The foundations and development of lipidomics

Abstract

For over a century, the importance of lipid metabolism in biology was recognized but difficult to mechanistically understand due to the lack of sensitive and robust technologies for identification and quantification of lipid molecular species. The enabling technological breakthroughs emerged in the 1980s with the development of soft ionization methods (Electrospray Ionization and Matrix Assisted Laser Desorption/Ionization) that could identify and quantify intact individual lipid molecular species. These soft ionization technologies laid the foundations for what was to be later named the field of lipidomics. Further innovative advances in multistage fragmentation, dramatic improvements in resolution and mass accuracy, and multiplexed sample analysis fueled the early growth of lipidomics through the early 1990s. The field exponentially grew through the use of a variety of strategic approaches, which included direct infusion, chromatographic separation, and charge-switch derivatization, which facilitated access to the low abundance species of the lipidome. In this Thematic Review, we provide a broad perspective of the foundations, enabling advances, and predicted future directions of growth of the lipidomics field.

Keywords: charge-switch derivatization; chromatographic separation; electrospray ionization; lipid metabolism; lipids; mass spectrometry; matrix-assisted laser desorption/ionization; shotgun lipidomics; soft ionization.

Fig. 1

Summary of classes, subclasses, and molecular species in glycerophospholipid. The polar moiety (X), which is connected to the phosphate group, defines the individual class of glycerophospholipid (GPL). The linkage (i.e., ester, ether, and vinyl ether) of the aliphatic chain to the hydroxy group at the sn-1 position of glycerol defines the structure of an individual subclass of phosphatidyl-, plasmanyl-, or plasmenyl-, respectively. The identities at R₁ and R₂, which vary with different number of carbon atoms, number of double bonds, the location of the double bonds, etc. define the individual molecular species of each lipid class.

Fig. 2

The pleiotropic roles of lipids in cellular functions. Lipids fulfill multiple roles in cellular function including cellular signaling (top left) through the following: i) harboring latent second messengers of signal transduction that are released by phospholipases; ii) covalent transformation of membrane lipids into biologically active ligands by kinases (e.g., PI 3,4,5-triphosphate); iii) providing molecular scaffolds for the assembly of protein complexes mediating receptor/effector coupling (e.g., G protein-coupled receptors); and iv) coupling the vibrational, rotational, and translational energies and dynamics of membrane lipids to transmembrane proteins such as ion channels and transporters (top right), thereby facilitating dynamic cooperative lipid-protein interactions that collectively regulate transmembrane protein function. Moreover, lipids play essential roles in mitochondrial cellular bioenergetics (bottom) through the use of fatty acids as substrates for mitochondrial β-oxidation (bottom left) that result in the production of reducing equivalents (e.g., NADH). The chemical energy in NADH is harvested through oxidative phosphorylation whose flux is tightly regulated by mitochondrial membrane constituents including cardiolipins, which modulate electron transport chain (ETC) supercomplex formation. A second mechanism modulating mitochondrial energy production is the dissipation of the proton gradient by the transmembrane flip-flop of fatty acids in the mitochondrial inner membrane bilayer and the fatty acid-mediated regulation of uncoupling proteins (UCP). Reprinted with permission from ref. (15). Copyright 2011 Elsevier Ltd.

Fig. 3

Schematic illustration of functional lipidomics. Functional lipidomics represents a new research direction in lipidomics, in which the altered lipids between different states are uncovered through lipidomic analysis; then the molecular mechanism(s) underpinning the changed lipids and the biological/pathological sequala of the changed lipids are identified; and finally, potential therapeutics for treatment of diseases and/or aging based on the identified signaling, regulators, and sequala are developed.