Fisetin represses oxidative stress and mitochondrial dysfunction in NAFLD through suppressing GRP78-mediated endoplasmic reticulum (ER) stress

Fisetin (FisT) is a bioactive flavonoid polyphenol with antioxidant, anti-inflammatory and anti-tumor activities. Although the effects of FisT to meliorate non-alcoholic fatty liver disease (NAFLD) have been investigated, the underlying mechanisms are not fully understood. In the present study, we found that FisT remarkably suppressed cellular and mitochondrial reactive oxygen species (ROS) generation in human and murine hepatocytes with palmitate (PA) stimulation. Additionally, mitochondrial impairment and dysfunction induced by PA were considerably abrogated in hepatocytes with FisT co-incubation. Furthermore, Cyto-c releases and mitochondrial apoptosis were detected in PA-treated hepatocytes, while being greatly repressed by FisT. PA-induced inflammation and lipid deposition were also strongly reduced by FisT in hepatocytes. Importantly, our in vitro experiments showed that promoting ROS by nuclear factor erythroid 2-related factor 2 (Nrf2) deletion significantly abolished the function of FisT to meliorate apoptosis, inflammation and lipid accumulation in PA-incubated hepatocytes. What’s more, ER stress was strongly induced by PA via increasing 78-kDa glucose-regulated protein (GRP78) and C/EBP-homologous protein (CHOP), which were, however, dramatically repressed after FisT co-exposure. Intriguingly, we found that strengthening ER stress by GRP78 over-expression considerably abolished the capacity of FisT to retard ROS generation and mitochondrial impairment in PA-stimulated hepatocytes, but GRP78 knockdown exhibited totally opposite effects. Thus, ER stress blockage was required for FisT to ameliorate NAFLD development in vitro. Consistently, our in vivo studies using high fat diet (HFD)-fed mice confirmed that FisT administration exerted inhibitory and therapeutic potential on fatty liver progression via the same mechanisms monitored in vitro. Collectively, all our findings disclosed that FisT can efficiently attenuate NAFLD through restraining ROS generation and mitochondrial impairment mediated by ER stress.