Systemic and heart autonomous effects of sphingosine Δ4 desaturase deficiency in lipotoxic cardiac pathophysiology.

Stanley M Walls,Greg L Harris,Dale A Chatfield,Karen Ocorr,Rolf Bodmer

doi:10.1242/dmm.043083

Abstract

ABSTRACTLipotoxic cardiomyopathy (LCM) is characterized by cardiac steatosis, including the accumulation of fatty acids, triglycerides and ceramides. Model systems have shown the inhibition of ceramide biosynthesis to antagonize obesity and improve insulin sensitivity. Sphingosine Δ4 desaturase (encoded by ifc in Drosophila melanogaster) enzymatically converts dihydroceramide into ceramide. Here, we examine ifc mutants to study the effects of desaturase deficiency on cardiac function in Drosophila. Interestingly, ifc mutants exhibited classic hallmarks of LCM: cardiac chamber dilation, contractile defects and loss of fractional shortening. This outcome was phenocopied in global ifc RNAi-mediated knockdown flies. Surprisingly, cardiac-specific ifc knockdown flies exhibited cardiac chamber restriction with no contractile defects, suggesting heart autonomous and systemic roles for ifc activity in cardiac function. Next, we demonstrated that ifc mutants exhibit suppressed Sphingosine kinase 1 (Sk1) expression. Ectopic overexpression of Sk1 was sufficient to prevent cardiac chamber dilation and loss of fractional shortening in ifc mutants. Partial rescue was also observed with cardiac- and fat-body-specific Sk1 overexpression. Finally, we showed that cardiac-specific expression of Drosophila inhibitor of apoptosis (dIAP) also prevented cardiac dysfunction in ifc mutants, suggesting a role for caspase activity in the observed cardiac pathology. Collectively, we show that spatial regulation of sphingosine Δ4 desaturase activity differentially affects cardiac function in heart autonomous and systemic mechanisms through tissue interplay.

Highlights

Sphingolipid metabolism is an important cellular pathway for the synthesis of key regulatory bioactive lipids including ceramide and sphingosine 1-phosphate
Ifc4 mutant flies exhibit decreased global expression of Sphingosine Kinase 1 (Sk1), which appears to account, in part, for the differential phenotype exhibited by global versus cardiac-specific ifc knockdown flies, as Sphingosine Kinase 1 expression (Sk1) is not expressed in the heart
Cardiac expression of Drosophila inhibitor of apoptosis (dIAP) is cardioprotective in ifc4 mutants Previously, we provided evidence that ceramide-associated lipotoxic cardiomyopathy was in part mediated by caspase activation via interactions with

Summary

Introduction

Sphingolipid metabolism is an important cellular pathway for the synthesis of key regulatory bioactive lipids including ceramide and sphingosine 1-phosphate. More recent studies have shown that ifc mutants exhibit classic hallmarks of obesity, including elevated triglyceride (TG) levels, fat body (adipocyte) hypertrophy, and resistance to starvation-induced expiration (Walls et al, 2013). These studies suggested that lipid accumulation reported in ifc mutants were directly associated with loss of adipokinetic hormone (akh) mediated fat mobilization. Ifc-encoded sphingosine delta-4 desaturase activity appears to be necessary for akh-producing cell (akhpc) viability and function in flies These findings correlate with previous studies which showed that apoptosisinduced cell death of akhpc suppressed TG mobilization from Drosophila fat body cells(Gronke et al, 2007). These results correlate strongly with previously reported cardiac-specific dIAP overexpression rescue of ceramide dietarily induced cardiac dilation and contractile dysfunction(Walls et al, 2018)

Results

Discussion

Data Availability Not applicable