Oroxylin A induces apoptosis of activated hepatic stellate cells through endoplasmic reticulum stress
Oroxylin A induces apoptosis of activated hepatic stellate cells through endoplasmic reticulum stress
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Oroxylin A 通过内质网应激诱导活化肝星状细胞凋亡
DOI：
10.1007/s10495-019-01568-2
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发表时间：
2019-12-01
期刊：
影响因子：
7.2
通讯作者：
Zheng, Shizhong
中科院分区：
文献类型：
--
作者：
Bian, Mianli;He, Jianlin;Zheng, Shizhong
肝星状细胞（HSC）活化在肝纤维化中起着不可或缺的作用。诱导活化的HSC凋亡可以减弱或逆转纤维化。在这项研究中，我们初步发现，oroxylin A（OA）保护四氯化碳诱导的肝损伤伴随着内质网应激（ERS）激活的HSC在小鼠中。在体外，OA治疗通过调节细胞外基质的合成和降解显着减少纤维化。OA可抑制HSC的增殖，并使细胞周期阻滞于S期。此外，观察到OA诱导HSC凋亡，如半胱天冬酶激活所示。使用eIF2 α去磷酸化抑制剂salubrinal，我们发现ERS通路激活是OA诱导HSC凋亡所必需的。ERS相关蛋白被OA处理显著上调，salubrinal消除OA对HSC的影响。因此，我们推断OA通过促进ERS而减弱HSC活化。在体内，抑制ERS salubrinal部分废除OA在四氯化碳处理的小鼠的肝保护作用。总之，我们的研究结果表明ERS在OA改善肝纤维化的机制中发挥作用。
Hepatic stellate cell (HSC) activation plays an indispensable role in hepatic fibrosis. Inducing apoptosis of activated HSCs can attenuate or reverse fibrogenesis. In this study, we initially found that oroxylin A (OA) protected CCl4-induced liver injury accompanied by endoplasmic reticulum stress (ERS) activation of HSCs in mice. In vitro, OA treatment markedly reduced fibrogenesis by modulating extracellular matrix synthesis and degradation. OA inhibited cell proliferation and induced cell cycle arrest of HSCs at S phase. Further, OA was observed to induce HSC apoptosis, as indicated by caspase activation. Using the eIF2 alpha dephosphorylation inhibitor salubrinal, we found that ERS pathway activation was required for OA to induce HSC apoptosis. ERS-related proteins were significantly upregulated by OA treatment, and salubrinal abrogated the effects of OA on HSCs. Thus, we inferred that OA attenuated HSC activation by promoting ERS. In vivo, inhibition of ERS by salubrinal partly abrogated the hepatoprotective effect of OA in CCl4-treated mice. In conclusion, our findings suggest a role for ERS in the mechanism underlying amelioration of hepatic fibrosis by OA.