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.
Highlights
Liver fibrosis is the end result of many chronic liver diseases with various etiologies [1]
We recently demonstrated that the loss of Fyn, SRC family kinase, inhibits transforming growth factor β (TGF-β)-induced the expression of the α-smooth muscle actin (αSMA) in kidney cell lines and prevents unilateral ureteral obstruction (UUO) induced renal fibrosis [15]
This study investigated the role of Src in hepatic stellate cells (HSC) and liver fibrosis
Summary
Liver fibrosis is the end result of many chronic liver diseases with various etiologies [1]. Connective tissue growth factor (CTGF) is an ECM protein that is involved in many biological processes, such as proliferation, migration, and differentiation. STAT3, AKT, and epidermal growth factor receptor (EGFR), thereby regulating various biological activities, including cell survival, proliferation, and migration [10,11,12]. We recently demonstrated that the loss of Fyn, SRC family kinase, inhibits TGF-β-induced the expression of the αSMA in kidney cell lines and prevents unilateral ureteral obstruction (UUO) induced renal fibrosis [15]. These observations suggest that Src activation is a pathologic observation in fibrotic diseases. This study investigated the role of Src in HSCs and liver fibrosis
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