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Loss of Nrf2 markedly exacerbates nonalcoholic steatohepatitis

Loss of Nrf2 markedly exacerbates nonalcoholic steatohepatitis,10.1016/j.freeradbiomed.2009.11.007,Free Radical Biology and Medicine,Sudhir Chowdhry,M

Loss of Nrf2 markedly exacerbates nonalcoholic steatohepatitis   (Citations: 5)
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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.
Journal: Free Radical Biology and Medicine - FREE RADICAL BIOL MED , vol. 48, no. 2, pp. 357-371, 2010
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