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首页> 外文期刊>Hepatology: Official Journal of the American Association for the Study of Liver Diseases >Cylindromatosis gene CYLD regulates hepatocyte growth factor expression in hepatic stellate cells through interaction with histone deacetylase 7
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Cylindromatosis gene CYLD regulates hepatocyte growth factor expression in hepatic stellate cells through interaction with histone deacetylase 7

机译：柱状体病基因CYLD通过与组蛋白脱乙酰基酶7的相互作用来调节肝星状细胞中肝细胞生长因子的表达

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摘要

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.
机译：肝纤维化被认为是对肝损伤的生理伤口愈合反应。该过程涉及多种因素，例如肝细胞生长因子（HGF），该因子可抑制肝损伤并促进急性反应引起的纤维化反应的可逆性。慢性肝损伤和持续性炎症导致进行性纤维化，最终导致器官功能障碍。平衡从恢复到进行性肝组织瘢痕形成的机制尚不十分清楚。在本研究中，我们确定了一种机制，其中肿瘤抑制基因cylindromatosis（CYLD）赋予保护免受肝细胞损伤和纤维化的作用。与野生型（WT）动物相比，缺乏CYLD（CYLD-/-）的小鼠对肝细胞损伤，炎症和纤维化高度敏感，并显示出肝HGF水平明显降低。 HGF的外源应用挽救了CYLD-/-小鼠的肝损伤表型。在没有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基酶7（HDAC7）与HGF的启动子结合而受到抑制。在野生型细胞中，CYLD从HGF启动子中去除了HDAC7，并诱导HGF表达。值得注意的是，这种相互作用独立于CYLD的去泛素化活性而发生。结论：我们的发现突出了CYLD和HDAC7之间的新型联系，从而提供了对这些蛋白在肝病进展中的作用的机械观察。因此，通过调节HGF水平，CYLD改善了肝细胞损伤和肝纤维化。

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