The CYP2E1 inhibitor DDC up-regulates MMP-1 expression in hepatic stellate cells via an ERK1/2- and Akt-dependent mechanism
| العنوان: | The CYP2E1 inhibitor DDC up-regulates MMP-1 expression in hepatic stellate cells via an ERK1/2- and Akt-dependent mechanism |
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| المؤلفون: | Min Cong, Tianhui Liu, Ping Wang, Hong You, Jidong Jia, Youqing Xu |
| المصدر: | Bioscience Reports Bioscience Reports, Vol 33, Iss 3, p e00041 (2013) |
| بيانات النشر: | Portland Press Ltd., 2013. |
| سنة النشر: | 2013 |
| مصطلحات موضوعية: | collagen, lcsh:Life, lcsh:QR1-502, Matrix metalloproteinase, p38 Mitogen-Activated Protein Kinases, Biochemistry, lcsh:Microbiology, ERK, extracellular signal-regulated kinase, Enzyme Inhibitors, reactive oxygen species, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, integumentary system, Kinase, CYP2E1, cytochrome P450 2E1, HSC, hepatic stellate cell, ECM, extracellular matrix, Up-Regulation, Cell biology, Cytochrome P-450 CYP2E1 Inhibitors, medicine.anatomical_structure, ASH, alcoholic steatohepatitis, Hepatocyte, Matrix Metalloproteinase 1, Ditiocarb, NASH, non-alcoholic steatohepatitis, p38 mitogen-activated protein kinases, Biophysics, S6, Biology, matrix metalloproteinase-1, DDC, diethyldithiocarbamate, Cell Line, ROS, reactive oxygen species, Downregulation and upregulation, Hepatic Stellate Cells, medicine, Humans, MMP-1, matrix metalloproteinase-1, Molecular Biology, Protein kinase B, diethyldithiocarbamate, Original Paper, Cell Biology, DCF, dichlorofluorescin, Molecular biology, Coculture Techniques, lcsh:QH501-531, MAPK, mitogen-activated protein kinases, Cell culture, mitogen-activated protein kinases, Akt, protein kinase B, Hepatocytes, Hepatic stellate cell, cytochrome P450 2E1, Proto-Oncogene Proteins c-akt |
| الوصف: | 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. |
| تدمد: | 1573-4935 0144-8463 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e01ac7daf71e54de0634a9a8e15e192eTest https://doi.org/10.1042/bsr20130033Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....e01ac7daf71e54de0634a9a8e15e192e |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15734935 01448463 |
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