Loss of Nrf2 markedly exacerbates nonalcoholic steatohepatitis

• Published in: Free radical biology & medicine Vol. 48; no. 2; pp. 357 - 371
• Main Authors: Chowdhry, Sudhir, Nazmy, Maiiada H., Meakin, Paul J., Dinkova-Kostova, Albena T., Walsh, Shaun V., Tsujita, Tadayuki, Dillon, John F., Ashford, Michael L.J., Hayes, John D.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.01.2010
• Subjects: Animals; Choline - chemistry; Cyclooxygenase 2 - biosynthesis; Cyclooxygenase 2 - genetics; Disease Progression; Fatty Liver - blood; Fatty Liver - genetics; Fatty Liver - metabolism; Fatty Liver - pathology; Fatty Liver - physiopathology; Food, Formulated; Free radicals; Glutathione; Interleukin-1beta - biosynthesis; Interleukin-1beta - genetics; Liver - metabolism; Liver - pathology; Male; Methionine - chemistry; Methionine- and choline-deficient diet; Mice; Mice, Inbred C57BL; Mice, Knockout; Neutrophil Infiltration - genetics; NF-E2-Related Factor 2 - genetics; NF-E2-Related Factor 2 - metabolism; NF-kappa B - metabolism; NF-κB; Nitric Oxide Synthase Type II - biosynthesis; Nitric Oxide Synthase Type II - genetics; Nonalcoholic steatohepatitis; Nrf2; Oxidative Stress - genetics; Tumor Necrosis Factor-alpha - biosynthesis; Tumor Necrosis Factor-alpha - genetics; NAFLD; TNFα; MPO; NF-κB; RTU; Nonalcoholic steatohepatitis; NRF2; PPAR; RNS; COX2; CYP; GSH; WT; Glutathione; GSSG; L-FABP; NQO1; SREBP; Free radicals; KO; NOS2; TBARS; IL-1β; NASH; MCD; Methionine- and choline-deficient diet; bZIP; GCLC; ROS; Keap1; CNC; GCLM; ADRP
• ISSN: 0891-5849; 1873-4596; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2009.11.007

Nonalcoholic steatohepatitis (NASH) arises from nonalcoholic fatty liver disease (NAFLD) as a consequence of oxidative stress. Herein we report that the development of NASH is greatly accelerated in mice lacking transcription factor Nrf2 when they are challenged with a methionine- and choline-deficient (MCD) diet. After 14 days of feeding on an MCD diet, livers from Nrf2 −/− mice showed a substantial increase in macro- and microvesicular steatosis and a massive increase in the number of neutrophil polymorphs, compared to livers from wild-type mice treated similarly. Livers of Nrf2 −/− mice on the MCD diet suffered more oxidative stress than their wild-type counterparts as assessed by a significant depletion of reduced glutathione that was coupled with increases in oxidized glutathione and malondialdehyde. Furthermore, livers from Nrf2 −/− mice on the MCD diet suffered heightened inflammation as judged by an ∼10-fold increase in the amount of nuclear NF-κB p65 protein and ∼5-fold increases in the levels of mRNA for interleukin-1β, tumor necrosis factor α, cyclooxygenase 2, and inducible nitric oxide synthase compared with livers from similarly treated wild-type mice. Thus, impairment of Nrf2 activity may represent a major risk factor for the evolution of NAFLD to NASH.