Abstract

Understanding the underlying molecular mechanisms of liver fibrosis is important to develop effective therapy. Herein, we show that focal-adhesion-kinse (FAK) plays a key role in promoting hepatic stellate cells (HSCs) activation in vitro and liver fibrosis progression in vivo. FAK activation is associated with increased expression of α-smooth muscle actin (α-SMA) and collagen in fibrotic live tissues. Transforming growth factor beta-1 (TGF-β1) induces FAK activation in a time and dose dependent manner. FAK activation precedes the α-SMA expression in HSCs. Inhibition of FAK activation blocks the α-SMA and collagen expression, and inhibits the formation of stress fibers in TGF-β1 treated HSCs. Furthermore, inhibition of FAK activation significantly reduces HSC migration and small GTPase activation, and induces apoptotic signaling in TGF-β1 treated HSCs. Importantly, FAK inhibitor attenuates liver fibrosis in vivo and significantly reduces collagen and α-SMA expression in an animal model of liver fibrosis. These data demonstrate that FAK plays an essential role in HSC activation and liver fibrosis progression, and FAK signaling pathway could be a potential target for liver fibrosis.

Highlights

  • Normal tissue repair and remodeling is a tightly controlled and self-limited process

  • Mice were challenged with intraperitoneal injections of carbon tetrachloride (CCl4) or control vehicle; hepatic fibrosis in mice induced by carbon tetrachloride is a widely used mouse model to study liver fibrosis[35, 36]

  • The main findings in this manuscript are that Focal adhesion kinase (FAK) plays an important role in liver fibrosis progression through modulating hepatic stellate cells (HSCs) activation and promoting TGF-β-driven pro-fibrotic responses in HSCs

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Summary

Introduction

Normal tissue repair and remodeling is a tightly controlled and self-limited process. Focal adhesion kinase (FAK) is a non-receptor cytoplasmic protein tyrosine kinase and activated when cells bind to ECM proteins through integrin receptors[10,11,12,13,14]. Activated FAK promotes cell migration and invasion, and mediates myofibroblast differentiation and resistance to apoptosis[10, 26,27,28], suggesting a potential role for FAK in the pro-fibrotic actions of HSCs and in liver fibrosis. Bidirectional cross-talk between integrins and ECM proteins is critical for myofibroblast differentiation, and in turn, for activation of latent TGF-β130, 32–34, in which FAK mediated signaling is likely to play a direct role. The results demonstrate that FAK regulates fibrotic actions through promoting HSC activation, myofibroblast differentiation, cell migration, survival, as well as ECM protein expression. Pharmacologic inhibition of FAK attenuates liver fibrosis in vivo in a mouse model of liver fibrosis, suggesting that targeting FAK mediated signaling is likely to attenuate the progression of liver fibrosis

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