Physalin B attenuates liver fibrosis via suppressing LAP2 alpha-HDAC1-mediated deacetylation of the transcription factor GLI1 and hepatic stellate cell activation
Physalin B attenuates liver fibrosis via suppressing LAP2 alpha-HDAC1-mediated deacetylation of the transcription factor GLI1 and hepatic stellate cell activation
复制标题
Physalin B 通过抑制 LAP2 α-HDAC1 介导的转录因子 GLI1 脱乙酰化和肝星状细胞活化来减轻肝纤维化
DOI：
10.1111/bph.15490
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发表时间：
2021
影响因子：
7.3
通讯作者：
Kong Lingyi
中科院分区：
文献类型：
--
作者：
Zhu Xiaoyun;Ye Shengtao;Yu Dongke;Zhang Yanqiu;Li Jie;Zhang Meihui;Leng Yingrong;Yang Ting;Luo Jianguang;Chen Xinlin;Zhang Hao;Kong Lingyi
背景和目的肝纤维化是全世界发病和死亡的主要原因之一，但缺乏任何可接受的治疗方法。转录因子胶质瘤相关癌基因同源物 1 (GLI1) 是肝纤维化的潜在重要治疗靶点。本研究探讨了植物化学物质 physalin B 的抗纤维化活性和潜在机制。实验方法使用两种小鼠模型（CCl4 挑战和胆管结扎）来评估 physalin B 的体内抗纤维化作用。小鼠原代肝星状细胞 (pHSC) 和人 HSC 系 LX-2 也可用作体外肝纤维化模型。使用蛋白质印迹和实时定量 PCR (qRT-PCR) 检查肝纤维化基因、GLI1 和 GLI1 下游基因。通过免疫共沉淀分析 GLI1 乙酰化和 LAP2α-HDAC1 相互作用。 主要结果 在体内，给予 physalin B 可以减轻肝组织病理学损伤和胶原蛋白积累，并减少纤维形成基因的表达。 Physalin B 剂量依赖性抑制 LX-2 细胞和小鼠 pHSC 中纤维化标志物的表达。机制研究表明，physalin B 通过非经典 Hedgehog 信号传导抑制 GLI 活性。酸浆素 B 阻断核纤层相关多肽 2α (LAP2α)/组蛋白脱乙酰酶 1 (HDAC1) 复合物的形成，从而抑制 HDAC1 介导的 GLI1 脱乙酰化。 Physalin B 上调 GLI1 的乙酰化，下调 GLI1 的表达，从而抑制 HSC 活化。 结论和意义 Physalin B 通过破坏 LAP2α/HDAC1 复合物、增加 GLI1 乙酰化和灭活 GLI1 在体外和体内发挥有效的抗纤维化作用。这表明植物化学酸浆蛋白B可能是治疗肝纤维化的潜在候选药物。
Background and PurposeLiver fibrosis is one of the leading causes of morbidity and mortality worldwide but lacks any acceptable therapy. The transcription factor glioma‐associated oncogene homologue 1 (GLI1) is a potentially important therapeutic target in liver fibrosis. This study investigates the anti‐fibrotic activities and potential mechanisms of the phytochemical, physalin B.Experimental ApproachTwo mouse models (CCl4challenge and bile duct ligation) were used to assess antifibrotic effects of physalin B in vivo. Mouse primary hepatic stellate cells (pHSCs) and human HSC line LX‐2 also served as in vitro liver fibrosis models. Liver fibrogenic genes, GLI1 and GLI1 downstream genes were examined using Western blot and quantitative real‐time PCR (qRT‐PCR). GLI1 acetylation and LAP2α–HDAC1 interaction were analysed by co‐immunoprecipitation.Key ResultsIn vivo, physalin B administration attenuated hepatic histopathological injury and collagen accumulation and decreased expression of fibrogenic genes. Physalin B dose‐dependently suppressed fibrotic marker expression in LX‐2 cells and mouse pHSCs. Mechanistic studies showed that physalin B inhibited GLI activity by non‐canonical Hedgehog signalling. Physalin B blocked formation of lamina‐associated polypeptide 2α (LAP2α)/histone deacetylase 1 (HDAC1) complexes, thus inhibiting HDAC1‐mediated GLI1 deacetylation. Physalin B up‐regulated acetylation of GLI1, down‐regulated expression of GLI1 and subsequently inhibited HSC activation.Conclusion and ImplicationsPhysalin B exerted potent antifibrotic effects in vitro and in vivo by disrupting LAP2α/HDAC1 complexes, increasing GLI1 acetylation and inactivating GLI1. This indicates that the phytochemical physalin B may be a potential therapeutic candidate for the treatment of liver fibrosis.