Department of Basic Science, Guangxi University of Chinese Medicine, Nanning 541100, Guangxi Zhuang Autonomous Region, China.
Department of Science and Technology, Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning 541100, Guangxi Zhuang Autonomous Region, China.
World J Gastroenterol. 2024 Apr 21;30(15):2143-2154. doi: 10.3748/wjg.v30.i15.2143.
Liver fibrosis is a compensatory response during the tissue repair process in chronic liver injury, and finally leads to liver cirrhosis or even hepatocellular carcinoma. The pathogenesis of hepatic fibrosis is associated with the progressive accumulation of activated hepatic stellate cells (HSCs), which can transdifferentiate into myofibroblasts to produce an excess of the extracellular matrix (ECM). Myofibroblasts are the main source of the excessive ECM responsible for hepatic fibrosis. Therefore, activated hepatic stellate cells (aHSCs), the principal ECM producing cells in the injured liver, are a promising therapeutic target for the treatment of hepatic fibrosis.
To explore the effect of taurine on aHSC proliferation and the mechanisms involved.
Human HSCs (LX-2) were randomly divided into five groups: Normal control group, platelet-derived growth factor-BB (PDGF-BB) (20 ng/mL) treated group, and low, medium, and high dosage of taurine (10 mmol/L, 50 mmol/L, and 100 mmol/L, respectively) with PDGF-BB (20 ng/mL) treated group. Cell Counting Kit-8 method was performed to evaluate the effect of taurine on the viability of aHSCs. Enzyme-linked immunosorbent assay was used to estimate the effect of taurine on the levels of reactive oxygen species (ROS), malondialdehyde, glutathione, and iron concentration. Transmission electron microscopy was applied to observe the effect of taurine on the autophagosomes and ferroptosis features in aHSCs. Quantitative real-time polymerase chain reaction and Western blot analysis were performed to detect the effect of taurine on the expression of α-SMA, Collagen I, Fibronectin 1, LC3B, ATG5, Beclin 1, PTGS2, SLC7A11, and p62.
Taurine promoted the death of aHSCs and reduced the deposition of the ECM. Treatment with taurine could alleviate autophagy in HSCs to inhibit their activation, by decreasing autophagosome formation, downregulating LC3B and Beclin 1 protein expression, and upregulating p62 protein expression. Meanwhile, treatment with taurine triggered ferroptosis and ferritinophagy to eliminate aHSCs characterized by iron overload, lipid ROS accumulation, glutathione depletion, and lipid peroxidation. Furthermore, bioinformatics analysis demonstrated that taurine had a direct targeting effect on nuclear receptor coactivator 4, exhibiting the best average binding affinity of -20.99 kcal/mol.
Taurine exerts therapeutic effects on liver fibrosis mechanisms that involve inhibition of autophagy and trigger of ferroptosis and ferritinophagy in HSCs to eliminate aHSCs.
肝纤维化是慢性肝损伤组织修复过程中的一种代偿反应，最终导致肝硬化甚至肝癌。肝纤维化的发病机制与活化的肝星状细胞（HSCs）的渐进性积累有关，这些细胞可以转分化为肌成纤维细胞，产生过量的细胞外基质（ECM）。肌成纤维细胞是导致肝纤维化的过量 ECM 的主要来源。因此，活化的肝星状细胞（aHSCs）是治疗肝纤维化的有希望的治疗靶点，是受损肝脏中产生 ECM 的主要细胞。
探讨牛磺酸对 aHSC 增殖的影响及其机制。
人 HSCs（LX-2）随机分为五组：正常对照组、血小板衍生生长因子-BB（PDGF-BB）（20ng/ml）处理组、低、中、高剂量牛磺酸（10mmol/L、50mmol/L、100mmol/L，分别）与 PDGF-BB（20ng/ml）处理组。用细胞计数试剂盒-8 法评价牛磺酸对 aHSC 活力的影响。酶联免疫吸附试验用于估计牛磺酸对活性氧（ROS）、丙二醛、谷胱甘肽和铁浓度的影响。透射电子显微镜观察牛磺酸对 aHSCs 自噬体和铁死亡特征的影响。实时定量聚合酶链反应和 Western blot 分析检测牛磺酸对α-SMA、胶原 I、纤维连接蛋白 1、LC3B、ATG5、Beclin 1、PTGS2、SLC7A11 和 p62 表达的影响。
牛磺酸促进 aHSCs 死亡，减少 ECM 沉积。牛磺酸处理可通过减少自噬体形成、下调 LC3B 和 Beclin 1 蛋白表达、上调 p62 蛋白表达，减轻 HSCs 中的自噬，抑制其激活。同时，牛磺酸触发铁死亡和铁蛋白自噬以消除铁过载、脂质 ROS 积累、谷胱甘肽耗竭和脂质过氧化的 aHSCs。此外，生物信息学分析表明，牛磺酸对核受体共激活因子 4 具有直接靶向作用，表现出最佳平均结合亲和力为-20.99kcal/mol。
牛磺酸通过抑制 HSCs 中的自噬并触发铁死亡和铁蛋白自噬来消除 aHSCs，从而对肝纤维化发挥治疗作用。
