Systemic and heart autonomous effects of sphingosine Δ-4 desaturase deficiency in lipotoxic cardiac pathophysiology

• Published in: Disease models & mechanisms
• Main Authors: Walls, Stanley M., Chatfield, Dale A., Ocorr, Karen, Harris, Greg L., Bodmer, Rolf
• Format: Journal Article
• Language: English
• Published: 01-08-2020
• ISSN: 1754-8403; 1754-8411
• DOI: 10.1242/dmm.043083

Lipotoxic cardiomyopathy (LCM) is characterized by cardiac steatosis including accumulation of fatty acids, triglycerides and ceramides. Inhibition of ceramide biosynthesis has been shown in model systems to antagonize obesity and improve insulin sensitivity. Sphingosine Δ-4 desaturase (encoded by ifc in flies) enzymatically converts dihydroceramide into ceramide. Here, we examine ifc mutants to study the effects of desaturase deficiency on cardiac function in flies. Interestingly, ifc mutants exhibited classic hallmarks of LCM: cardiac chamber dilation, contractile defects and loss of fractional shortening. This was phenocopied in global ifc RNAi-mediated knockdowns. Surprisingly, cardiac-specific ifc knockdowns exhibited cardiac chamber restriction with no contractile defects, suggesting heart autonomous and systemic roles for ifc activity in cardiac function. Next, we determined that ifc mutants exhibit suppressed Sphingosine Kinase 1 expression (Sk1). 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 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 desaturase activity differentially effects cardiac function in heart autonomous and systemic mechanisms via tissue interplay.