Alfred Merrill
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Professor and Smithgall Chair in Molecular Cell Biology, School of Biology |
Alfred Merrill |
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Abstract: Abstract:
Organisms usually contain a diverse variety of sphingolipid subspecies and knowledge about the types and amounts is imperative because they influence membrane structure, interactions with the extracellular matrix and neighboring cells, vesicular traffic and the formation of specialized structures such as membrane rafts, phagosomes and autophagosomes, as well as participate in intracellular and extracellular signaling. Fortunately, the first generation of "sphingolipidomic" analysis has begun using mass spectrometric methods developed as part of the LIPID MAPS Consortium (www.lipidmaps.org). Current technology allows quantitative analysis of important subsets of sphingolipids such as all of the backbone "signaling" subspecies (ceramides, ceramide 1-phosphates, sphingoid bases, sphingoid base 1-phosphates, inter alia) and methods for sulfatides, gangliosides and other complex species are becoming available. Use of these methods is revealing many surprises, such as that under certain conditions cells contain significant amounts of "unusual" species such as 3-ketoceramides, N-mono-, di-, and tri-methyl-sphingoid bases, dihydroceramides (DHCer), or galactosylCer. The finding of DHCer was initially befuddling because it appears to mediate the anti-cancer activity of fenretinide although DHCer have not been thought to be active in cell signaling. As DHCer have been studied further, we have found that they induce autophagy and may be important in the regulation of this important cellular process. The complexity of the sphingolipidome is hard to imagine, but one hopes that, when partnered with other systems biology approaches, the causes and consequences of the complexity will explain how these intriguing compounds are involved in almost every aspect of cell behavior and the malfunctions of many diseases.
This research was supported by NIH-GM069338 (Lipid MAPS).
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