| Aberrant N-glycosylation caused by altered N-acetylglucosaminyltransferase V (GnT-V) expression is known to regulate tumor invasion and metastasis by modulating multiple cytokine signaling pathways. However, the role of GnT-V in liver fibrosis has not yet been reported. Here, we induced hepatic fibrosis in mouse by repetitive intraperitoneal injections of thioacetamide (TAA) and detected marked upregulation of GnT-V in the fibrotic liver, suggesting that GnT-V might contribute to hepatic fibrogenesis. To knockdown GnT-V expression level, an adenovirus, AdMS1, that can express the small interfering RNA (siRNA) targeting GnT-V was contructed. Our results demonstrated that AdMS1infection significantly downregulated the GnT-V expression level and reduced the GnT-V-modified β1,6-branched N-glycan on the cell surface of hepatic stellate cells (HSCs) in vitro. Knockdown of GnT-V in HSCs significantly deactivated the myofibroblastic status and consequently reduced collagen secretion. More importantly, knockdown of hepatic GnT-V expression level in vivo in TAA-treated mice efficiently reduced liver fibrosis as assessed through collagen deposition, hepatic hydroxyproline content and profiles of profibrogenic markers. Subsequent investigations revealed that the fibrotic liver from AdMS1-treated mice displayed substantially inhibition of HSC activation and TGF-β/Smad signaling. In vitro experiments further demonstrated that inhibition of TGF-β/Smad signaling in GnT-V knockdown HSCs correlated with decreased β1,6-branched N-glycan in TGF-β receptors. In addition, knockdown of GnT-V suppressed PDGF-induced HSC proliferation and migration through the inhibition of PDGF/Erk signaling. Finally, we demonstrated that downregulation of GnT-V significantly suppressed TGF-β1-induced EMT in cultured hepatocytes. Conclusions: This study demonstrates that GnT-V is implicated in hepatic fibrogenesis. Targeting GnT-V may be a feasible and promising approach for treating liver fibrosis. |
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