Nrf2 counteracts cholestatic liver injury via stimulation of hepatic defense systems.
The transcription factor Nrf2 is a key regulator for hepatic induction of detoxifying enzymes, antioxidative stress genes and Mrp efflux transporters. We aimed to investigate whether Nrf2 activation counteracts liver injury associated with cholestasis. The role of Nrf2 activation in counteracting cholestatic liver injury was studied using a bile duct-ligation (BDL) model of Keap1 gene-knockdown (Keap1-kd) mice that represent the sustained activation of Nrf2 in the liver. Upon Nrf2 activation, Keap1-kd mice showed large increases in Mrp efflux transporters, detoxifying enzymes and antioxidative stress genes in the livers. After BDL, the number of hepatic parenchymal necrosis and the reactive oxygen species content were significantly smaller in the livers of the Keap1-kd mice than in those of the WT mice. Moreover, the increase in serum bilirubin levels was attenuated in the Keap1-kd mice. In conclusion, the results suggest a hepatoprotective role of sustained Nrf2 activation against liver injury associated with cholestasis.
Okada
Kosuke
K
Department of Molecular and Cellular Physiology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan.
Shoda
Junichi
J
Taguchi
Keiko
K
Maher
Jonathan M
JM
Ishizaki
Kaoru
K
Inoue
Yoshimi
Y
Ohtsuki
Makio
M
Goto
Nobuharu
N
Sugimoto
Hirokazu
H
Utsunomiya
Hirotoshi
H
Oda
Koji
K
Warabi
Eiji
E
Ishii
Tetsuro
T
Yamamoto
Masayuki
M
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000818:Animals; D002779:Cholestasis / Q000150:complications*; D003598:Cytoskeletal Proteins / Q000235:genetics; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D041781:Jaundice, Obstructive / Q000150:complications*; D000072019:Kelch-Like ECH-Associated Protein 1; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008107:Liver Diseases / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; D000072019:Kelch-Like ECH-Associated Protein 1; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D051267:NF-E2-Related Factor 2; C117301:Keap1 protein, mouse; C495636:Nfe2l2 protein, mouse