Survival Response to Increased Ceramide Involves Metabolic Adaptation through Novel Regulators of Glycolysis and Lipolysis

Abstract

The sphingolipid ceramide elicits several stress responses, however, organisms survive despite increased ceramide but how they do so is poorly understood. We demonstrate here that the AKT/FOXO pathway regulates survival in increased ceramide environment by metabolic adaptation involving changes in glycolysis and lipolysis through novel downstream targets. We show that ceramide kinase mutants accumulate ceramide and this leads to reduction in energy levels due to compromised oxidative phosphorylation. Mutants show increased activation of Akt and a consequent decrease in FOXO levels. These changes lead to enhanced glycolysis by upregulating the activity of phosphoglyceromutase, enolase, pyruvate kinase, and lactate dehydrogenase to provide energy. A second major consequence of AKT/FOXO reprogramming in the mutants is the increased mobilization of lipid from the gut through novel lipase targets, CG8093 and CG6277 for energy contribution. Ubiquitous reduction of these targets by knockdown experiments results in semi or total lethality of the mutants, demonstrating the importance of activating them. The efficiency of these adaptive mechanisms decreases with age and leads to reduction in adult life span of the mutants. In particular, mutants develop cardiac dysfunction with age, likely reflecting the high energy requirement of a well-functioning heart. The lipases also regulate physiological triacylglycerol homeostasis and are important for energy metabolism since midgut specific reduction of them in wild type flies results in increased sensitivity to starvation and accumulation of triglycerides leading to cardiac defects. The central findings of increased AKT activation, decreased FOXO level and activation of phosphoglyceromutase and pyruvate kinase are also observed in mice heterozygous for ceramide transfer protein suggesting a conserved role of this pathway in mammals. These data reveal novel glycolytic and non-autonomous lipolytic pathways in response to increased ceramide for sustenance of high energy demanding organ functions like the heart.

Ceramide-Protein Interactions Modulate Ceramide-Associated Lipotoxic Cardiomyopathy

“…We have previously reported that dCERK (ceramide kinase) mutants exhibit a dilated LCM-like phenotype (Nirala et al, 2013), as we observe here in Sk2 and Ceramidase-deficient flies (Figures 1D–1G, 3A–3D, and 4A–4D). dCERK mutant flies exhibit ceramide accumulation and reduced C1P levels.…”

Identification of Sphingolipid Metabolites That Induce Obesity via Misregulation of Appetite, Caloric Intake and Fat Storage in Drosophila

“…Despite the dramatic reduction of S1P, these mutants are viable into adulthood. Interestingly, Sk2 KG050894 mutant flies don't appear to exhibit metabolic adaptation to elevated ceramide levels as was recently observed in early adult dcerk 1 (ceramide kinase 1) mutant flies [24]. This might explain why early onset of the obese phenotype is observed in Sk2 but not dcerk1 mutants.…”

Genetic and Genomic Response to Selection for Food Consumption in Drosophila melanogaster

“…Given the location of the latter SNP in a gene desert, it is a putative enhancer. ImpL3 encodes a lactate dehydrogenase involved in carbohydrate metabolism (St. Pierre et al 2014) and that regulates glucose metabolism in the glycolytic pathway to coordinate metabolism with growth (Nirala et al 2013; de la Cova et al 2014; Tennessen et al 2014b) and nutrient availability (Teleman et al 2008). The mammalian orthologs of ImpL3 are selectively down-regulated in healthy pancreatic β cells and up-regulated in type 2 diabetes to induce excessive insulin secretion (Pullen and Rutter 2013).…”