Activation of nuclear factor E2-related factor 2 in hereditary tyrosinemia type 1 and its role in survival and tumor development.
In tyrosinemia type 1 (HT1), accumulation of toxic metabolites results in oxidative stress and DNA damage, leading to a high incidence of hepatocellular carcinomas. Nuclear factor erythroid-2 related factor 2 (Nrf2) is a key transcription factor important for cellular protection against oxidative stress and chemical induced liver damage. To specifically address the role of Nrf2 in HT1, fumarylacetoacetate hydrolase (Fah)/Nrf2(-/-) mice were generated. In acute HT1, loss of Nrf2 elicited a strong inflammatory response and dramatically increased the mortality of mice. Following low grade injury, Fah/Nrf2(-/-) mice develop a more severe hepatitis and liver fibrosis. The glutathione and cellular detoxification system was significantly impaired in Fah/Nrf2(-/-) mice, resulting in increased oxidative stress and DNA damage. Consequently, tumor development was significantly accelerated by loss of Nrf2. Potent pharmacological inducers of Nrf2 such as the triterpenoid analogs 1[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole have been developed as cancer chemoprevention agents. Pretreatment with 1[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole dramatically protected Fah(-/-) mice against fumarylacetoacetate (Faa)-induced toxicity. Our data establish a central role for Nrf2 in the protection against Faa-induced liver injury; the Nrf2 regulated cellular defense not only prevents acute Faa-induced liver failure but also delays hepatocarcinogenesis in HT1.
Marhenke
Silke
S
Department of Hepatology, Medical School Hannover, Hannover, Germany.
Lamlé
Jutta
J
Buitrago-Molina
Laura Elisa
LE
Cañón
José Manuel Fernández
JM
Geffers
Robert
R
Finegold
Milton
M
Sporn
Michael
M
Yamamoto
Masayuki
M
Manns
Michael P
MP
Grompe
Markus
M
Vogel
Arndt
A
D000818:Animals; D003512:Cyclohexanones / Q000008:administration & dosage; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D005978:Glutathione / Q000378:metabolism; D006505:Hepatitis / Q000209:etiology / Q000401:mortality; D006867:Hydrolases / Q000172:deficiency / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D008658:Inactivation, Metabolic; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000209:etiology; D017093:Liver Failure / Q000517:prevention & control; D008113:Liver Neoplasms / Q000209:etiology* / Q000517:prevention & control; D051379:Mice; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000096:biosynthesis / Q000172:deficiency / Q000378:metabolism*; D009579:Nitrobenzoates / Q000008:administration & dosage; D009828:Oleanolic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D018384:Oxidative Stress; D020176:Tyrosinemias / Q000150:complications* / Q000378:metabolism / Q000401:mortality / Q000503:physiopathology*
C472829:1-(2-cyano-3,12-dioxooleana-1,9-dien-28-oyl) imidazole; D003512:Cyclohexanones; D007093:Imidazoles; D051267:NF-E2-Related Factor 2; D009579:Nitrobenzoates; D009828:Oleanolic Acid; D006867:Hydrolases; C020156:fumarylacetoacetase; D005978:Glutathione; C077073:nitisinone