Figure 8. Schematic proposal of the molecular events involved in the lipotoxic effects of PA and the potentiation by MA.

PA fuels ceramide synthesis by providing sphinganine in a reaction catalyzed by SPT. MA in turn potentiates ceramide generation by stimulating the activity of DES, and therefore the combination of MA plus PA results in kinetically sustained de novo ceramide production. This event is upstream of the induction of ER stress, which in turn recruits the mitochondrial apoptosis program eliciting ROS generation and caspase activation, leading to hepatocyte apoptosis. On the hand right side, we show the different specific inhibitors used to interrupt this signaling cascade. In addition to ceramide generation, PA is also known to activate other cellular events, including lysosomal membrane permeabilization (LMP) and activation of death receptor 5 (DR5), which then contribute to PA-induced lipoapoptosis. While myriocin blocks the central events shown (blue rectangle) it is not expected to interfere with LMP and DR5 activation. Further work is required to examine the involvement of ceramide synthesis in the recruitment and activation of LMP and DR5 by saturated fatty acids.