Low-Molecular-Weight Fibroblast Growth Factor 2 Attenuates Hepatic Fibrosis by Epigenetic Down-Regulation of Delta-Like1
Low-Molecular-Weight Fibroblast Growth Factor 2 Attenuates Hepatic Fibrosis by Epigenetic Down-Regulation of Delta-Like1
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DOI：
10.1002/hep.27649
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发表时间：
2015-05-01
期刊：
影响因子：
13.5
通讯作者：
Shao, Jian-Zhong
中科院分区：
文献类型：
--
作者：
Pan, Ruo-Lang;Xiang, Li-Xin;Shao, Jian-Zhong
肝纤维化是终末期肝病的主要原因，受多种生长因子和细胞因子的密切调控。成纤维细胞生长因子2（FGF 2）与慢性肝损伤的相关性已有报道，但不同FGF 2亚型在肝纤维化发生中的确切功能尚不清楚。在这里，我们报告的差异表达模式和功能的低分子量和高分子量的FGF 2（即，FGF 2（lmw）和FGF 2（hmw），分别）在肝纤维化使用四氯化碳诱导的小鼠肝纤维化模型。FGF 2（hmw）在CCl 4诱导的肝纤维化中表现出强烈的增加，并促进纤维形成。相反，内源性FGF 2（lmw）表现出肝纤维化的轻微增加并抑制这种病理进展。此外，外源性施用重组FGF 2（lmw）有效地改善CCl 4诱导的肝纤维化。从机制上讲，我们发现FGF 2（lmw）治疗通过p38丝裂原活化蛋白激酶途径表观遗传下调Delta样1表达来减弱肝星状细胞活化和纤维化。结论：FGF 2（lmw）和FGF 2（hmw）在肝纤维化中的作用不同。这些发现证明了FGF 2（lmw）施用的有效抗纤维化作用，这可能提供治疗慢性肝病的新方法。（肝病学2015;61：1708-1720）
Liver fibrosis, a major cause of end-stage liver diseases, is closely regulated by multiple growth factors and cytokines. The correlation of fibroblast growth factor 2 (FGF2) with chronic liver injury has been reported, but the exact functions of different FGF2 isoforms in liver fibrogenesis remain unclear. Here, we report on the differential expression patterns and functions of low- and high-molecular-weight FGF2 (namely, FGF2(lmw) and FGF2(hmw), respectively) in hepatic fibrogenesis using a CCl4-induced mouse liver fibrosis model. FGF2(hmw) displayed a robust increase in CCl4-induced hepatic fibrosis and promoted fibrogenesis. In contrast, endogenous FGF2(lmw) exhibited a slight increase in hepatic fibrosis and suppressed this pathological progression. Moreover, exogenous administration of recombinant FGF2(lmw) potently ameliorated CCl4-induced liver fibrosis. Mechanistically, we showed that FGF2(lmw) treatment attenuated hepatic stellate cell activation and fibrosis by epigenetic down-regulation of Delta-like 1 expression through the p38 mitogen-activated protein kinase pathway. Conclusion: FGF2(lmw) and FGF2(hmw) have distinct roles in liver fibrogenesis. These findings demonstrate a potent antifibrotic effect of FGF2(lmw) administration, which may provide a novel approach to treat chronic liver diseases. (Hepatology 2015;61:1708-1720)