认为是肝脏中的促纤维化激素，但所涉及的机制尚未阐明。金属蛋白酶组织抑制剂（TIMP）-1是由肝星状细胞（HSC）对纤维化物质的反应而合成的，通过抑制胶原降解发挥作用。在人HSC细胞系LX-2中研究了瘦素诱导TIMP-1及其信号传导分子的能力。瘦素刺激TIMP-1蛋白、mRNA和启动子活性。JAK 1和-2以及STAT 3和-5被激活。瘦素后，酪氨酸1141磷酸化瘦素受体的表达增加，这可能有助于STAT 3激活。JAK抑制剂AG 490阻断JAK磷酸化，同时抑制STAT活化、TIMP-1 mRNA表达和启动子活性。瘦素还诱导氧化应激，这是由AG 490抑制，表明JAK介导的过程。ERK 1/2 MAPK和p38被激活，这是由过氧化氢酶阻止，表明H2 O2依赖性机制。过氧化氢酶处理导致TIMP-1 mRNA表达和启动子活性的总抑制。SB 203580是一种p38抑制剂，可阻止p38激活，并降低TIMP-1的信息半衰期，下调TIMP-1 mRNA。这些变化通过显性负性p38 α和p38 β突变体的过度表达而再现。ERK 1/2抑制剂PD 098059对抗ERK 1/2激活和TIMP-1启动子活性，导致TIMP-1 mRNA下调。因此，瘦素通过刺激活化HSC中TIMP-1的产生对肝纤维化具有直接作用。这一过程似乎是由JAK/STAT途径通过瘦素受体长型和H2 O2依赖性p38和ERK 1/2途径通过激活JAK介导的。
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.