Loss of Nrf2 markedly exacerbates nonalcoholic steatohepatitis.
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 approximately 10-fold increase in the amount of nuclear NF-kappaB p65 protein and approximately 5-fold increases in the levels of mRNA for interleukin-1beta, tumor necrosis factor alpha, 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.
Chowdhry
Sudhir
S
Biomedical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, Scotland, UK.
Nazmy
Maiiada H
MH
Meakin
Paul J
PJ
Dinkova-Kostova
Albena T
AT
Walsh
Shaun V
SV
Tsujita
Tadayuki
T
Dillon
John F
JF
Ashford
Michael L J
ML
Hayes
John D
JD
D000818:Animals; D002794:Choline / Q000737:chemistry; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000235:genetics; D018450:Disease Progression; D005234:Fatty Liver / Q000097:blood / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D005526:Food, Formulated; D053583:Interleukin-1beta / Q000096:biosynthesis / Q000235:genetics; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008715:Methionine / Q000737:chemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D020556:Neutrophil Infiltration / Q000235:genetics; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis / Q000235:genetics; D018384:Oxidative Stress / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics
D053583:Interleukin-1beta; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D008715:Methionine; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D002794:Choline