Gene expression during chemically induced liver fibrosis:: effect of halofuginone on TGF-β signaling
Gene expression during chemically induced liver fibrosis:: effect of halofuginone on TGF-β signaling
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DOI：
10.1007/s00441-006-0330-1
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发表时间：
2007-04-01
影响因子：
3.6
通讯作者：
Pines, M.
中科院分区：
文献类型：
--
作者：
Gnainsky, Y.;Kushnirsky, Z.;Pines, M.
肝纤维化与星状细胞（HSC）的活化有关，星状细胞是细胞外基质（ECM）蛋白的主要来源。转化生长因子-β（TGF-β），通过Smad 3信号传导，是最促纤维化的细胞因子和ECM合成的主要启动子。常山酮，一种肝纤维化抑制剂，抑制培养的人HSC中TGF-β依赖性Smad 3磷酸化。我们已经使用转录谱来评估常山酮对硫代乙酰胺（TAA）诱导的大鼠肝纤维化进展过程中基因表达的影响，并专注于与TGF-β相关的基因。TAA治疗导致7%的肝脏基因表达改变。Halofuginone治疗阻止了41%这些基因表达的变化，并导致HSC活化和胶原合成的抑制。在疾病的早期阶段，常山酮影响参与酒精，脂质，蛋白质和磷酸盐代谢和细胞粘附的基因，并在后期阶段，在细胞周期（细胞发育，分化，细胞增殖和凋亡）。在化学诱导的纤维化过程中，常山酮可阻止TGF-β依赖性基因的激活，如抗酒石酸酸性磷酸酶、其假定底物骨桥蛋白、星状细胞激活相关蛋白和β-淀粉样蛋白-1。因此，这项研究强调了TGF-β信号在肝纤维化中的作用，特别是其药物干预的潜力。已经在动物和人类中证明有效性和耐受性的常山酮可能成为肝纤维化的有效和新的治疗方法。
Hepatic fibrosis is associated with the activation of stellate cells (HSCs), the major source of extracellular matrix (ECM) proteins. Transforming growth factor-beta (TGF-beta), signaling via Smad3, is the most profibrogenic cytokine and the major promoter of ECM synthesis. Halofuginone, an inhibitor of liver fibrosis, inhibits TGF-beta-dependent Smad3 phosphorylation in human HSCs in culture. We have used transcriptional profiling to evaluate the effect of halofuginone on gene expression during the progression of thioacetamide (TAA)-induced liver fibrosis in the rat and have focused on genes that are associated with TGF-beta. TAA treatment causes alterations in the expression of 7% of liver genes. Halofuginone treatment prevents the changes in the expression of 41% of these genes and results in the inhibition of HSC activation and collagen synthesis. During the early stages of the disease, halofuginone affects genes involved in alcohol, lipid, protein, and phosphate metabolism and cell adhesion and, at later stages, in the cell cycle (cell development, differentiation, cell proliferation, and apoptosis). The activation of TGF-beta-dependent genes, such as tartrate-resistant acid phosphatase, its putative substrate osteopontin, stellate cell activation-association protein, and fibrillin-1, during chemically induced fibrosis is prevented by halofuginone. This study thus highlights the role of TGF-beta signaling in liver fibrosis and especially its potential for pharmacological intervention. Halofuginone, which has demonstrated efficacy and tolerance in animals and humans, could become an effective and novel therapy for liver fibrosis.