Lip up: Fatty molecules investigated

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  • Published: Jul 1, 2013
  • Author: David Bradley
  • Channels: UV/Vis Spectroscopy
thumbnail image: Lip up: Fatty molecules investigated

A time and place for lipids

Fatty lipid molecules in the human body act not only as energy storage molecules and structural elements but are also important signalling compounds.

Fatty lipid molecules in the human body act not only as energy storage molecules and structural elements but are also important signalling compounds. Lipids with their head in a molecular cage have now been used to study such molecules and their roles in diseases such as atherosclerosis and diabetes.

The fatty acid composition of diacylglycerols determines local signalling patterns, according to Carsten Schultz of the European Molecular Biology Laboratory, Heidelberg, Germany, and colleagues. When lipid signal transmission is disrupted various health problems can arise and there is a strong association with diseases such as atherosclerosis and diabetes, as well as general inflammatory conditions and pain. Schultz and colleagues now report in the journal Angewandte Chemie light-activated lipids that can be used to manipulate signalling processes in cells with resolution in both the spatial and temporal domains.

Caged fatty acids

To communicate with each other and react to external stimuli, cells need signal-transmission mechanisms. The signal cascades involved are extremely complex and vary greatly from one cell type to the next. For example, one type of cascade involves the activation of the enzyme phospholipase C. This enzyme cleaves a membrane building block into inositol trisphosphate and the lipid diacylglycerol (DAG); the compounds thus released then act as secondary messengers within the cell. DAG anchors the enzyme protein kinase C (PKC) to the cell membrane and activates it. In addition, DAG can open up certain calcium channels in the cell membrane, allowing calcium ions to flow into the cell. The calcium influx then triggers additional steps within the signalling network and initiates physiological responses including the necessary changes involved in starting gene expression and protein production.

Despite their apparent prominent in cell signalling and the implications of understanding the roles lipid play in disease, there has been something of a dearth of research into lipids in this context. Lipids are generally thought of as head and tail molecules. While most research has focused on lipid heads, the "tail" is crucial to the overall behaviour of lipids too. The "tail" often comprises a hydrocarbon chain and these can vary greatly in terms of their length and the number of double bonds within the chain, as well as the distribution, and arrangement of those double bonds.

A trick of the tail

Schultz and his team have now focused on lipid tails. They synthesized DAG lipids with several different hydrocarbon tails and locked their glycerol heads into a molecular cage - based on a coumarinylmethylene or nitroveratroyl group - that essentially disengages the head from activity. The cages have a breakaway point that can be released with a flash of light allowing the activity of the DAG to be controlled entirely by photoactivation. The team points out that they can thus deliver an essentially inert unit to a specific place and then trigger its biological activation at a precise time and place of their choosing thus gaining sub-cellular resolution for their studies.

The approach has allowed the team to demonstrate that the activation of protein kinase C is indeed limited locally by the lipid DAG. In contrast, a rise in internal calcium ion concentration through activation of the calcium channels affects the entire cell. Interestingly and perhaps surprisingly given the lack of importance granted to the hydrocarbon tails of lipids, these effects seem to have a strong dependence on the composition of the fatty acid tail. One of the DAG variants examined by the team caused fewer, shorter, and weaker elevations of the calcium level, while another caused stronger, long-lasting calcium signals. A third had no significant influence on the intracellular calcium concentration.

"If this variability concerning the fatty acid composition should influence the control of cellular processes in most lipids, a completely new level of complexity has to be considered in cell biology," Schultz explains. "Furthermore, our results demonstrate that cells can respond to a given spatially confined signal both with a local and a global response pattern. Local signalling is particularly important in polarized and migrating cells, where different signals are needed at opposite ends of the cell."

Related Links

Angew Chem Int Edn 2013, 52, online: "The Fatty Acid Composition of Diacylglycerols Determines Local Signaling Patterns"

Article by David Bradley

The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.

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