Ceramide-induced starvation triggers homeostatic autophagy.

Autophagy is triggered by ceramide, a sphingolipid that regulates diverse cellular processes including survival, differentiation and senescence. Both ceramide and autophagy play important, but incompletely understood, roles in type 2 diabetes and cancer. We reasoned that defining the connection between ceramide and autophagy might provide an important insight into these highly prevalent diseases. Our recently published work demonstrates that ceramide-induced autophagy is a homeostatic response to starvation caused by nutrient transporter downregulation. Preventing nutrient transporter loss or supplementation with transporter-independent nutrients protects cells from ceramide-induced death and delays the onset of autophagy. Thus, we propose a model where ceramide kills cells by inducing acute and severe intracellular nutrient limitation. Consistent with this idea, AMPK-deficient cells that are less able to deal with bioenergetic stress are also more sensitive to ceramide than wild-type cells. Our observation that gradually adapting cells to tolerate low levels of extracellular nutrients confers striking resistance to ceramide toxicity further supports this model. These results highlight the value of measuring nutrient transporter expression in cells undergoing protective autophagy. In addition, this novel mechanism for ceramide-induced cell death suggests new approaches to studying and treating multiple human diseases.