AKT/FOXO mediates survival to increased ceramide through metabolic adaptation involving altered glycolysis and lipolysis

Abstract

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.