It is well known that the sphingolipid, ceramide, mediates several stress responses,
including apoptosis, senescence, inflammation and recent studies show that it can
affect cellular metabolism. However, many organisms can survive despite increased
ceramide but how they do so is poorly understood. In our study, we address this issue
using Drosophila loss of function mutants in ceramide kinase (CERK) that show increased
ceramide levels due to failure to convert ceramide to ceramide 1-phosphate (C1P).
These mutants show reduced energy levels due to compromised oxidative phosphorylation.
We have identified that the AKT/FOXO pathway regulates survival in the presence of
increased ceramide levels in Drosophila through metabolic adaptation involving specific
changes in glycolysis and lipolysis. In ceramide kinase mutants, increased activation
of AKT and decreased FOXO level enhances glycolytic flux through phosphoglycerate
mutase and downstream enzymes of glycolysis. AKT/FOXO also mediate mobilization of
lipid stores in the gut through novel lipases CG8093 and CG6277. The efficiency of
these compensatory mechanisms decreases with age and contribute to hyperglycemia,
hypertriglyceridemia and cardiac dysfunction resulting in reduction in adult life
span of the mutants. These lipases also regulate physiological triacylglycerol homeostasis
and are important for energy metabolism since midgut specific reduction of them in
wild type flies results in accumulation of triacylglycerol, increased sensitivity
to starvation and cardiac defects. The identification of novel downstream targets
in the AKT/FOXO pathway opens the possibility of new therapeutic candidates in treatment
of hyperglycemia and hypertriglyceridemia.
