Abstract
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.
Original language | English (US) |
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Pages (from-to) | 357-371 |
Number of pages | 15 |
Journal | Free Radical Biology and Medicine |
Volume | 48 |
Issue number | 2 |
DOIs | |
State | Published - Jan 15 2010 |
Keywords
- Free radicals
- Glutathione
- Methionine- and choline-deficient diet
- NF-κB
- Nonalcoholic steatohepatitis
- Nrf2
ASJC Scopus subject areas
- Biochemistry
- Physiology (medical)