HDL activation of endothelial sphingosine-1-phosphate receptor-1 (S1P1) promotes regeneration and suppresses fibrosis in the liver
Bi-Sen Ding ... Shahin Rafii, Timothy Hla
Bi-Sen Ding ... Shahin Rafii, Timothy Hla
Published December 22, 2016
Citation Information: JCI Insight. 2016;1(21):e87058. doi:10.1172/jci.insight.87058.
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Categories: Research Article Therapeutics Vascular biology

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

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.

Authors

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

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Regeneration of liver mass and vascular structure in mice deficient of H...

Figure 1

Regeneration of liver mass and vascular structure in mice deficient of HDL component ApoM after partial hepatectomy (PH).

(A) Strategy to test liver regeneration in mice with genetic depletion of ApoM (Apom-/-). Both Apom-/- and wild-type (WT) control mice were subjected to surgical resection of 70% liver mass (partial hepatectomy, PH). To perform PH, three most anterior lobes (right medial, left medial and left lateral lobes) (which comprise 70% of the liver weight) were resected without injuring the blood supply to the caudate and the right lobes. Restoration of functional liver mass and vascular architecture after PH was analyzed in both mouse genotypes. Histological analysis of the liver from WT and Apom-/- mice after sham operation is shown in Supplemental Figure 1A. (B–G) Recovery of liver weight (B), body weight (C), mouse survival rate (D), restoration of hepatic function (E), and extent of liver parenchymal injury (F and G) in Apom-/- and WT mice at indicated time points after PH. Levels of plasma bilirubin and serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were measured to examine hepatic function and liver damage. N = 6-8 mice per group. Each dot in the dot plot indicates individual animal throughout all figures. Statistical difference was determined by One way ANOVA throughout Figure 1. (H and I) Sinusoidal vascular regeneration in hepatectomized mice. Expression of VEGFR3, a specific marker of liver sinusoidal endothelial cell (LSEC) was tested by immunostaining. To examine functional sinusoidal vessels that are perfused, 2 mg/kg B4-Isolectin binding to endothelial cell surface was intravenously (i.v.) injected into the mice after PH. Representative image of immunostaining is shown in H, and percentage of VEGFR3+ and isolectin+ vascular area was quantified in (I). Note the increased lumen size in non-perfused isolectin-VEGFR3+ liver sinusoidal vasculature of Apom-/- mice after PH. N = 5 mice per group. Scale bar = 50 μm.