Galectin-1 is essential for efficient liver regeneration following hepatectomy

Tamara Potikha,Lina Mizrahi,Daniel S Goldenberg,Gabriel A Rabinovich,Ezra Ella,Orit Pappo,Juan P Cerliani,Eithan Galun

doi:10.18632/oncotarget.9194

Abstract

Galectin-1 (Gal1) is a known immune/inflammatory regulator which acts both extracellularly and intracellularly, modulating innate and adaptive immune responses. Here, we explored the role of Gal1 in liver regeneration using 70% partial hepatectomy (PHx) of C57BL/6 wild type and Gal1-knockout (Gal1-KO, Lgals1−/−) mice. Gene or protein expression, in liver samples collected at time intervals from 2 to 168 hours post-operation, was tested by either RT-PCR or by immunoblotting and immunohistochemistry, respectively. We demonstrated that Gal1 transcript and protein expression was induced in the liver tissue of wild type mice upon PHx. Liver regeneration following PHx was significantly delayed in the Gal1-KO compared to the control liver. This delay was accompanied by a decreased Akt phosphorylation, and accumulation of the hepatocyte nuclear p21 protein in the Gal1-KO versus control livers at 24 and 48 hours following PHx. Transcripts of several known regulators of inflammation, cell cycle and cell signaling, including some known PHx-induced genes, were aberrantly expressed (mainly down-regulated) in Gal1-KO compared to control livers at 2, 6 and 24 hours post-PHx. Transient steatosis, which is imperative for liver regeneration following PHx, was significantly delayed and decreased in the Gal1-KO compared to the control liver and was accompanied by a significantly decreased expression in the mutant liver of several genes encoding lipid metabolism regulators. Our results demonstrate that Gal1 protein is essential for efficient liver regeneration following PHx through the regulation of liver inflammation, hepatic cell proliferation, and the control of lipid storage in the regenerating liver.

Highlights

Galectin-1 (Gal1) is a β-galactoside-binding lectin, encoded by the galectin-1 gene symbol (Lgals1) gene, which is widely expressed in multiple cell types including immune cells and acts both extracellularly and intracellularly, modulating innate and adaptive immune responses
Monitoring markers of the proliferative machinery demonstrated a reduced level of BrdU incorporation into hepatocyte nuclei of Gal1-KO compared to wild type (WT) mice at 48 hours following partial hepatectomy (PHx), while the situation reversed at 96 hours following PHx (Figure 1B, Supplementary Figure 1A)
Phosphorylation of histone H3, which is a highly specific marker of mitosis, was significantly reduced in the hepatocyte nuclei of Gal1-KO compared to WT mice at 48 and 72 hours following PHx, while it was significantly increased in mutants at 96 hours following PHx (Figure 1C, Supplementary Figure 1B)

Summary

Introduction

Galectin-1 (Gal1) is a β-galactoside-binding lectin, encoded by the Lgals gene, which is widely expressed in multiple cell types including immune cells and acts both extracellularly and intracellularly, modulating innate and adaptive immune responses. This lectin blunts inflammatory responses by promoting apoptosis of activated, but not resting T cells, suppressing the secretion of pro-inflammatory cytokines and favoring secretion of anti-inflammatory IL-10 [1, 2]. Recent studies identified a role for Gal as a compensatory mechanism that preserves angiogenesis in anti-VEGF refractory tumors by co-opting the VEGFR2 signaling pathway [10], suggesting that it may mimic canonical ligands to sustain signaling pathways in different biological processes

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Conclusion