HDL activation of endothelial sphingosine-1-phosphate receptor-1 (S1P1) promotes regeneration and suppresses fibrosis in the liver

Bi-Sen Ding, Catherine H Liu, Yue Sun, Yutian Chen, Steven L Swendeman, Bongnam Jung, Deebly Chavez, Zhongwei Cao, Christina Christoffersen, Lars Bo Nielsen, Susan R Schwab, Shahin Rafii, Timothy Hla

Research output: Contribution to journalJournal articleResearchpeer-review

64 Citations (Scopus)

Abstract

Regeneration of hepatic sinusoidal vasculature is essential for non-fibrotic liver regrowth and restoration of its metabolic capacity. However, little is known about how this specialized vascular niche is regenerated. Here we show that activation of endothelial sphingosine-1-phosphate receptor-1 (S1P1) by its natural ligand bound to HDL (HDL-S1P) induces liver regeneration and curtails fibrosis. In mice lacking HDL-S1P, liver regeneration after partial hepatectomy was impeded and associated with aberrant vascular remodeling, thrombosis and peri-sinusoidal fibrosis. Notably, this "maladaptive repair" phenotype was recapitulated in mice that lack S1P1 in the endothelium. Reciprocally, enhanced plasma levels of HDL-S1P or administration of SEW2871, a pharmacological agonist specific for S1P1 enhanced regeneration of metabolically functional vasculature and alleviated fibrosis in mouse chronic injury and cholestasis models. This study shows that natural and pharmacological ligands modulate endothelial S1P1 to stimulate liver regeneration and inhibit fibrosis, suggesting that activation of this pathway may be a novel therapeutic strategy for liver fibrosis.

Original languageEnglish
Article numbere87058
JournalJCI insight
Volume1
Issue number21
Number of pages16
ISSN2379-3708
DOIs
Publication statusPublished - 22 Dec 2016

Cite this