LECT2, a Ligand for Tie1, Plays a Crucial Role in Liver Fibrogenesis
LECT2, a Ligand for Tie1, Plays a Crucial Role in Liver Fibrogenesis
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LECT2 是 Tie1 的配体，在肝纤维形成中发挥着至关重要的作用
DOI：
10.1016/j.cell.2019.07.021
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发表时间：
2019-09-05
期刊：
影响因子：
64.5
通讯作者：
Zhou, Wei-Jie
中科院分区：
文献类型：
--
作者：
Xu, Meng;Xu, Hong-Hai;Zhou, Wei-Jie
肝纤维化是数以百万计的各种肝脏疾病患者的一种非常常见的疾病，但由于分子发病机制的不明确，尚无有效的治疗方法。在这里，我们发现白细胞来源的趋化素2 （LECT2）是一种功能配体，Tie1是一种特征不佳的内皮细胞特异性孤儿受体。与Tie1结合后，LECT2阻断Tie1/Tie2异源二聚化，促进Tie2/Tie2同型二聚化，激活PPAR信号，抑制EC的迁移和管状形成。体内研究表明，LECT2过表达抑制门静脉血管生成，促进窦状毛细血管形成，并加重纤维化，而这些变化在LECT2 - ko小鼠中是逆转的。腺相关病毒载体血清型9 (AAV9)-LECT2小发夹RNA （shRNA）治疗显著减轻纤维化。LECT2的上调与人类肝纤维化的晚期分期有关。我们得出结论，靶向LECT2/Tie1信号可能是肝纤维化的潜在治疗靶点，血清LECT2水平可能是筛查和诊断肝纤维化的潜在生物标志物。
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.