Getting To The Heart Of The Sphingolipid Riddle

Obesity, type 2 diabetes, and metabolic syndrome induce dyslipidemia resulting in inundation of peripheral organs with fatty acids. These not only serve as substrates for energy production, but also contribute to aberrant production of bioactive lipids. Moreover, lipid metabolism is affected in many cardiac disorders including heart failure, ischemia reperfusion injury, and others. While lipids serve crucial homeostatic roles, perturbing biosynthesis of lipid mediators leads to aberrant cell signaling, which contributes to maladaptive cardiovascular programs. Bioactive sphingolipids, in particular, have been implicated in pathophysiology in the heart and vasculature by a variety of studies in cells, animal models, and humans. Because of the burgeoning interest in sphingolipid-driven biology in the cardiovascular system, it is necessary to discuss the experimental considerations for studying sphingolipid metabolism and signaling, emphasizing the caveats to some widely available experimental tools and approaches. Additionally, there is a growing appreciation for the diversity of ceramide structures generated via specific enzymes and bearing disparate cellular functions. While targeting these individual species and enzymes constitutes a major advance, studies show that sphingolipid synthesis readily adapts to compensate for experimental targeting of any individual pathway, thereby convoluting data interpretation. Furthermore, though some molecular mechanisms of sphingolipid action are known, signaling pathways impacted by sphingolipids remain incompletely understood. In this review, we discuss these issues and highlight recent studies as well as future directions that may extend our understanding of the metabolism and signaling actions of these enigmatic lipids in the cardiovascular context.