Cylindromatosis Gene CYLD Regulates Hepatocyte Growth Factor Expression in Hepatic Stellate Cells Through Interaction With Histone Deacetylase 7
Cylindromatosis Gene CYLD Regulates Hepatocyte Growth Factor Expression in Hepatic Stellate Cells Through Interaction With Histone Deacetylase 7
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DOI：
10.1002/hep.27209
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发表时间：
2014-09-01
期刊：
影响因子：
13.5
通讯作者：
Massoumi, Ramin
中科院分区：
文献类型：
--
作者：
Pannem, Rajeswara R.;Dorn, Christoph;Massoumi, Ramin
肝纤维化被认为是对肝损伤的生理性伤口愈合反应。该过程涉及多种因素，例如肝细胞生长因子（HGF），它可以抑制肝损伤并促进急性损伤时纤维化反应的可逆性。慢性肝损伤和持续炎症会导致进行性纤维化，并最终导致器官功能障碍。从恢复到进行性肝组织疤痕的平衡机制尚不清楚。在本研究中，我们确定了一种机制，其中肿瘤抑制基因圆柱瘤病（CYLD）可以保护肝细胞免受损伤和纤维化。与野生型 (WT) 动物相比，缺乏 CYLD (CYLD-/-) 的小鼠非常容易受到肝细胞损伤、炎症和纤维化的影响，并且肝脏 HGF 水平显着降低。外源性应用HGF可挽救CYLD-/-小鼠的肝损伤表型。在缺乏 CYLD 的情况下，肝星状细胞中 HGF 的基因转录通过组蛋白脱乙酰酶 7 (HDAC7) 与 HGF 启动子的结合而受到抑制。在WT细胞中，CYLD从HGF启动子中去除HDAC7并诱导HGF表达。值得注意的是，这种相互作用的发生与 CYLD 的去泛素化活性无关。结论：我们的研究结果强调了 CYLD 和 HDAC7 之间的新联系，为这些蛋白质对肝病进展的贡献提供了机制见解。因此，通过调节 HGF 水平，CYLD 可改善肝细胞损伤和肝纤维化。
Hepatic fibrosis is considered as a physiological wound-healing response to liver injury. The process involves several factors, such as hepatocyte growth factor (HGF), which restrains hepatic injury and facilitates reversibility of fibrotic reaction in response to an acute insult. Chronic liver injury and sustained inflammation cause progressive fibrosis and, ultimately, organ dysfunction. The mechanisms tipping the balance from restoration to progressive liver tissue scarring are not well understood. In the present study, we identify a mechanism in which the tumor-suppressor gene, cylindromatosis (CYLD), confers protection from hepatocellular injury and fibrosis. Mice lacking CYLD (CYLD-/-) were highly susceptible to hepatocellular damage, inflammation, and fibrosis and revealed significantly lower hepatic HGF levels, compared to wild-type (WT) animals. Exogenous application of HGF rescued the liver injury phenotype of CYLD-/- mice. In the absence of CYLD, gene transcription of HGF in hepatic stellate cells was repressed through binding of histone deacetylase 7 (HDAC7) to the promoter of HGF. In WT cells, CYLD removed HDAC7 from the HGF promoter and induced HGF expression. Of note, this interaction occurred independently of the deubiquitinating activity of CYLD. Conclusions: Our findings highlight a novel link between CYLD and HDAC7, offering mechanistic insight into the contribution of these proteins to progression of liver disease. Thus, through regulation of HGF level, CYLD ameliorates hepatocellular damage and liver fibrogenesis.