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.
Highlights
Liver fibrosis is a major medical problem of liver diseases, especially in Asian countries
During the development of hepatic fibrosis, chronic liver damage leads to hepatic stellate cells (HSCs) activation, characterized by a transformation from the quiescent state to a proliferative, contractile and fibrogenic myofibroblast-like phenotype that terminates in excessive hepatic matrix deposition, liver function impairment, cirrhosis and organ failure [6,7]
N-Myc downstream-regulated gene 2 (NDRG2) was expressed in LX-2 cells and was mainly localized to the cytoplasm, together with alpha smooth muscle actin (a-SMA), a marker of HSCs activation (Figure 1A)
Summary
Liver fibrosis is a major medical problem of liver diseases, especially in Asian countries. Metabolic disorders, genetic mutations and cholestatic diseases are common causes of liver fibrosis and even cirrhosis and hepatocellular carcinoma (HCC) [1,2]. HSCs play a central role in liver fibrosis. HSCs are in a quiescent state and their main function is to store retinoids. During the development of hepatic fibrosis, chronic liver damage leads to HSCs activation, characterized by a transformation from the quiescent state to a proliferative, contractile and fibrogenic myofibroblast-like phenotype that terminates in excessive hepatic matrix deposition, liver function impairment, cirrhosis and organ failure [6,7]
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