Inhibition of thrombospondin-1 reduces glutathione activity and worsens acute liver injury during acetaminophen hepatotoxicity in mice.
Toxicol Appl Pharmacol
; 409: 115323, 2020 12 15.
Article
em En
| MEDLINE
| ID: mdl-33176120
ABSTRACT
Acetaminophen (N-Acetyl-p-Aminophenol or APAP)-induced hepatotoxicity is the most common cause of acute liver failure in the United States and Western Europe. Previous studies have shown that TGFß1 is elevated during APAP-induced hepatotoxicity and promotes liver injury by reducing liver regeneration while inducing hepatocyte senescence. At this time, little is known about the role of proteins that activate latent TGFß1 and their effects during APAP-induced hepatotoxicity. Thrombospondin-1 (TSP1) is a homotrimeric protein that can not only activate latent TGFß1 but can also interact with other proteins including Nrf2 to induce antioxidant signaling. The aim of the current study was to assess the role of thrombospondin-1 (TSP1) in both TGFß1 activation and its contribution to APAP-induced liver injury. C57Bl/6 mice or TSP1 null mice (TSP1-/-) were administered 300 mg/kg or 600 mg/kg of APAP. TGFß1 signaling, TSP1 expression, measures of hepatic injury, Nrf2 expression, measures of oxidative/nitrosative stress and GSH metabolism were assessed. The expression of TGFß1, TSP1 and phosphorylation of SMAD proteins increased in APAP-treated mice compared to controls. TSP1-/- mice had reduced TGFß1 expression and phosphorylation of SMAD proteins but increased liver injury. Hepatocyte cell death was increased in TSP1-/- mice and this was associated with decreased Nrf2 activity, decreased GSH levels and increased oxidative stress in comparison to wild-type C57Bl/6 mice. Together, these data demonstrate that elimination of TSP1 protein in APAP-treated mice reduces TGFß1 signaling but leads to increased liver injury by reducing Nrf2 expression and GSH activity, ultimately resulting in increased cell death.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Falência Hepática Aguda
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Trombospondina 1
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Doença Hepática Induzida por Substâncias e Drogas
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Glutationa
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Fígado
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Acetaminofen
Limite:
Animals
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article