南方医科大学周伟杰/丁彦青团队发现LECT2是Tie1的配体，并在肝纤维化过程中发挥关键作用。2019年8月29日国际学术期刊《细胞》在线发表了这一成果。
研究人员发现，白细胞来源的趋化因子2（LECT2）是Tie1的功能性配体，Tie1是一种了解甚少的内皮细胞（EC）特异性孤儿受体。在与Tie1结合后，LECT2中断Tie1/Tie2异源二聚化，促进Tie2/Tie2同源二聚化，激活PPAR信号传导，并抑制EC的迁移和管形成。体内研究表明，LECT2过表达抑制门静脉血管生成，促进血窦毛细血管化，并恶化纤维化，而这些变化在Lect2-KO小鼠中被逆转。腺相关病毒载体血清型9（AAV9）-LECT2小发夹RNA（shRNA）的处理能够显著减弱纤维化。LECT2的上调与晚期人肝纤维化分期相关。研究人员认为，靶向LECT2/Tie1信号传导可能是肝纤维化的潜在治疗靶标，并且血清LECT2水平可能是筛选和诊断肝纤维化的潜在生物标志物。
据了解，肝纤维化是数百万各种肝病患者中非常常见的病症，但由于分子发病机制的特征不明确，尚无有效的治疗方法。
附：英文原文
Title: LECT2, a Ligand for Tie1, Plays a Crucial Role in Liver Fibrogenesis
Author: Meng Xu, Hong-Hai Xu , Yuan Lin, Xiangnan Sun, Li-Jing Wang, Zhe-Ping Fang, Xue-Han Su, Xiang-Jing Liang, Yang Hu, Zhi-Min Liu, Yuanxiong Cheng, Yuanyuan Wei, Jiabin Li, Li Li, Hong-Juan Liu, Zhiqiang Cheng, Na Tang, Chao Peng, Tingting Li, Tengfei Liu, Liang Qiao, Dalei Wu, Yan-Qing Ding, Wei-Jie Zhou
Issue&Volume: 29 August 2019
Abstract: Liver fibrosis is a very common condition seen in millions of patients with various liver diseases, and yet no effective treatments are available owing to poorly characterized molecular pathogenesis. Here, we show that leukocyte cell-derived chemotaxin 2 (LECT2) is a functional ligand of Tie1, a poorly characterized endothelial cell (EC)-specific orphan receptor. Upon binding to Tie1, LECT2 interrupts Tie1/Tie2 heterodimerization, facilitates Tie2/Tie2 homodimerization, activates PPAR signaling, and inhibits the migration and tube formations of EC. In vivo studies showed that LECT2 overexpression inhibits portal angiogenesis, promotes sinusoid capillarization, and worsens fibrosis, whereas these changes were reversed in Lect2-KO mice. Adeno-associated viral vector serotype 9 (AAV9)-LECT2 small hairpin RNA (shRNA) treatment significantly attenuates fibrosis. Upregulation of LECT2 is associated with advanced human liver fibrosis staging. We concluded that targeting LECT2/Tie1 signaling may represent a potential therapeutic target for liver fibrosis, and serum LECT2 level may be a potential biomarker for the screening and diagnosis of liver fibrosis.
DOI: https://doi.org/10.1016/j.cell.2019.07.021
Source: https://www.cell.com/cell/fulltext/S0092-8674(19)30786-X#