临港实验室臧奕等研究人员合作发现，一种新型的PTP1B抑制剂Luteolin-7-二葡糖苷酸能够改善小鼠的肝星状细胞活化和肝纤维化。2024年8月5日，国际知名学术期刊《中国药理学报》在线发表了这一成果。

研究人员探讨了Luteolin-7-二葡糖苷酸（L7DG）的抗纤维化活性及其潜在机制。研究人员建立了TGF-β1激活的小鼠原代肝星状细胞（pHSC）和人HSC细胞系LX-2作为体外肝纤维化模型。L7DG（5、20、50 μM）的联合处理能剂量依赖性地减少TGF-β1诱导的纤维化标志物胶原1、α-SMA和纤维连接蛋白的表达。

在CCl4单独或与高脂高糖饮食联用诱导的小鼠肝纤维化模型中，L7DG（40、150 mg/kg每天，口服，4或8周）能够剂量依赖性地减轻肝组织病理损伤和胶原积累，降低纤维化基因的表达。通过靶点预测、分子对接和酶活性检测，研究人员发现L7DG是一种有效的PTP1B抑制剂，其IC50值为2.10 μM。

进一步研究表明，L7DG抑制了PTP1B活性，上调了AMPK磷酸化水平，随后抑制了HSC的活化。该研究表明，植物化学物质L7DG可能是治疗肝纤维化的潜在治疗候选药物。

据了解，肝纤维化是全球发病率和死亡率较高的疾病之一，目前尚缺乏有效的治疗方法。HSC的活化是肝纤维化的主要事件。Luteolin-7-二葡糖苷酸（L7DG）是从紫苏和马鞭草中提取的主要黄酮类化合物，其在肝病治疗中的有益效果已得到广泛证实。

附：英文原文

Title: Luteolin-7-diglucuronide, a novel PTP1B inhibitor, ameliorates hepatic stellate cell activation and liver fibrosis in mice

Author: Tang, Bi-xi, Zhang, Yong, Sun, Dan-dan, Liu, Qin-yi, Li, Cong, Wang, Pei-pei, Gao, Li-xin, Zhang, Xue-mei, Li, Jia, Zhu, Wei-liang, Zang, Yi

Issue&Volume: 2024-08-05

Abstract: Liver fibrosis, one of the leading causes of morbidity and mortality worldwide, lacks effective therapy. The activation of hepatic stellate cells (HSCs) is the dominant event in hepatic fibrogenesis. Luteolin-7-diglucuronide (L7DG) is the major flavonoid extracted from Perilla frutescens and Verbena officinalis. Their beneficial effects in the treatment of liver diseases were well documented. In this study we investigated the anti-fibrotic activities of L7DG and the potential mechanisms. We established TGF-β1-activated mouse primary hepatic stellate cells (pHSCs) and human HSC line LX-2 as in vitro liver fibrosis models. Co-treatment with L7DG (5, 20, 50μM) dose-dependently decreased TGF-β1-induced expression of fibrotic markers collagen 1, α-SMA and fibronectin. In liver fibrosis mouse models induced by CCl4 challenge alone or in combination with HFHC diet, administration of L7DG (40, 150mg·kg–1·d–1, i.g., for 4 or 8 weeks) dose-dependently attenuated hepatic histopathological injury and collagen accumulation, decreased expression of fibrogenic genes. By conducting target prediction, molecular docking and enzyme activity detection, we identified L7DG as a potent inhibitor of protein tyrosine phosphatase 1B (PTP1B) with an IC50 value of 2.10μM. Further studies revealed that L7DG inhibited PTP1B activity, up-regulated AMPK phosphorylation and subsequently inhibited HSC activation. This study demonstrates that the phytochemical L7DG may be a potential therapeutic candidate for the treatment of liver fibrosis.

DOI: 10.1038/s41401-024-01351-3

Source: https://www.nature.com/articles/s41401-024-01351-3