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

Program in Gene Function and Expression, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America
PLoS Genetics (Impact Factor: 7.53). 06/2013; 9(6):e1003556. DOI: 10.1371/journal.pgen.1003556
Source: PubMed


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

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    • "Our earlier study combined metabolomic profiling with genetic and biochemical approaches and demonstrated that dcerk 1 mutants show an increased reliance on glycolysis, which leads to an increase in lactate to compensate for the decreased production of ATP through OXPHOS (Nirala et al., 2013). The increase in glycolytic flux is also observed in a mammalian model of ceramide increase, mice heterozygous for the ceramide transfer protein (Wang et al., 2009; Nirala et al., 2013). In addition to changes in glycolytic intermediates, metabolomic profiling revealed that dcerk 1 mutants have a significantly decreased level of NAD + compared with that in w 1118 (control) flies (Fig. 1 A). "
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