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) |
|---|---|
| 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 |
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Keywords
- Free radicals
- Glutathione
- Methionine- and choline-deficient diet
- NF-κB
- Nonalcoholic steatohepatitis
- Nrf2
ASJC Scopus subject areas
- Biochemistry
- Physiology (medical)
Cite this
Loss of Nrf2 markedly exacerbates nonalcoholic steatohepatitis. / 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.
In: Free Radical Biology and Medicine, Vol. 48, No. 2, 15.01.2010, p. 357-371.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Loss of Nrf2 markedly exacerbates nonalcoholic steatohepatitis
AU - Chowdhry, Sudhir
AU - Nazmy, Maiiada H.
AU - Meakin, Paul J.
AU - Dinkova-Kostova, Albena T.
AU - Walsh, Shaun V.
AU - Tsujita, Tadayuki
AU - Dillon, John F.
AU - Ashford, Michael L J
AU - Hayes, John D.
PY - 2010/1/15
Y1 - 2010/1/15
N2 - 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.
AB - 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.
KW - Free radicals
KW - Glutathione
KW - Methionine- and choline-deficient diet
KW - NF-κB
KW - Nonalcoholic steatohepatitis
KW - Nrf2
UR - http://www.scopus.com/inward/record.url?scp=72649103895&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=72649103895&partnerID=8YFLogxK
U2 - 10.1016/j.freeradbiomed.2009.11.007
DO - 10.1016/j.freeradbiomed.2009.11.007
M3 - Article
C2 - 19914374
AN - SCOPUS:72649103895
VL - 48
SP - 357
EP - 371
JO - Free Radical Biology and Medicine
JF - Free Radical Biology and Medicine
SN - 0891-5849
IS - 2
ER -