Bioactive Compound Reveals a Novel Function for Ribosomal Protein S5 in Hepatic Stellate Cell Activation and Hepatic Fibrosis
Bioactive Compound Reveals a Novel Function for Ribosomal Protein S5 in Hepatic Stellate Cell Activation and Hepatic Fibrosis
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生物活性化合物揭示核糖体蛋白 S5 在肝星状细胞活化和肝纤维化中的新功能
DOI：
10.1002/hep.27138
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发表时间：
2014-08-01
期刊：
影响因子：
13.5
通讯作者：
Zhang, Jun-Ping
中科院分区：
文献类型：
--
作者：
Xu, Wei-Heng;Hu, Hong-Gang;Zhang, Jun-Ping
肝纤维化及其终末期肝硬化是世界范围内的一个主要公共卫生问题。肝星状细胞（HSC）的激活是肝纤维化的核心事件。然而，控制 HSC 激活的蛋白质尚不完全清楚。在这里，我们发现 (6aS, 10S, 11aR, 11bR, 11cS)-10-methylamino-dodecaHydro-3a, 7a-diaza-苯并[de]anthracene-8-thione (MASM) 在体外和体内表现出与 Akt 磷酸化减少相关的有效的肝纤维化抑制活性。此外，核糖体蛋白 S5 (RPS5) 被确定为 MASM 的直接靶标，MASM 可以稳定培养的 HSC 以及二甲基亚硝胺 (DMN) 或胆管结扎 (BDL) 后实验动物肝脏中的 RPS5。功能研究表明 RPS5 可以阻止 HSC 激活。 HSC 中 RPS5 的过表达导致 Akt Ser473 和 Thr308 去磷酸化，并导致随后的 GSK3 beta 或 P70S6K 去磷酸化。 DMN 和 BDL 诱导的肝纤维化的进展因 Rps5 敲低而加剧，并因 RPS5 过表达而减轻，这与纤维化肝脏中 Akt 磷酸化和 HSC 数量的调节相关。此外，RPS5在转分化的HSC、实验性纤维化肝脏和人肝硬化样本中显着降低。结论：这些结果表明 RPS5 与肝纤维化有关，并且可能代表肝纤维化疾病潜在治疗干预的有希望的靶标。
Liver fibrosis and its endstage, cirrhosis, represent a major public health problem worldwide. Activation of hepatic stellate cells (HSCs) is a central event in hepatic fibrosis. However, the proteins that control HSC activation are incompletely understood. Here we show that (6aS, 10S, 11aR, 11bR, 11cS)-10-methylamino-dodecahydro-3a, 7a-diaza-benzo [de]anthracene-8-thione (MASM) exhibits potent inhibitory activity against liver fibrosis in vitro and in vivo associated with the reduction of Akt phosphorylation. Furthermore, ribosomal protein S5 (RPS5) was identified as a direct target of MASM, which stabilized RPS5 in cultured HSCs and in the liver of experimental animals after dimethylnitrosamine (DMN) or bile duct ligation (BDL). Functional studies revealed that RPS5 could prevent HSC activation. RPS5 overexpression in HSCs resulted in Akt dephosphorylation at both Ser473 and Thr308, and led to subsequent dephosphorylation of GSK3 beta or P70S6K. Progression of DMN- and BDL-induced hepatic fibrosis was aggravated by Rps5 knockdown and alleviated by RPS5 overexpression, which correlated with the modulation of Akt phosphorylation and HSC number in the fibrotic livers. Moreover, RPS5 was substantially reduced in the transdifferentiated HSCs, experimental fibrotic livers, and human cirrhosis samples. Conclusion: These results demonstrate that RPS5 is implicated in hepatic fibrogenesis and may represent a promising target for potential therapeutic intervention in liver fibrotic diseases.