Ceramide and Ceramide‐1‐phosphate: Enigmatic Lipids Generating New Signaling Paradigms

In 1884, Johann Thudichum first described sphingolipids naming these lipids due to their enigmatic nature. Over 100 years later, new roles for sphingolipids such as ceramide, ceramide-1-phosphate (C1P), and sphingosine-1-phosphate continue to emerge. My research, for example, has implicated C1P as a major regulator of eicosanoid synthesis, and despite the importance of eicosanoids in the inflammatory process, the regulation of eicosanoid synthesis proximal to the activation of Group IVA phospholipase A2 (cPLA2α) is still an enigma. In this regard, my laboratory demonstrated that C1P is a direct and required lipid cofactor for cPLA2α activation. Specifically, we demonstrated that the interaction of C1P with cPLA2α was required for this enzyme to translocate to membranes in response to A23187 and ATP. Furthermore, mutation of the C1P interaction site blocked the ability of re-expressed cPLA2α to “rescue” eicosanoid synthesis in the cPLA2α −/− cells. These findings solidified a role for C1P, and the enzyme that produces C1P from ceramide, ceramide kinase (CERK), in eicosanoid synthesis. Recently, the role for CERK in eicosanoid synthesis has recently become controversial due to studies with the CERK −/− mouse. Our laboratory explains this conundrum showing that the conventional knock-out of CERK has developmentally adapted by increasing novel C1P subspecies. To overcome this adaptation and examine the role of the C1P/cPLA2α interaction site in eicosanoid synthesis in vivo, our laboratory generated a cPLA2α knock-in mouse. In this lecture, the progress in the initial characterization and inflammatory phenotypes of this intriguing mouse model will be overviewed. Furthermore, biological mechanisms implicated by the identification of the C1P binding site in cPLA2α will be described. Overall, data will be presented that strongly implicate C1P in modulating eicosanoid synthesis.