Up-regulation of HO-1 by Nrf2 activation protects against palmitic acid-induced ROS increase in human neuroblastoma BE(2)-M17 cells.

Saturated fatty acids (SFAs) induce reactive oxygen species (ROS) production in neurons. Extracellular signal regulated kinase (ERK)/nuclear factor erythroid-2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) is a ROS response pathway. Therefore, high ROS is always accompanied by increase of HO-1, an anti-oxidative enzyme; but it remains unknown why there is no significant reduction of ROS with the increase of HO-1 in SFAs-treated neurons. We hypothesized that the up-regulation of HO-1 is compensatory for response to fatty acid-induced oxidative stress but not enough to reduce ROS levels. We evaluated the anti-ROS effect of HO-1 and the involved pathway in palmitic acid (PA)-treated human neuroblastoma BE(2)-M17 cells. As expected, PA-induced ROS increase was accompanied by activation of the ERK-Nrf2-HO-1 pathway, as demonstrated by an increase in ERK phosphorylation, Nrf2 phosphorylation and nuclear accumulation, and HO-1 expression at the mRNA and protein levels, in a PA-dose-dependent manner. In contrast, administration of the ROS scavenger NAC significantly reduced the levels of PA-regulated ROS and HO-1 protein. However, the ERK inhibitor U0126 not only reversed the activating effect of PA on the ERK-Nrf2-HO-1 pathway but also aggravated PA-induced ROS. Furthermore, the Nrf2-specific activator NK-252 significantly increased PA-up-regulated HO-1 protein and alleviated PA-induced ROS. Therefore, our results suggest that up-regulation of HO-1 in PA-treated neurons is a compensatory response to ROS increase and that increasing HO-1 expression by Nrf2 activation can prevent the process of ROS production in PA-treated neurons.