@article {Shimozonomol.112.084269, author = {Rieko Shimozono and Yoshiji Asaoka and Yoshitaka Yoshizawa and Takumi Aoki and Hidetoshi Noda and Masateru Yamada and Mie Kaino and Hidenori Mochizuki}, title = {Nrf2-activators Attenuate the Progression of Nonalcoholic Steatohepatitis-Related Fibrosis in a Dietary Rat Model}, elocation-id = {mol.112.084269}, year = {2013}, doi = {10.1124/mol.112.084269}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, 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 plays a central role in stimulating expression of various antioxidant-associated genes in the cellular defense against oxidative stress. As the cytosolic repressor 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 utilized 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. 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 employed rats on a choline-deficient L-amino acid-defined (CDAA)-diet, which demonstrate pathological findings similar to those seen in human NASH. The administration of OPZ or NK-252 significantly attenuated the progression of histological abnormalities in rats on a CDAA diet, especially hepatic fibrosis. In conclusion, by using Nrf2-activators with independent mechanisms of action, we show in a rat model of NASH that the activation of Nrf2 is responsible for the anti-fibrotic effects of these drugs. This strategy of Nrf2 activation presents new opportunities for treatment of NASH patients with hepatic fibrosis.}, issn = {0026-895X}, URL = {https://molpharm.aspetjournals.org/content/early/2013/04/16/mol.112.084269}, eprint = {https://molpharm.aspetjournals.org/content/early/2013/04/16/mol.112.084269.full.pdf}, journal = {Molecular Pharmacology} }