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Gclm/Nrf2 DKO (Gclm−/−/Nrf2−/−) strain

Fig 1. Gclm-/-/Nrf2-/- (DKO) mice have hepatitis. Livers from 5 mo-old male mice were harvested and evaluated by H&E. Panels A and B show H&E-stained liver sections obtained from Gclm-/-/Nrf2-/- mice. Panel A shows areas of hepatocyte degeneration and necrosis (black arrow). There are multiple foci of inflammation (circled areas). Panel B shows areas of necrosis, leukocyte infiltration and fibroblast proliferation (circled areas) extending from the central vein (CV) to portal area (PA). Panel C is a Gclm heterozygous and Nrf2 (Gclm+/-/Nrf2+/+) wild-type mouse that exhibits occasional areas of degeneration, necrosis (circled area) and very mild steatosis (red arrow heads) present in zones 1 and 2. Magnification = 100x (A and C), 40x (B).

In examining the effects of GSH effects on alcohol metabolism, Nrf2 was shown to be up-regulated in Gclm−/− mice by ethanol treatment (1). In a state of chronic GSH depletion, the Keap1-Nrf2-ARE signaling pathway appears necessary for the paradoxical resilience to ethanol-induced liver toxicity (2). Nrf2 KO mice are highly sensitive to ethanol toxicity and have increased morbidity and mortality upon ethanol treatment (3). We have cross-bred Nrf2 KO mice with the Gclm KO mice and have preliminary data that suggests that the resultant Nrf2/Gclm DKO mice experience more hepatitis than either Gclm KO or wild-type mice (Fig. 1). These DKO mice are viable and reach maturity; however, they have yet to produce progeny.

References

  1. Chen Y, Singh S, Matsumoto A, Manna SK, Abdelmegeed MA, Golla S, Murphy RC, Dong H, Song BJ, Gonzalez FJ, Thompson DC, Vasiliou V. (2016). Chronic Glutathione Depletion Confers Protection against Alcohol-induced Steatosis: Implication for Redox Activation of AMP-activated Protein Kinase Pathway. Sci Rep 6: 29743.
  2. Kensler TW, Wakabayashi N, Biswal S. (2007). Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway. Annu Rev Pharmacol Toxicol 47: 89-116.
  3. Lamle J, Marhenke S, Borlak J, von Wasielewski R, Eriksson CJ, Geffers R, Manns MP, Yamamoto M, Vogel A. (2008). Nuclear factor-eythroid 2-related factor 2 prevents alcohol-induced fulminant liver injury. Gastroenterology 134: 1159-68.