Journal
CELL
Volume 178, Issue 6, Pages 1478-+Publisher
CELL PRESS
DOI: 10.1016/j.cell.2019.07.021
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Funding
- National Basic Research Program of China (973 program) [2015CB554002]
- National Natural Science Foundation of China [81573015, 81600496, 31700114, 81773101, 31771578]
- Guangdong Provincial Natural Science Foundation [2015A030306048]
- Guangzhou Science and Technology Collaborative Innovation Major Projects [201704020071]
- Guangdong Key Research and Development Plan [2019B020234003]
- Frontier Research Program of Guangzhou Regenerative Medicine and Health Guangdong Laboratory [2018GZR110105002]
- Shandong University [86963072]
- Natural Science Foundation of Jiangsu Province [BK20170399]
- Project of the National Natural Science Foundation of China
- NSFC-Guangdong Joint Fund [U1201226]
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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.
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