Abstract
Liver fibrosis is a worldwide clinical issue. It has been well established that activated hepatic stellate cells (HSCs) are responsible for excessive extracellular matrix (ECM) deposition in chronically damaged livers. The identification of key elements that control HSCs activation will help to further our understanding of liver fibrosis and improve the outcome of clinical treatment. This study demonstrates that N-Myc downstream-regulated gene 2 (NDRG2) is a potential regulator of liver fibrosis as NDRG2 mRNA and protein levels were reduced during HSCs activation. In addition, enhanced NDRG2 expression reduced Smad3 transcription and phosphorylation, which inhibited HSCs activation by blocking the TGF-β1 signal. Moreover, NDRG2 contributed to an increase in the ratio of matrix metalloproteinase 2 (MMP2) to tissue inhibitor of matrix metalloproteinase 2 (TIMP2), which may facilitate the degradation of the ECM. In dimethylnitrosamine (DMN)-induced fibrotic rat livers, adenovirus-mediated NDRG2 overexpression resulted in decreased ECM deposition and improved liver function compared with controls. In conclusion, the present findings indicate that the modulation of NDRG2 is a promising strategy for the treatment of liver fibrosis.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenoviridae / genetics
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Animals
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Cell Line
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Cell Proliferation / drug effects
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Dimethylnitrosamine / pharmacology
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Extracellular Matrix / drug effects
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Extracellular Matrix / enzymology
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Extracellular Matrix / metabolism
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Gene Expression Regulation, Enzymologic / drug effects
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Hepatic Stellate Cells / drug effects
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Hepatic Stellate Cells / enzymology
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Hepatic Stellate Cells / metabolism
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Hepatic Stellate Cells / pathology
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Hepatocytes / drug effects
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Hepatocytes / enzymology
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Hepatocytes / metabolism
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Hepatocytes / pathology
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Humans
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Liver / drug effects
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Liver / metabolism
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Liver / pathology
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Liver / physiopathology
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Liver Cirrhosis / enzymology
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Liver Cirrhosis / metabolism*
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Liver Cirrhosis / pathology*
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Liver Cirrhosis / physiopathology
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Matrix Metalloproteinase 2 / metabolism*
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Phosphorylation / drug effects
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Rats
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Signal Transduction / drug effects
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Smad Proteins / metabolism*
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Tissue Inhibitor of Metalloproteinase-2 / metabolism*
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Transforming Growth Factor beta1 / metabolism*
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Transforming Growth Factor beta1 / pharmacology
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism*
Substances
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NDRG2 protein, human
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Smad Proteins
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Transforming Growth Factor beta1
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Tumor Suppressor Proteins
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Tissue Inhibitor of Metalloproteinase-2
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Matrix Metalloproteinase 2
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Dimethylnitrosamine