The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
Biochim Biophys Acta Gen Subj. 2022 Oct;1866(10):130202. doi: 10.1016/j.bbagen.2022.130202. Epub 2022 Jul 9.
Liver fibrosis has been the focus and difficulty of medical research in the world and its concrete pathogenesis remains unclear. This study aims to observe the high-mobility group box 1 (HMGB1)-induced hepatic endothelial to mesenchymal transition (EndoMT) during the development of hepatic fibrosis, and further to explore the crucial involvement of Egr1 in this process.
Carbon tetrachloride (CCl), diosbulbin B (DB), N-acetyl-p-aminophenol (APAP) and bile duct ligation (BDL) were used to induce liver fibrosis in mice. Serum HMGB1 content, the occurrence of EndoMT and the production of extracellular matrix (ECM) in vitro and in vivo were detected by Western-blot.
The elevated serum HMGB1 content, the occurrence of EndoMT, the production of ECM and the activation of Egr1 were observed in mice with liver fibrosis induced by CCl, DB, APAP or BDL. HMGB1 induced EndoMT and ECM production in human hepatic sinusoidal endothelial cells (HHSECs), and then HHSECs lost the ability to inhibit the activation of hepatic stellate cells (HSCs). The hepatic deposition of collagen, the increased serum HMGB1 content and hepatic EndoMT were further aggravated in Egr1 knockout mice. Natural compound silymarin attenuated liver fibrosis in mice induced by CCl via increasing Egr1 nuclear accumulation, decreasing serum HMGB1 content and inhibiting hepatic EndoMT.
Egr1 regulated the expression of HMGB1 that induced hepatic EndoMT, which plays an important role in the development of liver fibrosis.
This study provides a novel therapeutic strategy for the treatment of liver fibrosis in clinic.
肝纤维化一直是世界医学研究的焦点和难点，其具体发病机制尚不清楚。本研究旨在观察高迁移率族蛋白 B1（HMGB1）诱导肝内皮向间充质转化（EndoMT）在肝纤维化发展过程中的作用，并进一步探讨 Egr1 在这一过程中的关键作用。
采用四氯化碳（CCl）、莪术醇（DB）、N-乙酰对氨基酚（APAP）和胆管结扎（BDL）诱导小鼠肝纤维化。通过 Western blot 检测血清 HMGB1 含量、体外和体内 EndoMT 发生、细胞外基质（ECM）产生。
在 CCl、DB、APAP 或 BDL 诱导的肝纤维化小鼠中，观察到血清 HMGB1 含量升高、EndoMT 发生、ECM 产生和 Egr1 激活。HMGB1 诱导人肝窦内皮细胞（HHSECs）发生 EndoMT 和 ECM 产生，然后 HHSECs 丧失抑制肝星状细胞（HSCs）激活的能力。Egr1 基因敲除小鼠肝胶原沉积、血清 HMGB1 含量升高和肝 EndoMT 进一步加重。天然化合物水飞蓟素通过增加 Egr1 核积累、降低血清 HMGB1 含量和抑制肝 EndoMT，减轻 CCl 诱导的小鼠肝纤维化。
Egr1 调节 HMGB1 的表达，诱导肝 EndoMT，在肝纤维化的发展中起重要作用。
本研究为临床治疗肝纤维化提供了一种新的治疗策略。
