Mammalian cells synthesize thousands of distinct lipids, yet the function of many of these lipid species is unknown. Of particular interest are ceramides, a class of sphingolipids implicated in several cell-signaling pathways. Natural ceramide levels play an integral role in insulin resistance, endosomal sorting pathways, gene regulation, and programmed cell death. Despite considerable interest in the biological function of ceramides, direct study of their effects in vivo is limited by their impermeability to the cell membrane. Recently, we have developed a strategy which overcomes the inherent biological limitations of ceramide delivery by chemoselectively ligating cell permeable lipid precursors in vivo to yield natural ceramides in a traceless manner. This method offers the unique capability to deliver individual and specific ceramides to cells, something not possible through manipulation of cellular metabolism. Using this technique, we uncovered the apoptotic effects of several ceramide species and observed differences in their apoptotic activity based on acyl chain saturation. Additionally, using photocaged lipid precursors, we demonstrate spatiotemporally controlled ceramide synthesis within live cells. This in situ lipid ligation approach addresses the long-standing problem of species-specific delivery and study of ceramides in live cells.

Nonenzymatic and chemoselective synthesis of ceramides in living cells

255th National Meeting (2018)

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