Abstract
RNA-binding protein HuR mediates transforming growth factor (TGF)-β1-induced profibrogenic actions. Up-regulation of Sphingosine kinase 1 (SphK1) is involved in TGF-β1-induced activation of hepatic stellate cells (HSCs) in liver fibrogenesis. However, the molecular mechanism of TGF-β1 regulates SphK1 remains unclear. This study was designed to investigate the role of HuR in TGF-β1-induced SphK1 expression and identify a new molecular mechanism in liver fibrogenensis. In vivo, HuR expression was increased, translocated to cytoplasm, and bound to SphK1 mRNA in carbon tetrachloride- and bile duct ligation-induced mouse fibrotic liver. HuR mRNA expression had a positive correlation with mRNA expressions of SphK1 and fibrotic markers, α-smooth muscle actin (α-SMA) and Collagen α1(I), respectively. In vitro, up-regulation of SphK1 and activation of HSCs stimulated by TGF-β1 depended on HuR cytoplasmic accumulation. The effects of TGF-β1 were diminished when HuR was silenced or HuR cytoplasmic translocation was blocked. Meanwhile, overexpression of HuR mimicked the effects of TGF-β1. Furthermore, TGF-β1 prolonged half-life of SphK1 mRNA by promoting its binding to HuR. Pharmacological or siRNA-induced SphK1 inhibition abrogated HuR-mediated HSC activation. In conclusion, our data suggested that HuR bound to SphK1 mRNA and played a crucial role in TGF-β1-induced HSC activation.
Highlights
We demonstrate the crucial role of Human antigen R (HuR) in transforming growth factor (TGF)-β 1-induced Sphingosine kinase 1 (SphK1) up-regulation and hepatic stellate cells (HSCs) activation
Our study suggests that HuR is an important player in TGF-induced activation of HSCs and might be a useful therapeutic target for liver fibrosis
A recent report demonstrates that HuR expression is highly increased in activated HSCs, and silence of HuR in bile duct ligation (BDL) mice results in a decrease of histological liver damage and fibrosis[24]
Summary
It has been reported that HuR mRNA level increases in activated HSCs isolated from livers of bile duct ligation (BDL)-treated mice and involves in TGF-β 1-induced profibrogenic action[24]. The results showed that HuR mRNA and protein levels were significantly increased by ~2.20-fold and ~2.09-fold in the BDL-induced fibrotic livers, respectively (Fig. 1a,b). In BDL or CCl4-induced fibrotic livers, HuR protein expression was significantly increased, especially in cytoplasm of non-parenchymal cells.
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