Abstract
BackgroundExpression of insulin-like growth factor binding protein 5 (IGFBP5) is strongly induced upon activation of hepatic stellate cells and their transdifferentiation into myofibroblasts in vitro. This was confirmed in vivo in an animal model of liver fibrosis. Since IGFBP5 has been shown to promote fibrosis in other tissues, the aim of this study was to investigate its role in the progression of liver fibrosis.MethodsThe effect of IGFBP5 was studied in LX2 cells, a model for partially activated hepatic stellate cells, and in human primary liver myofibroblasts. IGFBP5 signalling was modulated by the addition of recombinant protein, by lentiviral overexpression, and by siRNA mediated silencing. Furthermore, the addition of IGF1 and silencing of the IGF1R was used to investigate the role of the IGF-axis in IGFBP5 mediated effects.ResultsIGFBP5 enhanced the survival of LX2 cells and myofibroblasts via a >50% suppression of apoptosis. This effect of IGFBP5 was not modulated by the addition of IGF1, nor by silencing of the IGF1R. Additionally, IGFBP5 was able to enhance the expression of established pro-fibrotic markers, such as collagen Iα1, TIMP1 and MMP1.ConclusionIGFBP5 enhances the survival of (partially) activated hepatic stellate cells and myofibroblasts by lowering apoptosis via an IGF1-independent mechanism, and enhances the expression of profibrotic genes. Its lowered expression may, therefore, reduce the progression of liver fibrosis.
Highlights
Expression of insulin-like growth factor binding protein 5 (IGFBP5) is strongly induced upon activation of hepatic stellate cells and their transdifferentiation into myofibroblasts in vitro
In order to investigate a potential role of IGFBP5 in liver fibrosis, we developed methods to modulate its
In order to investigate if lowering of IGFBP5 would increase apoptosis, we studied the effect of small interfering RNA (siRNA) mediated silencing on its expression
Summary
Expression of insulin-like growth factor binding protein 5 (IGFBP5) is strongly induced upon activation of hepatic stellate cells and their transdifferentiation into myofibroblasts in vitro. This was confirmed in vivo in an animal model of liver fibrosis. Liver damage induces HSC activation and, upon repeated and/or chronic injury, they transdifferentiate into myofibroblast-like cells [1,3]. These cells migrate to the damaged regions of the liver [4,5,6] where they play a central role in the pathogenic deposition of ECM [7,8]. The decrease in IGF1 signalling seems to provide a profibrotic environment, since the progression of liver fibrosis could be delayed by IGF1 administration [18,19]
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