Curcumin inhibits hepatic stellate cell activation via suppression of succinate-associated HIF-1α induction
Curcumin inhibits hepatic stellate cell activation via suppression of succinate-associated HIF-1α induction
复制标题
姜黄素通过抑制琥珀酸相关的 HIF-1α 诱导来抑制肝星状细胞活化
DOI：
10.1016/j.mce.2018.05.002
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发表时间：
2018-11-15
影响因子：
4.1
通讯作者：
Xie, Yuan
中科院分区：
文献类型：
--
作者：
She, Linlin;Xu, Dan;Xie, Yuan
目的：异常琥珀酸积累是炎症和氧化应激的统一机制。本研究旨在探讨姜黄素是否通过阻断琥珀酸信号传导来改善肝纤维化。方法：我们研究了姜黄素对高脂饮食（HFD）小鼠肝脏琥珀酸积累和肝纤维化的影响。同时，我们用琥珀酸刺激小鼠原代肝星状细胞（HSC），观察姜黄素对琥珀酸信号传导的抑制作用。结果：口服姜黄素和二甲双胍可通过抑制琥珀酸脱氢酶（SDH）活性来对抗线粒体脂肪酸氧化，减少肝脏琥珀酸积累，从而显示出对肝纤维化的抑制作用。在小鼠原代 HSC 中，姜黄素通过抑制 ROS 产生来阻止琥珀酸和 CoCl2 诱导的缺氧诱导转录因子 1 α (HIF-1 α) 诱导，并有效降低 Col1 α、Col3 α、纤连蛋白和 TGF-β 1 的基因表达，并抑制炎症。用小干扰RNA敲低HIF-1a可阻断琥珀酸诱导HSC活化的作用，表明HIF-1a在琥珀酸信号转导中的重要作用。结论：肝脏琥珀酸积累作为代谢信号，通过HIF-1α诱导促进肝纤维化。姜黄素通过对抗脂肪酸氧化来减少琥珀酸积累，并通过阻断琥珀酸/HIF-1 α 信号通路来防止 HSC 活化。
Purpose: Aberrant succinate accumulation emerges as a unifying mechanism for inflammation and oxidative stress. This study aims to investigate whether curcumin ameliorates hepatic fibrosis via blocking succinate signaling.Methods: We investigated the effects of curcumin on hepatic succinate accumulation and liver fibrosis in mice fed a high-fat diet (HFD). Meanwhile, we stimulated mouse primary hepatic stellate cells (HSCs) with succinate and observed the inhibitory effects of curcumin on succinate signaling.Results: Oral administration of curcumin and metformin combated mitochondrial fatty acid oxidation and reduced hepatic succinate accumulation due to the inhibition of succinate dehydrogenase (SDH) activity and demonstrated inhibitory effect on hepatic fibrosis. In mouse primary HSCs, curcumin prevented succinate- and CoCl2-induced hypoxia-inducible transcription factor-1 alpha (HIF-1 alpha) induction via suppression of ROS production and effectively reduced gene expressions of Col1 alpha, Col3 alpha, fibronectin and TGF-beta 1 with inflammation inhibition. Knockdown of HIF-1 a with small interfering RNA blocked the action of succinate to induce HSCs activation, indicative of the essential role of HIF-1 a in succinate signaling.Conclusions: Hepatic succinate accumulation served as a metabolic signal to promote liver fibrosis through HIF-1 alpha induction. Curcumin reduced succinate accumulation by combating fatty acid oxidation and prevented HSCs activation by blocking succinate/HIF-1 alpha signaling pathway.