Neal Devaraj

Exploring the Lipid World

Despite their importance, studying specific lipid structures and their generation is incredibly challenging. Disentangling the precise roles of specific lipid species, particularly in higher organisms, is technically daunting for various reasons.Over the last several years, my laboratory has developed methods to synthesize specific lipids in situ from reactive lipid fragments. In situ lipid synthesis using traceless chemistries can assemble lipids identical to natural products. This approach allows unequivocal association of specific lipids generated in vivo with their cellular function. While reactive lipid fragments can be delivered exogenously, we can also use endogenous reactive lipid precursors, leading to applications in imaging lipid distributions and even perturbing lipid post-translational modifications. Our initial studies have focused on generating sphingolipid ceramides. Ceramides represent one of the most enigmatic classes of molecules within the realm of bioactive lipids. Using our approach, we have been able to directly probe the biological activity of specific ceramide species. We find that delivery of fully saturated ceramides, such as C16:0, using in situ lipid synthesis significantly reduces cell viability while there is no reduction in cell viability following delivery of monounsaturated ceramides, such as C24:1. Our results suggest that ceramide saturation plays a crucial role in their apoptotic activity. These striking observations highlight the importance of species-specific study of ceramides and demonstrate the power of tools, such as TCL, to circumvent the limitations of endogenous lipid synthesis pathways to uncover the function of individual lipid molecules in vivo. Thus, our ongoing work with in situ lipid synthesis demonstrates great promise as a general tool to study lipid biology.