Cellular lipidomics

Abstract

The cellular lipidome comprises over 1000 different lipids. Most lipids look similar having a polar head and hydrophobic tails. Still, cells recognize lipids with exquisite specificity. The functionality of lipids is determined by their local concentration, which varies between organelles, between the two leaflets of the lipid bilayer and even within the lateral plane of the membrane. To incorporate function, cellular lipidomics must not only determine which lipids are present but also the concentration of each lipid at each specific intracellular location in time and the lipid's interaction partners. Moreover, cellular lipidomics must include the enzymes of lipid metabolism and transport, their specificity, localization and regulation. Finally, it requires a thorough understanding of the physical properties of lipids and membranes, especially lipid-lipid and lipid-protein interactions. In the context of a cell, the complex relationships between metabolites can only be understood by viewing them as an integrated system. Cellular lipidomics provides a framework for understanding and manipulating the vital role of lipids, especially in membrane transport and sorting and in cell signaling.

Figure 1

The structure of the major membrane lipids. The more or less cylindrical glycerophospholipid phosphatidylcholine (PC) carries a zwitterionic phosphocholine headgroup on a glycerol with two fatty acyl chains (diacylglycerol), usually one unsaturated (bent). Phosphatidylethanolamine (PE) has a small headgroup and a conical shape and creates a stress in the bilayer: the PE-containing monolayer has a tendency to adopt a negative curvature. The phosphosphingolipid sphingomyelin (SM) tends to order membranes via its straight chains and its high affinity for the flat ring structure of cholesterol (chol). For chemical structures, see Fahy et al (2005).

Figure 2

Lipid organization in animal cells. The cellular membranes are in bidirectional contact with each other via vesicular traffic except for, maybe, the mitochondria (MITO) and peroxisomes. Whereas the endoplasmic reticulum (ER) and Golgi (G) nearly exclusively contain glycerophospholipids (gray), the trans Golgi network (TGN) and endosomes (E) contain >10% sphingolipids and 30–40 mol% cholesterol (red). The internal vesicles of late endosomes (LE) and lysosomes (L) contain the unique lipid lysobisphosphatidic acid, which is locally produced (Matsuo et al, 2004), like cardiolipin in mitochondria (blue).

Figure 3

Lipid sorting by lateral segregation. With a composition of 33% sphingolipids, 33% glycerophospholipids and 33% cholesterol, and with the sphingolipids situated in the noncytoplasmic leaflet the apical surface is practically covered by sphingolipids and cholesterol (see Simons and van Meer, 1988). The >4-fold enrichment of (glyco)sphingolipids on the apical over the basolateral surface (yellow) and the opposite situation for PC (red) is maintained by the tight junction (TJ). SM and complex glycosphingolipids are synthesized in the Golgi lumen. They do not cross membranes spontaneously, which is also true for PC. The 10-fold enrichment of cholesterol at (both domains of) the plasma membrane as compared to ER then suggests the following sorting events in the Golgi lumen: sphingolipids+cholesterol into apical carriers, PC+cholesterol into basolateral transport vesicles and PC into retrograde transport vesicles (pink). Possibly, a similar sorting event enriches the inner leaflet of the plasma membrane in PS, disaturated phospholipids and cholesterol (blue) (van Meer, 1989). The term ‘raft' is routinely used for the less fluid phase, but may be problematic when multiple phases coexist.

Figure 4

Lipid translocation across membranes. Lipids can freely flip bidirectionally across the ER membrane which is probably protein-mediated and nonspecific (Vishwakarma et al, 2005). This property is lost in the Golgi, where active translocation has been reported towards the cytosol (purple arrow) by one or more members of the ‘aminophospholipid translocator' subfamily of P-type ATPases (Natarajan et al, 2004). Transport towards the lumen (orange arrow) may occur by ABC transporters. Specific ABC transporters have been found in apical and basolateral membranes of epithelial cells (yellow and red arrow) (Borst and Oude Elferink, 2002) and the same probably applies to the inward transporting P-type ATPases (blue and green arrow).