Figure 10.

Scheme depicting the mechanisms used by ASMase in mediating the cytotoxic effects of TNF-α. Our present findings illustrate the consequences of the downregulation of MAT1A by ASMase resulting in GSH depletion, particularly in the mitochondria, subsequent to the decrease in SAM levels. Although this mechanism leaves hepatocytes unprotected, glycosphingolipids, especially GD3, synthesized from the pool of ceramide generated by ASMase activation, increase and traffic to the mitochondria, initiating the apoptosome activation responsible for hepatocellular apoptosis and liver failure. Both processes promote the damaging effects induced by TNF-α. SAM treatment would replenish GSH stores, including those in mitochondria (Mit), producing favorable conditions in which hepatocytes withstand the effects of TNF-α.