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Published on: February 10, 2015
Src Inhibition Attenuates Liver Fibrosis by Preventing Hepatic Stellate Cell Activation and Decreasing Connetive
Hye-Young Seo1,2, So-Hee Lee1,2, Ji-Ha Lee1,2
1Department of Internal Medicine, Keimyung University School of Medicine, Daegu 42601, Korea.
Abstract:
The SRC kinase family comprises non-receptor tyrosine kinases that are ubiquitously expressed in all cell types. Although Src is reportedly activated in pulmonary and renal fibrosis, little is known regarding its role in liver fibrosis. This study investigated whether the inhibition of Src protects against liver fibrosis. The expression of Src was upregulated in thioacetamide (TAA)-induced fibrotic mouse liver and cirrhosis of patients, and phospho-Src was upregulated during activation of hepatic stellate cells (HSC). In addition, Src inhibition reduced the expression of α-smooth muscle actin (αSMA) in primary HSCs and suppressed transforming growth factor β (TGF-β)-induced expression of connective tissue growth factor (CTGF) in hepatocytes. Src inhibitor Saracatinib also attenuated TAA-induced expression of type I collagen, αSMA, and CTGF in mouse liver tissues. The antifibrotic effect of Src inhibitors was associated with the downregulation of smad3, but not of signal transducer and activator of transcription 3 (STAT3). In addition, Src inhibition increased autophagy flux and protected against liver fibrosis. These results suggest that Src plays an important role in liver fibrosis and that Src inhibitors could be treat liver fibrosis.
Insights
Src kinase inhibition shows promise for treating liver fibrosis. Blocking Src reduced fibrotic markers and increased autophagy, suggesting a new therapeutic avenue for liver disease.
Area of Science:
- Cell Biology
- Biochemistry
- Pathology
Background:
- Src kinase is a non-receptor tyrosine kinase found in all cell types.
- Src activation is implicated in pulmonary and renal fibrosis, but its role in liver fibrosis is unclear.
Purpose of the Study:
- To investigate the role of Src in liver fibrosis.
- To determine if Src inhibition protects against liver fibrosis.
Main Methods:
- Studied thioacetamide (TAA)-induced liver fibrosis in mice and human cirrhosis.
- Examined Src expression and activation in hepatic stellate cells (HSCs) and hepatocytes.
- Assessed the effects of Src inhibition (using Saracatinib) on fibrotic markers and autophagy.
Main Results:
- Src expression and activation were elevated in fibrotic liver tissues and activated HSCs.
- Src inhibition reduced alpha-smooth muscle actin (αSMA) in HSCs and suppressed TGF-β-induced connective tissue growth factor (CTGF) in hepatocytes.
- Saracatinib treatment attenuated collagen I, αSMA, and CTGF expression in TAA-induced liver fibrosis.
- Src inhibition led to Smad3 downregulation and increased autophagy flux, correlating with antifibrotic effects.
Conclusions:
- Src plays a significant role in the development of liver fibrosis.
- Src inhibitors demonstrate potential as a therapeutic strategy for treating liver fibrosis by modulating fibrotic pathways and enhancing autophagy.
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