Glycosylation-dependent galectin-1/neuropilin-1 interactions promote liver fibrosis through activation of TGF-β- and PDGF-like signals in hepatic stellate cells.

Abstract

Concomitant expressions of glycan-binding proteins and their bound glycans regulate many pathophysiologic processes, but this issue has not been addressed in liver fibrosis. Activation of hepatic stellate cells (HSCs) is a rate-limiting step in liver fibrosis and is an important target for liver fibrosis therapy. We previously reported that galectin (Gal)-1, a β-galactoside-binding protein, regulates myofibroblast homeostasis in oral carcinoma and wound healing, but the role of Gal-1 in HSC migration and activation is unclear. Herein, we report that Gal-1 and its bound glycans were highly expressed in fibrotic livers and activated HSCs. The cell-surface glycome of activated HSCs facilitated Gal-1 binding, which upon recognition of the N-glycans on neuropilin (NRP)-1, activated platelet-derived growth factor (PDGF)- and transforming growth factor (TGF)-β-like signals to promote HSC migration and activation. In addition, blocking endogenous Gal-1 expression suppressed PDGF- and TGF-β1-induced signaling, migration, and gene expression in HSCs. Methionine and choline-deficient diet (MCD)-induced collagen deposition and HSC activation were attenuated in Gal-1-null mice compared to wild-type mice. In summary, we concluded that glycosylation-dependent Gal-1/NRP-1 interactions activate TGF-β and PDGF-like signaling to promote the migration and activation of HSCs. Therefore, targeting Gal-1/NRP-1 interactions could be developed into liver fibrosis therapy.

• Authors: Ming-Heng Wu, Yuh-Ling Chen, Kuen-Haur Lee, Che-Chang Chang, Tsai-Mu Cheng, Szu-Yuan Wu, Chao-Chiang Tu, Wan-Lin Tsui
• Journal: Scientific reports (Sci Rep) Vol. 7 Issue 1 Pg. 11006 (09 08 2017) ISSN: 2045-2322 [Electronic] England
• PMID: 28887481 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Galectin 1
• Platelet-Derived Growth Factor
• Transforming Growth Factor beta
• platelet-derived growth factor A
• Neuropilin-1
• Receptors, Platelet-Derived Growth Factor

Topics

• Animals
• Cell Line
• Cell Movement
• Galectin 1 (metabolism)
• Glycosylation
• Hepatic Stellate Cells (pathology)
• Liver Cirrhosis (pathology)
• Mice
• Mice, Knockout
• Neuropilin-1 (metabolism)
• Platelet-Derived Growth Factor (metabolism)
• Protein Binding
• Receptors, Platelet-Derived Growth Factor (metabolism)
• Signal Transduction
• Transforming Growth Factor beta (metabolism)