title: Sustained Glutathione Deficiency Interferes with the Liver Response to TNF-α and Liver Regeneration after Partial Hepatectomy in Mice.
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 levelsin vitrohave 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 inde novoGSH synthesis. We demonstrate thatGclm-/-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 inGclm-/-mice. These data suggest that GSH may play a role in hepatic NF-κB activationin vivo, which is necessary for accurate timing of liver regeneration.
authors.affiliation: Department of Surgery, University of Washington, Seattle, WA, USA ; Department of Pathology, University of Washington, Seattle, WA, USA.
authors.forename: Kimberly J
authors.initials: KJ
authors.lastname: Riehle
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA, USA.
authors.forename: Jamil
authors.initials: J
authors.lastname: Haque
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA, USA.
authors.forename: Ryan S
authors.initials: RS
authors.lastname: McMahan
authors.affiliation: Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, USA.
authors.forename: Terrance J
authors.initials: TJ
authors.lastname: Kavanagh
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA, USA.
authors.forename: Nelson
authors.initials: N
authors.lastname: Fausto
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA, USA.
authors.forename: Jean S
authors.initials: JS
authors.lastname: Campbell
keywords: Glutathione; Hepatocytes; Liver disease; Liver regeneration