title: Nrf2 activators attenuate the progression of nonalcoholic steatohepatitis-related fibrosis in a dietary rat model.
abstract: Oxidative stress is considered to be a key mechanism of hepatocellular injury and disease progression in patients with nonalcoholic steatohepatitis (NASH). The transcription factor Nrf2 (nuclear factor-erythroid-2-related factor 2) plays a central role in stimulating expression of various antioxidant-associated genes in the cellular defense against oxidative stress. As the cytosolic repressor kelch-like ECH-associated protein 1 (Keap1) negatively regulates Nrf2, activation of Nrf2 facilitated by its release from Keap1 may represent a promising strategy in the treatment of NASH. To test this hypothesis, we used two chemically distinct types of Nrf2 activator. One is the thiol-reactive agent oltipraz (OPZ), a typical Nrf2 activator, and the other is a novel biaryl urea compound, termed NK-252 (1-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)-3-(pyridin-2-ylmethyl)urea). NK-252 exhibits a greater Nrf2-activating potential than OPZ. Furthermore, in vitro binding studies revealed that NK-252 interacts with the domain containing the Nrf2-binding site of Keap1, whereas OPZ does not. This finding indicates that NK-252 is more potent than OPZ due to its unique mechanism of action. For in vivo animal model studies, we used rats on a choline-deficient L-amino acid-defined (CDAA) diet, which demonstrate pathologic findings similar to those seen in human NASH. The administration of OPZ or NK-252 significantly attenuated the progression of histologic abnormalities in rats on a CDAA diet, especially hepatic fibrosis. In conclusion, by using Nrf2 activators with independent mechanisms of action, we show that, in a rat model of NASH, the activation of Nrf2 is responsible for the antifibrotic effects of these drugs. This strategy of Nrf2 activation presents new opportunities for treatment of NASH patients with hepatic fibrosis.
authors.affiliation: Toray Industries, Inc., Pharmaceutical Research Laboratories, Kanagawa, Japan. Rieko_Shimozono@nts.toray.co.jp
authors.forename: Rieko
authors.initials: R
authors.lastname: Shimozono
authors.forename: Yoshiji
authors.initials: Y
authors.lastname: Asaoka
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Yoshizawa
authors.forename: Takumi
authors.initials: T
authors.lastname: Aoki
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Noda
authors.forename: Masateru
authors.initials: M
authors.lastname: Yamada
authors.forename: Mie
authors.initials: M
authors.lastname: Kaino
authors.forename: Hidenori
authors.initials: H
authors.lastname: Mochizuki
mesh_terms: D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D001665:Binding Sites / Q000187:drug effects / Q000235:genetics; D002460:Cell Line; D002794:Choline / Q000378:metabolism; D004032:Diet; D004095:Dihydropyridines / Q000494:pharmacology; D004147:Dioxins / Q000494:pharmacology; D018450:Disease Progression; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D005234:Fatty Liver / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D000072019:Kelch-Like ECH-Associated Protein 1; D008099:Liver / Q000378:metabolism; D008297:Male; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000235:genetics* / Q000378:metabolism*; D065626:Non-alcoholic Fatty Liver Disease; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D051381:Rats; D000637:Transaminases / Q000097:blood; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: D000596:Amino Acids; D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D004095:Dihydropyridines; D004147:Dioxins; D047908:Intracellular Signaling Peptides and Proteins; C486610:KEAP1 protein, rat; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; C066458:NK 252; D006861:Hydrogen Peroxide; D016660:NAD(P)H Dehydrogenase (Quinone); C507703:NQO1 protein, rat; D000637:Transaminases; D002794:Choline