View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Chemistry & Biology Crosstalk Lipidomics at the Interface of Structure and Function in Systems Biology Richard W. Gross1,2,3,4,* and Xianlin Han1,2 1Division of Bioorganic Chemistry and Molecular Pharmacology 2Departments of Medicine 3Developmental Biology Washington University School of Medicine, St. Louis, MO 63110, USA 4Department of Chemistry, Washington University, St. Louis, MO 63105, USA *Correspondence: [email protected] DOI 10.1016/j.chembiol.2011.01.014 Cells, tissues, and biological fluids contain a diverse repertoire of many tens of thousands of structurally distinct lipids that play multiple roles in cellular signaling, bioenergetics, and membrane structure and func- tion. In an era where lipid-related disease states predominate, lipidomics has assumed a prominent role in systems biology through its unique ability to directly identify functional alterations in multiple lipid metabolic and signaling networks. The development of shotgun lipidomics has led to the facile accrual of high density information on alterations in the lipidome mediating physiologic cellular adaptation during health and path- ologic alterations during disease. Through both targeted and nontargeted investigations, lipidomics has already revealed the chemical mechanisms underlying many lipid-related disease states. The Multiple Roles of Lipids (Zhang et al., 2002; Breen et al., 2005). Cantley, 2006; Chiang et al., 2006; Simon in Cellular Function On a third level, lipid membranes serve and Cravatt, 2006). During evolution, Lipids play multiple diverse roles in as molecular scaffolds that promote pro- adaptive alterations in membrane struc- cellular function that must be effectively ductive interactions among membrane- ture and function were selected by integrated into chemical and genetic associated moieties that regulate cellular their integrated effects on cellular metab- networks to allow each cell to fulfill its signaling to facilitate the transmission of olism and signaling. This evolutionary specific biological function. By some biological information across cell mem- process has led to the development of recent estimates, cellular lipids encom- branes, between intracellular compart- multiple membrane-delimited compart- pass tens of thousands of structurally ments or to other cells. Furthermore, the ments (e.g., mitochondria, peroxisomes, distinct compounds (van Meer, 2005; molecular dynamics and physical proper- endoplasmic reticulum, etc.) which Shevchenko and Simons, 2010). On the ties of membrane bilayers are critical perform integrated specialized processes most fundamental level, lipids are the determinants of the activities of trans- that are essential for efficient cellular func- main components of biological mem- membrane proteins such as ion channels tion and adaptation to external perturba- branes where they serve to sequester, and ion pumps (e.g., Schmidt and tions (Figure 1). organize, and distribute the molecular MacKinnon, 2008). Through the use of a entities necessary for life processes. On diverse structural repertoire of lipids to The Growth of Lipidomics a second level, lipids (e.g., fatty acids regulate membrane surface charge, in Systems Biology and triglycerides) are important fuel sour- curvature and molecular dynamics, many Similar to the Systems Biology fields of ces for many cell types. Lipids supply biological functions of membranes can genomics and proteomics, the field of energy for cellular function through oxida- be fulfilled. Thus, the precise covalent lipidomics begins with the identification tion and facilitate metabolic flexibility nature of membrane molecular constitu- and quantitation of lipids that collectively through their ability to store chemical ents within the lipid bilayers, including comprise the lipidome (i.e., the collection energy during times of caloric excess alterations in class, subclass and indi- of lipid molecular species) in each and harvest the energy stored in lipids vidual molecular species are important cell, tissue, or biologic fluid of interest. (e.g., triglycerides) during energy deple- determinants of membrane structure that Through identification and quantitation of tion. Moreover, lipids play prominent roles facilitate many specialized membrane- alterations in lipid molecular species, in the regulation of cellular bioenergetics mediated cellular functions (Figure 1). a high-density matrix containing funda- through integrating oxidative metabolic Finally, many classes of lipids serve as mental information on the metabolic state, programs (Michalik et al., 2006), modu- second messengers of signal transduc- nutritional history and functional status of lating systemic energy balance through tion (e.g., eicosanoids, lysolipids, phos- each cell type can be obtained. Moreover, eicosanoid and lysolipid production phoinositides, endocannabinoids) that the field of lipidomics encompasses the (Vegiopoulos et al., 2010; Skoura and reside in biologic membranes in a latent roles of specific membrane lipid constitu- Hla, 2009), and regulating mitochondrial state which can be activated either by ents in mediating membrane domain electron transport chain flux and coupling hydrolysis and/or covalent transformation formation (e.g., rafts), in facilitating efficiency (e.g., cardiolipin, fatty acids) (e.g., Wolf and Gross, 1985; Shaw and interactions among spatially interwoven 284 Chemistry & Biology 18, March 25, 2011 ª2011 Elsevier Ltd All rights reserved Chemistry & Biology Crosstalk Ion Channels Receptors and Transporters + + + PLA PLC Gx PLD Signaling Membrane Structure Cellular Function Bioenergetics Mitochondrial H+ H+ H+ Inner Membrane + UCP H F0 c I e- Q III IV β II CPT II α O2 Acyl- F1 carnitine β-Oxidation NADH Electron Transport Chain Acyl-CoA Trifunctional Complex ADP ATP Figure 1. The Pleiotropic Roles of Lipids in Cellular Function Lipids fulfill multiple roles in cellular function including cellular signaling (top left) through: (1) harboring latent second messengers of signal transduction that are released by phospholipases (PLA, PLC, and PLD enzymes); (2) covalent transformation of membrane lipids into biologically active ligands by kinases (e.g., PI 3,4,5 triphosphate); (3) providing molecular scaffolds for the assembly of protein complexes mediating receptor/effector coupling (e.g., G protein-coupled recep- tors); and (4) 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. More- over, lipids play essential roles in mitochondrial cellular bioenergetics (bottom) through the use of fatty acids as substrates for mitochondrial b-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 as well as the fatty acid-mediated regulation of uncoupling proteins (UCP). networks of signaling proteins (e.g., G disease states. Lipidomics has now The Challenges of Early Lipid protein receptor-effector coupling), and matured into a field that has already iden- Analytical Techniques in providing dynamic highly specialized tified biomarkers predictive of disease Historically, progress in lipid research has molecular scaffolds for the construction states, alterations in the profiles of lipids been hindered by the difficulties inherent of microscopic and macroscopic chemi- that reflect disease severity and can be in the identification of lipid structure cal assemblies necessary for life pro- used to determine treatment efficacy (e.g., the chemical nature and regiospeci- cesses (e.g., Klose et al., 2010). (Nomura et al., 2010; Porter et al., 2010; ficity of aliphatic chains in each lipid The large majority of diseases in indus- Bartz et al., 2007). Thus, through the class and subclass) and quantitation of trialized societies in the 21st century, comprehensive analysis of alterations in individual molecular species. Over many such as diabetes, obesity, atheroscle- lipid molecular species and their abun- decades multiple approaches have rosis, myocardial infarction, and stroke, dance, the field of lipidomics produces been applied to the separation, quantita- to name a few, are lipid-related disorders a high-density array of diagnostic, thera- tion and characterization of lipids in- (e.g., Unger, 2002; Unger et al., 2010; peutic and mechanistic information which cluding thin layer chromatography, gas Dixon, 2010). Thus, lipidomics offers a has greatly impacted our understanding chromatography, NMR, and HPLC in con- direct and unique perspective into the of the complex roles of lipids in health junction with a variety of complementary pathologic alterations in cellular regula- and disease (e.g., Nomura et al., 2010; procedures including chemical hydro- tory networks that promote lipid-mediated Mancuso et al., 2009; Liu et al., 2010). lysis, regiospecific enzymatic cleavage Chemistry & Biology 18, March