Abstract
Liver fibrosis is a continuous wound healing response caused by chronic liver injury, and the activation of hepatic stellate cells (HSCs) is considered as the main event for it. Core fucosylation catalyzed by FUT8 refers to adding the fucosyl moiety to the innermost GlcNAc residue of N-linked oligosaccharides and is involved in many biological processes such as cell differentiation, migration, and signaling transduction. Aberrant core fucosylation is associated with a variety of diseases including cardiovascular disease, tumors and neuroinflammation, but much less is understood in liver fibrosis. Herein, we reported FUT8 mRNA level was increased in patients with liver fibrosis from GEO database and positively correlated with fibrosis progression. FUT8 expression and the core fucosylation were also elevated in TAA-induced mouse liver fibrosis model, and were mainly distributed in the fibrous septum of mouse liver. TGF-β1, as the most pro-fibrogenic cytokine, could promote the expression of FUT8 and total core fucosylation levels in HSCs in vitro. However, up-regulation of FUT8 in turn inhibited TGF-β1-induced trans-differentiation, migration and pro-fibrogenic signaling pathways in HSCs. In conclusion, our results suggest that the up-regulation of FUT8 inhibits TGF-β1-induced HSC activation in a negative feedback loop, and provide potential new therapeutic strategy for liver fibrosis by targeting FUT8.
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Abbreviations
- ECM:
-
extracellular matrix.
- HBV:
-
hepatitis B virus.
- HCV:
-
hepatitis C virus.
- HCC:
-
hepatocellular carcinoma.
- HSCs:
-
hepatic stellate cells.
- MFs:
-
myofibroblasts.
- α-SMA:
-
α- smooth muscle actin.
- FUT8:
-
α1,6-fucosyltransferase.
- FUTs:
-
fucosyltransferases.
- LCA:
-
Lens culinaris lectin.
- TAA:
-
Thioacetamide.
- GEO:
-
Gene Expression Omnibus.
- TGF-β1:
-
Transforming growth factor β1.
- TGF-β R:
-
TGF-β receptors.
- TIMP:
-
tissue inhibitor of metalloproteinase.
- MAPK:
-
mitogen activated protein kinases.
- GnT-V:
-
N-acetylglucosamine aminotransferase V.
- IHC staining:
-
Immunohistochemical staining.
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This work was supported by grants from the National Key R&D Program of China (2018YFC0910303), and the National Natural Science Fund (31630088, 82073245, 31770855, 81802368, 31500645).
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MZK, XQZ and YYR conceived and designed the experiments; MZK, HW, LH, XYG, DCH, BL, MQC and JG performed the experiments;MZK, XQZ and YYR analyzed the data; MZK, XQZ and YYR wrote the paper. All authors read and approved the final manuscript.
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All animal experiments conformed to the criteria outlined in the Guide for the Care and Use of Laboratory Animals, prepared by the National Academy of Sciences and published by the National Institutes of Health, and also were approved by the ethics committee of Fudan University.
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Kuang, M., Wu, H., Hu, L. et al. Up‐regulation of FUT8 inhibits TGF-β1-induced activation of hepatic stellate cells during liver fibrogenesis. Glycoconj J 38, 77–87 (2021). https://doi.org/10.1007/s10719-021-09975-x
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DOI: https://doi.org/10.1007/s10719-021-09975-x