Curcumin regulates cell fate and metabolism by inhibiting hedgehog signaling in hepatic stellate cells
Curcumin regulates cell fate and metabolism by inhibiting hedgehog signaling in hepatic stellate cells
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姜黄素通过抑制肝星状细胞中的刺猬信号来调节细胞命运和代谢
DOI：
10.1038/labinvest.2015.59
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发表时间：
2015-07-01
影响因子：
5
通讯作者：
Zheng, Shizhong
中科院分区：
文献类型：
--
作者：
Lian, Naqi;Jiang, Yuanyuan;Zheng, Shizhong
越来越多的证据表明，Hedgehog（Hh）信号在慢性肝损伤中被激活，并在肝纤维化的发病机制中发挥作用。肝星状细胞（HSC）是Hh应答细胞，并且Hh通路的激活促进HSC转分化为肌成纤维细胞。靶向Hh信号通路可能是治疗肝纤维化的新策略。我们以前报道过姜黄素在体内和体外都具有有效的抗纤维化作用，但其潜在机制尚未完全阐明。这项研究表明，姜黄素下调Patched和Smoothened，Hh信号传导中的两个关键要素，但在四氯化碳诱导的纤维化大鼠肝脏和培养的HSC中恢复Hhip表达。姜黄素还阻止了Gli 1的核转位、DNA结合和转录活性。此外，Hh信号传导抑制剂环巴胺，如姜黄素，阻止细胞周期，诱导线粒体凋亡，减少纤维化基因表达，恢复脂质积累，并抑制HSC的侵袭和迁移。然而，姜黄素对HSC的细胞命运和纤维化特性的影响被Hh通路激动剂SAG消除。此外，姜黄素和环巴胺降低细胞内三磷酸腺苷和乳酸的水平，并抑制控制糖酵解的几个关键分子的表达和/或功能。然而，SAG废除了姜黄素对糖酵解的这些参数的影响。动物实验数据也显示，姜黄素下调大鼠肝纤维化中糖酵解调节蛋白。因此，这些聚集的数据表明，姜黄素通过破坏HSC中的Hh通路来调节细胞命运和代谢，为姜黄素减少HSC活化提供了新的分子见解。
Accumulating evidence indicates that Hedgehog (Hh) signaling becomes activated in chronic liver injury and plays a role in the pathogenesis of hepatic fibrosis. Hepatic stellate cells (HSCs) are Hh-responsive cells and activation of the Hh pathway promotes transdifferentiation of HSCs into myofibroblasts. Targeting Hh signaling may be a novel therapeutic strategy for treatment of liver fibrosis. We previously reported that curcumin has potent antifibrotic effects in vivo and in vitro, but the underlying mechanisms are not fully elucidated. This study shows that curcumin downregulated Patched and Smoothened, two key elements in Hh signaling, but restored Hhip expression in rat liver with carbon tetrachloride-induced fibrosis and in cultured HSCs. Curcumin also halted the nuclear translocation, DNA binding, and transcription activity of Gli1. Moreover, the Hh signaling inhibitor cyclopamine, like curcumin, arrested the cell cycle, induced mitochondrial apoptosis, reduced fibrotic gene expression, restored lipid accumulation, and inhibited invasion and migration in HSCs. However, curcumin's effects on cell fate and fibrogenic properties of HSCs were abolished by the Hh pathway agonist SAG. Furthermore, curcumin and cyclopamine decreased intracellular levels of adenosine triphosphate and lactate, and inhibited the expression and/or function of several key molecules controlling glycolysis. However, SAG abrogated the curcumin effects on these parameters of glycolysis. Animal data also showed that curcumin downregulated glycolysis-regulatory proteins in rat fibrotic liver. These aggregated data therefore indicate that curcumin modulated cell fate and metabolism by disrupting the Hh pathway in HSCs, providing novel molecular insights into curcumin reduction of HSC activation.