The CYP2E1 inhibitor DDC up-regulates MMP-1 expression in hepatic stellate cells via an ERK1/2- and Akt-dependent mechanism.
The CYP2E1 inhibitor DDC up-regulates MMP-1 expression in hepatic stellate cells via an ERK1/2- and Akt-dependent mechanism.
复制标题
CYP2E1 抑制剂 DDC 通过 ERK1/2 和 Akt 依赖性机制上调肝星状细胞中的 MMP-1 表达。
DOI：
10.1042/bsr20130033
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发表时间：
2013-06-05
影响因子：
4
通讯作者：
You H
中科院分区：
文献类型：
--
作者：
Liu T;Wang P;Cong M;Xu Y;Jia J;You H
二乙基二硫代氨基甲酸酯(DDC)可通过抑制肝细胞色素P450 2E1产生的活性氧(ROS)抑制肝星状细胞(HSC)胶原合成。然而，DDC对主要降解胶原的基质金属蛋白酶-1(MMP1)的影响尚未见报道。在共培养实验中，我们发现DDC显著增强了人HSC(LX-2)中基质金属蛋白酶-1的表达，该细胞与表达或不表达CYP2E1的肝细胞C3A细胞共同培养。在LX-2细胞中，酶原和活性的MMP1酶水平均上调，同时LX-2细胞和培养上清液中的MMP1酶活性升高，I型胶原减少。过氧化氢处理可抑制DDC诱导的基质金属蛋白酶-1表达上调，I型胶原减少，而过氧化氢酶处理轻微上调基质金属蛋白酶-1的表达。这些数据提示，DDC对ROS的抑制可能是导致MMP1上调的部分原因。DDC可显著激活ERK1/2、Akt和p38。ERK1/2抑制剂(U0126)和Akt抑制剂(T3830)可阻断DDC诱导的基质金属蛋白酶-1上调。此外，p38抑制剂(SB203580)通过刺激ERK1/2促进了MMP1的上调。我们的数据表明，DDC显著上调了LX-2细胞中MMP1的表达，从而导致MMP1酶活性增强，I型胶原减少。DDC促进MMP1的表达与H_2O_2抑制ERK1/2和Akt信号通路的协同调节有关。这些数据为肝纤维化的治疗策略提供了一些新的见解。
DDC (diethyldithiocarbamate) could block collagen synthesis in HSC (hepatic stellate cells) through the inhibition of ROS (reactive oxygen species) derived from hepatocyte CYP2E1 (cytochrome P450 2E1). However, the effect of DDC on MMP-1 (matrix metalloproteinase-1), which is the main collagen degrading matrix metalloproteinase, has not been reported. In co-culture experiments, we found that DDC significantly enhanced MMP-1 expression in human HSC (LX-2) that were cultured with hepatocyte C3A cells either expressing or not expressing CYP2E1. The levels of both proenzyme and active MMP-1 enzyme were up-regulated in LX-2 cells, accompanied by elevated enzyme activity of MMP-1 and decreased collagen I, in both LX-2 cells and the culture medium. H2O2 treatment abrogated DDC-induced MMP-1 up-regulation and collagen I decrease, while catalase treatment slightly up-regulated MMP-1 expression. These data suggested that the decrease in ROS by DDC was partially responsible for the MMP-1 up-regulation. ERK1/2 (extracellular signal-regulated kinase 1/2), Akt (protein kinase B) and p38 were significantly activated by DDC. The ERK1/2 inhibitor (U0126) and Akt inhibitor (T3830) abrogated the DDC-induced MMP-1 up-regulation. In addition, a p38 inhibitor (SB203580) improved MMP-1 up-regulation through the stimulation of ERK1/2. Our data indicate that DDC significantly up-regulates the expression of MMP-1 in LX-2 cells which results in greater MMP-1 enzyme activity and decreased collagen I. The enhancement of MMP-1 expression by DDC was associated with H2O2 inhibition and coordinated regulation by the ERK1/2 and Akt pathways. These data provide some new insights into treatment strategies for hepatic fibrosis.