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.