Lipids: Metabolism, Nutrition & Health

Biography

Biography: Charles E. Chalfant

Abstract

New roles for    sphingolipids    such as ceramide,   ceramide-1-phosphate   (C1P), and sphingosine-1-p hosphate 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   (cPLA₂a) is still an enigma. In this regard, my laboratory demonstrated that C1P is a direct and required lipid co-factor for cPLA₂a activation in cellular models. In further studies, the interaction site for C1P was localized to the calcium-lipid binding domain (C2 domain) of the enzyme allowing for the genetic ablation of the site in vivo via the generation of a cPLA₂a knock-in (KI) mouse. In this lecture, the characterization of this new mouse model in comparison to the full genetic ablation of the enzyme will be presented. Specifically, the loss of the C1P/cPLA₂a interaction induced a “class-switch” in the production specific   eicosanoids   and specialized  lipid mediators  driving both sepsis resistance and accelerated wound repair. In further mech anistic studies, C1P was found to modulate the substrate specificity of cPLA₂a explaining the “class switch” as to bioactive lipid mediators observed in the cPLA₂a KI mouse.  Overall, these observations led to two new findings: 1) C1P is a pro-inflammatory signaling molecule that directs cPLA₂a in the utilization of primarily  phospholipids  with sn-2 arachidonic acid while simultaneously blocking the utilization  of phospholipids with sn-2 docosahexaenoic acid; and 2) cPLA₂a has previously overlooked functions in the resolution of inflammation and immune responses.