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Raf Kinase Inhibitory Protein Down-Expression Exacerbates Hepatic Fibrosis In Vivo and In Vitro
Quanfang Huang1, Chunhong Liang, Ling Wei
1The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning, China.
Background/Aims:
Raf kinase inhibitory protein (RKIP) is closely associated with numerous tumors and participates in their development through regulating the growth, apoptosis, invasion and metastasis of tumor cells. However, the role of RKIP in chronic liver injury and particularly in liver fibrosis is still unclear.
Methods:
In the present study, hepatic fibrosis was induced by porcine serum (PS) in rats and primary hepatic stellate cells (HSCs) were isolated from rat livers. Moreover, locostatin was used to interfere with RKIP expression.
Results:
RKIP expression was significantly inhibited by locostatin in both liver tissues of rats and primary HSCs. Down-regulating RKIP expression resulted in serious liver injury, extensive accumulation of collagen, and significant increase in the levels of ALT, AST and TNF-α during liver fibrosis in rats. Moreover, down-regulating RKIP significantly promoted HSCs proliferation and colony formation in vitro. Reduced RKIP significantly increased the production of collagen and the level of α-SMA as well as the expression of MMP-1 and MMP-2 in both liver tissues and primary HSCs. Furthermore, down-regulating RKIP promoted the activation of the ERK and TLR4 signaling pathways.
Conclusion:
Our findings clearly indicate an inverse correlation between RKIP level and the degree of the liver injury and fibrosis. The decrease in RKIP expression may exacerbate chronic liver injury and liver fibrosis.
Insights
Decreased Raf kinase inhibitory protein (RKIP) expression worsens chronic liver injury and liver fibrosis by promoting hepatic stellate cell proliferation and collagen production. Lower RKIP levels correlate with increased liver damage.
Area of Science:
- Hepatology
- Molecular Biology
- Oncology
Background:
- Raf kinase inhibitory protein (RKIP) is implicated in tumor development.
- The role of RKIP in chronic liver injury and fibrosis remains unclear.
Purpose of the Study:
- To investigate the role of RKIP in liver fibrosis.
- To determine the effect of RKIP expression levels on liver injury and fibrosis progression.
Main Methods:
- Hepatic fibrosis induced in rats using porcine serum (PS).
- Primary rat hepatic stellate cells (HSCs) isolated.
- RKIP expression modulated using locostatin.
Main Results:
- Down-regulating RKIP exacerbated liver injury, collagen deposition, and elevated ALT, AST, and TNF-α.
- Reduced RKIP promoted HSC proliferation, collagen production, α-SMA, MMP-1, and MMP-2 expression.
- Decreased RKIP activated ERK and TLR4 signaling pathways.
Conclusions:
- RKIP expression is inversely correlated with the severity of liver injury and fibrosis.
- Reduced RKIP expression exacerbates chronic liver injury and liver fibrosis.
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