An oral phenylacrylic acid derivative suppressed hepatic stellate cell activation and ameliorated liver fibrosis by blocking TGF-β1 signalling
An oral phenylacrylic acid derivative suppressed hepatic stellate cell activation and ameliorated liver fibrosis by blocking TGF-β1 signalling
复制标题
口服苯丙烯酸衍生物通过阻断 TGF β1 信号传导抑制肝星状细胞活化并改善肝纤维化
DOI：
10.1111/liv.15488
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发表时间：
2022-12-14
影响因子：
6.7
通讯作者：
Ye，Tinghong
中科院分区：
文献类型：
--
作者：
Xue，Taixiong;Yue，Lin;Ye，Tinghong
背景与目的肝纤维化是一种由活化的肝星状细胞(HSCs)主导的过度创面修复反应。到目前为止，还没有治疗肝纤维化的药物。阿魏酸(FA)虽然具有多种药理作用，但其抗肝纤维化活性较弱。在对FA结构进行活性修饰的基础上，合成了一系列苯基丙烯酸衍生物，得到了一种性能较好的化合物FA11。本研究旨在探讨其抗肝纤维化作用及其机制。方法采用活化的HSC和CCl4诱导的小鼠肝纤维化模型，并进行FA11治疗。CCK-8比色法测定细胞存活率。用流式细胞仪进行细胞凋亡和细胞周期分析。Western印迹和实时定量定量聚合酶链式反应(Real-time qPCR)检测纤维化和M1/M2型巨噬细胞标志物的表达。结果在体外，FA11可抑制转化生长因子β1诱导的LX-2细胞增殖，并导致细胞凋亡和细胞周期停滞。此外，转化生长因子-β-1诱导的LX-2和原激活的肝星状细胞中纤维化标志物的升高被FA11逆转。在体内，FA11可减轻胶原沉积，抑制HSC活化和上皮-间质转化(EMT)。此外，FA11减少了纤维化肝脏中巨噬细胞的渗透，并阻止巨噬细胞极化为促纤维化表型。同时，FA11对CCl_4的全身毒性也有改善作用。结论口服苯丙烯酸衍生物FA11具有良好的抗肝纤维化活性，有望成为抗肝纤维化的候选药物。
Background and AimsLiver fibrosis is an excessive wound‐healing response governed by activated hepatic stellate cells (HSCs). To date, there is no drug available for liver fibrosis. Although ferulic acid (FA) has multiple pharmacological functions, its anti‐hepatic fibrosis activity is weak. Based on the activity modification of the FA structure, we synthesized a series of phenylacrylic derivatives and found a superior compound, FA11. In this study, we investigated its antifibrotic effect and mechanism.MethodsActivated HSC and CCl4‐induced mouse liver fibrosis were established and followed by FA11 treatment. Cell viability was measured by CCK‐8 assay. Apoptosis and cell cycle analysis were conducted by flow cytometry. Western blot and Real‐time qPCR were used to examine the expression of fibrotic and M1/M2‐type macrophages markers. Degree of liver fibrosis was shown by histological staining.ResultsIn vitro, FA11 inhibited TGF‐β1‐induced LX‐2 proliferation and led to apoptosis and cycle arrest. Furthermore, elevation of fibrotic markers in TGF‐β1‐induced LX‐2 and primary activated HSC was reversed by FA11. In vivo, FA11 administration alleviated collagen deposition and blocked HSC activation and epithelial‐mesenchymal transition (EMT). Additionally, FA11 reduced macrophage infiltration in fibrotic liver and prevented macrophage polarization to a profibrotic phenotype. Meanwhile, the systemic toxicity of CCl4was also ameliorated by FA11. Mechanistically, FA11 reversed the phosphorylation of canonical and noncanonical TGF‐β1 signalling, as well as FGFR1 signalling.ConclusionsWe reported an oral phenylacrylic acid derivative, FA11, which showed excellent antifibrotic activity and was expected to be an anti‐hepatic fibrosis candidate.