Of note was the much greater degree of ROS production after ovariectomy in transgenic mice than in non-transgenic mice. These results suggested that HCV protein
expression has the potential to increase AZD1208 the sensitivity to oxidative stress in the liver. At least two possibilities may account for the increased sensitivity to oxidative stress in FL-N/35 transgenic mice. One possibility is an additive effect of HCV-induced ROS production on ovariectomy-induced oxidative stress. The HCV core protein has been shown to inhibit mitochondrial electron transport[35] and to induce ROS production.[36] In fact, basal ROS production tended to be higher in transgenic mice than in non-transgenic mice, but was not significantly different. These results suggested that additive HCV-induced ROS production
was unlikely to be the cause of the significantly increased ROS production after ovariectomy in the transgenic mice. The other possibility is HCV-associated attenuation of antioxidant potential against ovariectomy-induced oxidative stress. In this respect, OVX transgenic mice had a lower ratio of BAP to dROM than OVX non-transgenic mice and the expression of SOD2 and GPx1 in the liver was not increased. These results suggest that HCV protein attenuated antioxidant potential against ovariectomy-induced oxidative stress. Proliferator-activated receptor-γ co-activator-1α is required
for the induction see more of many ROS-detoxifying MCE enzymes upon oxidative stress.[26] SIRT3 has been shown to function as a downstream target gene of PGC-1α and mediate the PGC-1α-dependent induction of ROS-detoxifying enzymes.[27] Additionally, AMPK, which is a crucial cellular energy sensor, regulates PGC-1α activity through both modulation of PGC-1α transcription and phosphorylation of the PGC-1α protein.[28, 37] Thus, AMPK/PGC-1α signaling is one of the important pathways that protect cells from oxidative stress through the induction of several key ROS-detoxifying enzymes. Recent evidence indicating that HCV replication inhibits AMPK activity[29] prompted us to investigate whether the antioxidant potential against ovariectomy-induced oxidative stress in FL-N/35 transgenic mice was attenuated through inhibition of this signaling pathway. As expected, upon ovariectomy, AMPK was activated in non-transgenic mice, but not in transgenic mice. This, in turn, led to the lower expression of PGC-1α in the nuclear fraction of the liver in OVX transgenic mice than in OVX non-transgenic mice, resulting in the absence of significant induction of SIRT3 in the mitochondrial fraction of the liver in the OVX transgenic mice. Thus, ROS production in the liver in OVX transgenic mice was increased by attenuation of the antioxidant potential through inhibition of AMPK/PGC-1α signaling.