Inhibition of O-glycosylation aggravates GalN/LPS-induced liver injury through activation of ER stress.
Immunopharmacol Immunotoxicol
; 43(6): 741-748, 2021 Dec.
Article
en En
| MEDLINE
| ID: mdl-34549685
ABSTRACT
OBJECTIVE:
O-glycosylation is the most common post-translational modification of proteins, which is involved in many pathophysiological processes including inflammation. Acute liver injury is characterized by an excessive, uncontrolled inflammatory response, but the effects of aberrant O-glycosylation on acute liver injury are yet to explore. Here we aimed to investigate the role of defective O-glycosylation in D-galactosamine (GalN)/lipopolysaccharide (LPS)-induced acute liver damage in mice. MATERIAL ANDMETHODS:
Experimental mice were administrated with an O-glycosylation inhibitor (benzyl-a-GalNac, 5 mg/kg) at 24 h before administration of GalN/LPS. At 12 h after GalN/LPS administration, mice were sacrificed to collect blood and liver samples for further analysis.RESULTS:
We found that benzyl-a-GalNac treatment-induced abundant expression of Tn antigen, which is an immature O-glycan representing abnormal O-glycosylation. Benzyl-a-GalNac pretreatment exacerbated considerably GalN/LPS-induced liver damage in mice, evidenced by significantly reduced survival rates, more severe histological alterations, and notable elevation of multiple inflammatory cytokines and chemokines. Mechanistically, benzyl-a-GalNac could trigger endoplasmic reticulum (ER) stress in the liver of mice, demonstrated by the elevated expression of glucose-regulated protein 78 (GRP78) and C/EBP-homologous protein (CHOP), both of which are hallmarks for ER stress. Inhibition of ER stress by 4-phenylbutyric acid (4-PBA) markedly abrogated benzyl-a-GalNac-mediated enhanced hepatotoxicity and systemic inflammation in GalN/LPS-treated mice.CONCLUSIONS:
This study demonstrated that inhibition of O-glycosylation caused by benzyl-a-GalNac aggravated GalN/LPS-induced liver damage and systemic inflammation, which may be due to activation of ER stress.Palabras clave
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Acetilgalactosamina
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Compuestos de Bencilo
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Lipopolisacáridos
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Fallo Hepático Agudo
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Estrés del Retículo Endoplásmico
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Galactosamina
Límite:
Animals
Idioma:
En
Revista:
Immunopharmacol Immunotoxicol
Asunto de la revista:
ALERGIA E IMUNOLOGIA
/
FARMACOLOGIA
/
TOXICOLOGIA
Año:
2021
Tipo del documento:
Article
País de afiliación:
China