title: Nrf2 counteracts cholestatic liver injury via stimulation of hepatic defense systems.
abstract: 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.
authors.affiliation: Department of Molecular and Cellular Physiology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Okada
authors.forename: Junichi
authors.initials: J
authors.lastname: Shoda
authors.forename: Keiko
authors.initials: K
authors.lastname: Taguchi
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Maher
authors.forename: Kaoru
authors.initials: K
authors.lastname: Ishizaki
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Inoue
authors.forename: Makio
authors.initials: M
authors.lastname: Ohtsuki
authors.forename: Nobuharu
authors.initials: N
authors.lastname: Goto
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Sugimoto
authors.forename: Hirotoshi
authors.initials: H
authors.lastname: Utsunomiya
authors.forename: Koji
authors.initials: K
authors.lastname: Oda
authors.forename: Eiji
authors.initials: E
authors.lastname: Warabi
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Ishii
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
mesh_terms: 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
chemical_list: 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