Lv Mengjia, Chen Shiyi, Shan Mengwen, Si Yuan, Huang Chenggang, Chen Jing, Gong Likun
School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing, 100049, China.
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing, 100049, China.
Eur J Pharmacol. 2024 Jul 5;974:176629. doi: 10.1016/j.ejphar.2024.176629. Epub 2024 Apr 26.
Arctigenin (ATG), a traditional Chinese herbal medicine, is a natural lignan compound extracted from the seeds of burdock (Arctium lappa L, Asteraceae). As a natural product with multiple biological activities, the effect and mechanism of ATG against liver fibrosis are not fully elucidated yet. In current work, we first discovered that ATG could improve CCl-induced liver injury reflected by lower plasma ALT and AST levels, liver coefficient and pathological scoring of ballooning. Furthermore, it also could reduce the positive areas of Masson, Sirius red and α-SMA staining, inhibit the expression of fibrosis-related genes (Col1a1, Col3a1, Acta2), and decrease the content of hydroxyproline, indicated ATG treatment had benefits in alleviating CCl-induced liver fibrosis. In vitro, we observed that ATG can inhibit collagen production stimulated by TGF-β1 in LX2 cells. By analysis of the information obtained from SymMap and GeneCards databases and in vitro validation experiments, ATG was proven to be an indirect PPARγ agonist and its effect on collagen production was dependent on PPARγ. Subsequently, we confirmed that ATG activating AMPK was the contributor of its effect on PPARγ and collagen production. Finally, the transformation of activated hepatic stellate cells was determined after treated with ATG, in which ATG treatment could return activated LX2 cells to quiescence because of the elevated quiescent markers and lipid droplets. Our work has highlighted the potential of ATG in the treatment of liver fibrosis and clarified that ATG can activate AMPK/PPARγ pathway to restore the activated hepatic stellate cell to quiescence thereby improving liver fibrosis.
牛蒡子苷元（ATG）是一种传统中药，是从牛蒡（菊科牛蒡属植物牛蒡）种子中提取的天然木脂素化合物。作为一种具有多种生物活性的天然产物，ATG抗肝纤维化的作用及机制尚未完全阐明。在当前的研究中，我们首先发现ATG可以改善CCl4诱导的肝损伤，这体现在较低的血浆ALT和AST水平、肝脏系数以及气球样变的病理评分上。此外，它还可以减少Masson、天狼星红和α-SMA染色的阳性面积，抑制纤维化相关基因（Col1a1、Col3a1、Acta2）的表达，并降低羟脯氨酸含量，表明ATG治疗在减轻CCl4诱导的肝纤维化方面具有益处。在体外，我们观察到ATG可以抑制LX2细胞中TGF-β1刺激的胶原蛋白产生。通过对从SymMap和GeneCards数据库获得的信息进行分析以及体外验证实验，证明ATG是一种间接的PPARγ激动剂，其对胶原蛋白产生的影响依赖于PPARγ。随后，我们证实ATG激活AMPK是其对PPARγ和胶原蛋白产生影响的原因。最后，在用ATG处理后确定了活化肝星状细胞发生转变，其中ATG处理可使活化的LX2细胞恢复静止，这是由于静止标志物和脂滴增加所致。我们的研究突出了ATG在治疗肝纤维化方面的潜力，并阐明ATG可以激活AMPK/PPARγ通路，使活化的肝星状细胞恢复静止，从而改善肝纤维化。
