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 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 down-regulation.  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 obs...