Encyclopedia of Lipidomics

Living Edition
| Editors: Markus R. Wenk

Oxidized (Phospho)lipids

  • Zhixu Ni
  • Maria FedorovaEmail author
Living reference work entry
DOI: https://doi.org/10.1007/978-94-007-7864-1_183-1


Oxidized (Phospho)lipids – molecular species generated from (poly)unsaturated diacyl- and alk(en)ylacyl phospholipids via enzymatic and non-enzymatic oxidation.


Oxidized glycerophospholipids, oxPL (abbr)

Oxidized glycerophospholipids, previously seen mainly as a toxic byproduct of free radical reactions, nowadays are recognized as an important mediator of various cellular responses and play a significant role in organism redox balance. Early studies mainly focused on free fatty acid (FFA)-derived lipid peroxidation products (LPPs), especially iso- and neuroprostanes, established them as biomarkers of inflammatory pathways in mammals. Recently, structural and biological activity studies have been translated from FFA-derived LPPs to oxidized phospholipids (oxPLs). oxPLs have been shown to play a significant role in various and often controversial biological functions including pro- and anti-inflammatory pathways, cell death signaling, and pro-survival effects (Greiq et al. 2012).

Lipid oxidation at the level of FFA may occur both enzymatically via reaction catalyzed by lipoxygenases (LOX) (Yamamoto 1991), cyclooxygenase (COX) (Brock et al. 1999), cytochromes P450 (McGiff et al. 1996), and nonenzymatically in reactions with transitional metal ions and free radicals (Girotti 1985). Oxidized lipids, generated by either process, are extremely diverse in structures and functional effects. Enzymatic lipid oxidations are usually characterized by high specificity. For example, 12-lipoxygenase (LOX) and 15-LOX isoforms of the LOX enzyme family can catalyze oxidation of arachidonic acid (20:4) into specific pro- or anti-inflammatory hydroxyeicosatetraenoic acids (HETEs), 12-HETE and 15-HETE, respectively (Kühn and O’Donnell 2006). On the other hand, COX-driven oxidation of arachidonic acid results in pro-inflammatory prostaglandins. Enzymatic polyunsaturated fatty acids (PUFA) oxidation was mostly studied for free PUFA (Dennis and Norris 2015). However, activity of PUFA oxidizing enzymes including 12/15-LOX was demonstrated for phospholipid-esterified fatty acyl chains as well (Murray and Brash 1988).

The presence of unsaturated fatty acids (FA) within phospholipids (PL) makes them highly susceptible towards radical-based oxidation reactions. Strongly reactive mono-allylic hydrogen in oleic acid and bis-allylic hydrogen atoms in PUFAs represent the major targets of reactive oxygen species (ROS). Nonenzymatic lipid peroxidation induced by ROS is a chain reaction characterized by three main steps known as initiation, propagation, and termination (Fig. 1). In the initiation step, the free radicals attack on the methylenic groups between or next to ethylenic bonds generating the primary carbon-centered lipid radical L•. During the propagation step, L• reacts with molecular oxygen forming a peroxyl radical LOO•, which can further propagate lipid peroxidation by abstracting protons from neighboring double bond systems in the same molecule or additional PUFAs and thus initiating a new peroxidation cycle. Peroxyl radicals over a series of rearrangements can form PL bound epoxides, ketones, and hydroxides, which can be further truncated via β-scission mechanisms resulting in wide array of free and PL-bound lipid peroxidation products including alkanals, alkenals, and their hydroxy- and keto-, carboxylic and carboxy-derivatives, thereby significantly contributing to the overall complexity of the oxidized lipidome (Fig. 1) (Yin et al. 2011).
Fig. 1

The scheme of PUFA peroxidation induced by a hydroxyl radical illustrated on the example of linoleic acid (18:2)

Furthermore, PL oxidation can lead to the nonenzymatic hydrolysis of the lipid head group leading to the formation of diacylglycerols (DAGs) and the free head group, moiety, both of which possess different functionalities and can further regulate various signaling pathways (Fig. 2). Nonenzymatic PL oxidation can also result in a release of free fatty acids from sn-1 or sn-2 positions, leading to lysophospholipid (lysoPL) formation. DAGs and lysoPLs can be also produced in an enzymatic manner, e.g., by the action of phospholipases of which phospholipase A2 currently attract much of the scientific attention in respect to redox related pathologies (Bochkov et al. 2009; Greiq et al. 2012).
Fig. 2

The general pathway of phospholipid oxidations and corresponding lipid peroxidation products. DAG – diacylglycerol, lysoPL – lysophospholipid, HG – head group, LMW – low molecular weight, HMW – high molecular weight LPPs, LPP -, HNE – 4-hydroxynonenal, HHE – 4-hydroxyhexenal, MDA – malondialdehyde, PONPC - 1-palmitoyl-2-(9′-oxo-nonanoyl)-sn-glycero-3-phosphocholin, PAzPC - 1-palmitoyl-2-azelaoyl-sn-glycero-3-phosphocholine

Another route to produce non-enzymatic lipid modifications involves myeloperoxidase (MPO). MPO is present in neutrophils and when activated in response to pathogen invasion, it can produce the highly reactive hypochlorite Hypochlorite can modify many biomolecules including lipids, forming chlorohydrins at the position of the double bonds in the PUFA moiety (Ford 2010).

Oxidation of PLs can affect not only the FA moieties and the glycerol backbone but can also involve the head group moiety (Naudí i Farré et al. 2013). Amino PLs such as phosphatidylethanolamine (PE) and phosphatidylserine (PS) are among the most susceptible ones with respect to modifications by sugars and lipid oxidation products. Thus, primary amino groups of PE and PS can be modified by a wide range of reactive carbonyls including reactive aldehydes, products of sugar oxidation, and glycated via the Milliard reaction of glucose. Moreover, PL with primary amino groups in the head group can be modified by hypochlorite as well yielding mono- and dichloroamines, imines, chloroamines, and nitriles.

However, PUFAs located at the sn-2 position is one of the main targets of ROS. According to the lipid peroxidation mechanisms described above, products of PL-esterified PUFA oxidation can be generally divided into two subgroups: the long chain oxygen addition products (OAP) and the short chain oxidative cleavage products (OCP). OAP include full-length PUFA with one or multiple peroxyl, hydroxyl, and/or keto groups. In the oxidative cleavage step, the lipid peroxyl radical drive the cleavage of the fatty acid chain with a formation of a short chain aldehyde and a truncated PL. Thus, the oxidative cleavage products (OCP) can be generally separated into low and high molecular weight LPPs (Fig. 2).

Generally, oxidized lipids can be divided into highly reactive compounds with short half-life times, such as carbonylated LPP (especially α,β-unsaturated aldehydes and ketones), and less reactive long-living metabolites (oxygenated phospholipids). In a short-time course, reactive LPPs might significantly alter the metabolic state of a cell by changing its redox balance, activating antioxidant and stress responses. However, stable LPP can also participate in cell signaling and regulation via interaction with various receptors (e.g., PPARγ, CD36). Biological activities of LPP are poorly defined so far, but it is evident that oxidized lipids play a significant role in regulation of pro- and anti-inflammatory effects (Fedorova and Hoffmann 2015).

Many of the low molecular weight LPPs, such as alkenals, hydroxy/oxo-alkenals, epoxy-alkenals, and γ-ketoaldehydes, retain a double bond and can readily react with nucleophilic groups in proteins. In this class, 4-hydroxy-nonenal (HNE) and malondialdehyde (MDA) are among the two most-studied species (Fig. 2). HNE is a highly reactive α,β-unsaturated aldehyde which can react with nucleophilic groups in DNA, proteins, and lipids due to its strong electrophilic character. HNE was reported to be involved in several signaling pathways such as the antioxidant response (Keap1/Nrf2 pathways), heat shock response, ER stress, stress-responsive MAP kinase signaling, NF-κB signaling, and DNA damage response signaling (Zhang and Forman 2017).

PL-esterified LPPs such as for instance 1-palmitoyl-2-(9′-oxo-nonanoyl)-sn-glycero-3-phosphocholine (PONPC; Fig. 2) can also form Schiff’s base adducts with proteins, which often leads to a conformational change of proteins and results in enzyme dysfunction. PONPC was also found to have a potentially protective effect for the activation of phospholipase A2 and associates with autophagy deficiency. Many of PL-bound LPPs were reported to have their specific regulations in inflammation (Bochkov et al. 2017).

Overall, oxidation of a single PL might result in an extremely large variety of chemically diverse compounds, including free and PL-bound electrophilic aldehydes and isoprostane species, oxygenated PL, DAG and lysoPL as well as headgroup modified derivatives (Fig. 3). Despite a relatively limited amount of available data, it becomes clear that the structure of LPPs is one of the main determinants of their diverse biological activities. Thus, systems wide profiling and identification of a large number of oxidized lipids in biological samples are required to understand structure-functional relationships determining their biological activities.
Fig. 3

Overview of possible lipid peroxidation products formed by PAPE oxidation. DAG: diacylglycerols, IsoPs: isoprostanes, Lyso PE: lysophosphatidylethanolamine, ROS: reactive oxygen species, PAPE: 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphoethanolamine, PE: phosphatidylethanolamine



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© Springer Science+Business Media B.V. 2018

Authors and Affiliations

  1. 1.Institute of Bioanalytical ChemistryFaculty of Chemistry and MineralogyLeipzigGermany
  2. 2.Center for Biotechnology and BiomedicineUniversität LeipzigLeipzigGermany