Abstract
Liver fibrosis represents the consequences of a sustained wound healing response to chronic liver injury, and activation of quiescent hepatic stellate cells (HSCs) into a myofibroblast-like phenotype is considered as the central event of liver fibrosis. RACK1, the receptor for activated C-kinase 1, is a classical scaffold protein implicated in numerous signaling pathways and cellular processes; however, the role of RACK1 in liver fibrosis is little defined. Herein, we report that RACK1 is up-regulated in activated HSCs in transforming growth factor beta 1 (TGF-β1)-dependent manner both in vitro and in vivo, and TGF-β1 stimulates the expression of RACK1 through NF-κB signaling. Moreover, RACK1 promotes TGF-β1 and platelet-derived growth factor (PDGF)-mediated activation of pro-fibrogenic pathways as well as the differentiation, proliferation and migration of HSCs. Depletion of RACK1 suppresses the progression of TAA-induced liver fibrosis in vivo. In addition, the expression of RACK1 in fibrogenic cells also positively correlates well with the stage of liver fibrosis in clinical cases. Our results suggest RACK1 as a downstream target gene of TGF-β1 involved in the modulation of liver fibrosis progression in vitro and in vivo, and propose a strategy to target RACK1 for liver fibrosis treatment.
Highlights
Liver fibrosis represents the consequences of a sustained wound healing response to various chronic liver injuries including viral, autoimmune, drug-induced, cholestatic and metabolic diseases [1]
Liver fibrosis is the excessive accumulation of extracellular matrix proteins including collagen that occurs in most types of chronic liver diseases [13]
We report that the expression of receptor for activated C-kinase 1 (RACK1) is increased in activated hepatic stellate cells (HSCs) in transforming growth factor beta 1 (TGF-b1)-dependent manner, and up-regulation of RACK1 induces TGF-b1 and platelet-derived growth factor (PDGF)-mediated pro-fibrogenic pathways as well as the differentiation, migration and proliferation of HSCs
Summary
Liver fibrosis represents the consequences of a sustained wound healing response to various chronic liver injuries including viral, autoimmune, drug-induced, cholestatic and metabolic diseases [1]. HSCs undergo a well-characterized activation process during which they lose their characteristic vitamin A and lipid stores, and obtain a myofibroblastic phenotype [2] This process is associated with the increased expression of contractile filaments such as a-smooth muscle actin (a-SMA) and production of extracellular matrix (ECM), and a large amount of production of pro-fibrogenic factors such as cytokines and reactive oxygen species (ROS) [3]. These cytokines, including interferons, interleukins, tumor necrosis factors (TNF), growth factors (e.g. TGF, PDGF) and chemokines, are released from hepatocytes, Kupffer cells, stellate cells, epithelial cells, endothelial cells and so on, and play critical roles in liver fibrosis through regulating hepatic inflammation, cell necrosis and apoptosis, and ECM production [4]. PDGF induces the activation of several signaling pathways such as MAPKs and AKT, which have been reported to involved in the modulation of HSCs proliferation and migration during the progression of liver fibrosis [14,15]
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