Phospholipid homeostasis regulates lipid metabolism and cardiac function through SREBP signaling in Drosophila

Abstract

The epidemic of obesity and diabetes is causing an increased incidence of dyslipidemia-related heart failure. While the primary etiology of lipotoxic cardiomyopathy is an elevation of lipid levels resulting from an imbalance in energy availability and expenditure, increasing evidence suggests a relationship between dysregulation of membrane phospholipid homeostasis and lipid-induced cardiomyopathy. In the present study, we report that the Drosophila easily shocked (eas) mutants that harbor a disturbance in phosphatidylethanolamine (PE) synthesis display tachycardia and defects in cardiac relaxation and are prone to developing cardiac arrest and fibrillation under stress. The eas mutant hearts exhibit elevated concentrations of triglycerides, suggestive of a metabolic, diabetic-like heart phenotype. Moreover, the low PE levels in eas flies mimic the effects of cholesterol deficiency in vertebrates by stimulating the Drosophila sterol regulatory element-binding protein (dSREBP) pathway. Significantly, cardiac-specific elevation of dSREBP signaling adversely affects heart function, reflecting the cardiac eas phenotype, whereas suppressing dSREBP or lipogenic target gene function in eas hearts rescues the cardiac hyperlipidemia and heart function disorders. These findings suggest that dysregulated phospholipid signaling that alters SREBP activity contributes to the progression of impaired heart function in flies and identifies a potential link to lipotoxic cardiac diseases in humans.

Dietary composition regulatesDrosophilamobility and cardiac physiology

“…reduction in TOR signaling both reduces triglyceride storage and protects aging cardiac performance in Drosophila (Luong et al, 2006;Wessells et al, 2009). Conversely, flies fed a high-fat diet (Birse et al, 2010) or flies with genetic mutations that increase lipid storage in the myocardium have decreased cardiac performance (Lim et al, 2011;Sujkowski et al, 2012). Taken together, these results are all consistent with the hypothesis that reduced lipid storage in cardiac or other muscle may be an important mechanism by which balanced, low-calorie diets protect endurance and cardiac performance.…”

Lipid droplet-based storage fat metabolism in Drosophila

“…In particular, DG is a substrate for the CDP-ethanolamine phosphotransferase, encoded by the Drosophila bb in a boxcar ( bbc ) gene, in the PE synthesis pathway starting from ethanolamine. Global downregulation of all three enzymatic steps of this pathway, i.e., the ethanolamine kinase encoded by the fl y easter gene , the phosphoethanolamine cytidylyltransferase (Pect), and Bbc, increases fl y body fat storage ( 37 ). Importantly, also organ-specifi c downregulation of PE synthesis causes lipid accumulation in the adult Drosophila heart, which leads to cardiac defi cits ( 37 ).…”

“…Importantly, also organ-specifi c downregulation of PE synthesis causes lipid accumulation in the adult Drosophila heart, which leads to cardiac defi cits ( 37 ). Lipid accumulation induced by dysfunction of PE homeostasis is driven by increased lipogenesis in the fl y, which is mediated by activation of the sterol regulatory element binding protein HLH106 (or Dm -SREBP) ( 37 ). In general, studies on the pathophysiological consequences of lipid accumulation in the heart represent the currently most advanced Drosophila lipotoxicity model (reviewed in Ref.…”

“…Global downregulation of all three enzymatic steps of this pathway, i.e., the ethanolamine kinase encoded by the fl y easter gene , the phosphoethanolamine cytidylyltransferase (Pect), and Bbc, increases fl y body fat storage ( 37 ). Importantly, also organ-specifi c downregulation of PE synthesis causes lipid accumulation in the adult Drosophila heart, which leads to cardiac defi cits ( 37 ). Lipid accumulation induced by dysfunction of PE homeostasis is driven by increased lipogenesis in the fl y, which is mediated by activation of the sterol regulatory element binding protein HLH106 (or Dm -SREBP) ( 37 ).…”

Lipid Metabolism, Metabolic Syndrome, and Cancer

“…Dysregulated phospholipid signaling that alters SREBP activity has been reported to contribute to the progression of impaired heart function in flies and also act as a potential link to lipotoxic cardiac diseases in humans [143]. Thus the role of SREBPs in modulating heart function and its associated phospholipid signaling maybe a candidate target for future therapies for obesity-and diabetes-related cardiac dysfunction.…”