Sustained Glutathione Deficiency Interferes with the Liver Response to TNF-α and Liver Regeneration after Partial Hepatectomy in Mice.
J Liver Disease Transplant
; 1(2)2013 Jan 12.
Article
em En
| MEDLINE
| ID: mdl-24611135
ABSTRACT
Glutathione (GSH) is a critical intracellular antioxidant that is active in free radical scavenging and as a reducing equivalent in biological reactions. Recent studies have suggested that GSH can affect cellular function at the level of gene transcription as well, in particular by affecting NF-κB activation. Additionally, increased or decreased GSH levels in vitro have been tied to increased or decreased hepatocyte proliferation, respectively. Here, we investigated the effect of GSH on the liver's response to TNF-α injection and 2/3 partial hepatectomy (PH), using mice deficient for the modifier subunit of glutamate-cysteine ligase (GCLM), the rate-limiting enzyme in de novo GSH synthesis. We demonstrate that Gclm-/- mice have a delay in IκBα degradation after TNF-α injection, resulting in delayed NF-κB nuclear translocation. These mice display profound deficiencies in GSH levels both before and during regeneration, and after PH, Gclm-/- mice have an overall delay in cell cycle progression, with slower DNA synthesis, mitosis, and expression of cell cycle proteins. Moreover, there is a delay in expression of downstream targets of NF-κB in the regenerating liver in Gclm-/- mice. These data suggest that GSH may play a role in hepatic NF-κB activation in vivo, which is necessary for accurate timing of liver regeneration.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Idioma:
En
Revista:
J Liver Disease Transplant
Ano de publicação:
2013
Tipo de documento:
Article
País de afiliação:
Estados Unidos