Sokolović Aleksandar, Sokolović Milka, Boers Willem, Elferink Ronald Pj Oude, Bosma Piter J
Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Fibrogenesis Tissue Repair. 2010 Feb 17;3:3. doi: 10.1186/1755-1536-3-3.
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. 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.
The 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.
IGFBP5 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 Ialpha1, TIMP1 and MMP1.
IGFBP5 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.
在体外，肝星状细胞激活并转分化为肌成纤维细胞时，胰岛素样生长因子结合蛋白5（IGFBP5）的表达会被强烈诱导。这在肝纤维化动物模型中得到了体内验证。由于IGFBP5已被证明在其他组织中促进纤维化，本研究的目的是探讨其在肝纤维化进展中的作用。
在LX2细胞（一种部分激活的肝星状细胞模型）和人原代肝肌成纤维细胞中研究IGFBP5的作用。通过添加重组蛋白、慢病毒过表达和siRNA介导的沉默来调节IGFBP5信号。此外，添加IGF1和沉默IGF1R用于研究IGF轴在IGFBP5介导的效应中的作用。
IGFBP5通过抑制>50%的细胞凋亡来提高LX2细胞和肌成纤维细胞的存活率。IGFBP5的这种作用不受添加IGF1或沉默IGF1R的调节。此外，IGFBP5能够增强已确定的促纤维化标志物的表达，如I型胶原α1、TIMP1和MMP1。
IGFBP5通过不依赖IGF1的机制降低细胞凋亡，从而提高（部分）激活的肝星状细胞和肌成纤维细胞的存活率，并增强促纤维化基因的表达。因此，其表达降低可能会减缓肝纤维化的进展。
