The variety of known lipid backbones is fairly comprehensive, but the diversity and combinations of fatty acids attached to these backbones provides many thousand possibilities and lipidomics shows that a large portion of this diversity is available in human cells.
This not addressable complexity has led to a situation where lipid signaling events are treated as head-group signaling events, and the existing chemical differences between individual species of the same lipid class are widely ignored, although a number of in vitro studies suggest significant differences in potency. Along the same lines, the influence of subcellular concentration gradients of defined lipid species on intracellular signaling has not been studied thoroughly so far.
Nadler A et al. (Angew. Chem. Int. Ed. 2013) show that both lipid species diversity and subcellular concentration gradients of distinct lipid species serve as molecular mechanisms to drive specific lipid-mediated signaling events. In particular, they analyze diacylglycerol (DAG) signaling, due to its important role in several cellular signaling pathways. Recent lipidomics analyses demonstrated the co-existence of 30–50 DAG species with different fatty acid compositions in mammalian cells.
It has been previously shown that a number of DAG- metabolizing enzymes maintain a certain specificity for individual DAG species depending on their fatty acid composition. Following this finding, it has been suggested that these differences reflect the need for a much tighter metabolic control of actual signaling species.
The data published in the paper indicate for the first time that lipid composition, metabolism, and effectiveness of lipid recognition are very relevant for the output of a cellular signaling network. Especially in lipid signaling, the diffusion-reaction mechanisms might be a common reason for the formation of different signal patterns.
It remains to be shown if other lipids are locally regulated by similar mechanisms and whether the fatty acid composition is of similar importance. Future studies should address the large diversity in the fatty acid composition of lipids, not only because of the difference in intrinsic signaling activity, but also in lipid metabolism and the resulting lifetime of a given species.