Figure 7.

Simplified graphical scheme representing the effect of Caspase-8 depletion on hepatic apoptosis and steatosis in the pathogenesis of ALD. Left: In WT hepatocytes, EtOH exposure induces both extrinsic and intrinsic apoptosis with a favorable shift towards Caspase-8-dependent extrinsic signaling. In addition, Caspase-8 plays an unexpected and presumably non-apoptotic role in the metabolism of hepatic free fatty acids (FFA) and triglycerides (TG) thereby contributing to pronounced liver steatosis. Right: Inhibition of Caspase-8 results in abrogation of the extrinsic apoptosis pathway. Instead, alcohol-dependent reactive oxygen species (ROS) result in enhanced mitochondrial permeability transition, enhanced cytoplasmic cytochrome c release and enhanced intrinsic apoptosis signaling eventually leading to equal net apoptosis. However, lack of Caspase-8 is associated with reduced production of FFA and TG eventually leading to attenuated liver steatosis