Isolevuglandin-modified phosphatidylethanolamine is metabolized by NAPE-hydrolyzing phospholipase D

Guo, Lilu; Gragg, Stephen D.; Chen, Zhongyi; Zhang, Yongqin; Amarnath, Venkataraman; Davies, Sean S.

doi:10.1194/jlr.m042556

Cited by 14 publications

(16 citation statements)

References 20 publications

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“…Isolevuglandins have been found to react with the head group of phosphatidylethanolamine, and the resulting adducts can be detoxified by an N-acyl phosphatidylethanolaminehydrolyzing phospholipase D [74]. Isolevuglandin-PE contributes to an NFkB-dependent inflammatory response in macrophages exposed to isolevuglandins by a mechanism involving binding to the receptor for advanced glycation end-products (RAGE).…”

Section: Isolevuglandinsmentioning

confidence: 99%

Chemistry and analysis of HNE and other prominent carbonyl-containing lipid oxidation compounds

Sousa

Pitt

Spickett

2017

Free Radical Biology and Medicine

145

105

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The process of lipid oxidation generates a diverse array of small aldehydes and carbonyl-containing compounds, which may occur in free form or esterified within phospholipids and cholesterol esters. These aldehydes mostly result from fragmentation of fatty acyl chains following radical oxidation, and the products can be subdivided into alkanals, alkenals (usually D,β-unsaturated), γ-substituted alkenals and bis-aldehydes.Isolevuglandins are non-fragmented di-carbonyl compounds derived from H 2 -isoprostanes, and oxidation of the ω-3-fatty acid docosahexenoic acid yield analogous 22 carbon neuroketals. Non-radical oxidation by hypochlorous acid can generate D-chlorofatty aldehydes from plasmenyl phospholipids. Most of these compounds are reactive and have generally been considered as toxic products of a deleterious process. The reactivity is especially high for the D,β-unsaturated alkenals, such as acrolein and crotonaldehyde, and for γ-substituted alkenals, of which 4-hydroxy-2-nonenal and 4-oxo-2-nonenal are best Page | 2 known. Nevertheless, in recent years several previously neglected aldehydes have been investigated and also found to have significant reactivity and biological effects; notable examples are 4-hydroxy-2-hexenal and 4-hydroxy-dodecadienal. This has led to substantial interest in the biological effects of all of these lipid oxidation products and their roles in disease, including proposals that HNE is a second messenger or signalling molecule.However, it is becoming clear that many of the effects elicited by these compounds relate to their propensity for forming adducts with nucleophilic groups on proteins, DNA and specific phospholipids. This emphasizes the need for good analytical methods, not just for free lipid oxidation products but also for the resulting adducts with biomolecules. The most informative methods are those utilizing HPLC separations and mass spectrometry, although analysis of the wide variety of possible adducts is very challenging. Nevertheless, evidence for the occurrence of lipid-derived aldehyde adducts in biological and clinical samples is building, and offers an exciting area of future research. AbbreviationsAcr-dG, 1,N2-propanodeoxyguanosine; AGEs, advanced glycation end-product; ALEs, advanced lipoxidation end product; ApoB100, apolipoprotein B100; ApoE, apolipoprotein E; ARP, aldehyde reactive probe; AspN, endoproteinase AspN (flavastacin); βLG, β-lactoglobulin; BHZ, biotin hydrazide; BN-PAGE, blue native polyacrylamide gel

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Section: Isolevuglandinsmentioning

confidence: 99%

Chemistry and analysis of HNE and other prominent carbonyl-containing lipid oxidation compounds

Sousa

Pitt

Spickett

2017

Free Radical Biology and Medicine

145

105

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“…Because we had previously found that IsoLG-PE is hydrolyzed to its ethanolamine analog (IsoLG-ETN) by the action of NAPE-PLD (29) and because NAPE-PLD is expressed in macrophages (75), we considered the possibility that hydrolysis of IsoLG-PE to IsoLG-ETN might be required to activate macrophages. If so, then IsoLG-ETN, rather than IsoLG-PE, would be the appropriate ligand to be used for receptor screening.…”

Section: Isolg-pe Induces Nfjb Activation and Inflammatory Cytokine Ementioning

confidence: 99%

Isolevuglandin-Type Lipid Aldehydes Induce the Inflammatory Response of Macrophages by Modifying Phosphatidylethanolamines and Activating the Receptor for Advanced Glycation Endproducts

Guo

Chen

Amarnath

et al. 2015

Antioxidants & Redox Signaling

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Aims: Increased lipid peroxidation occurs in many conditions associated with inflammation. Because lipid peroxidation produces lipid aldehydes that can induce inflammatory responses through unknown mechanisms, elucidating these mechanisms may lead to development of better treatments for inflammatory diseases. We recently demonstrated that exposure of cultured cells to lipid aldehydes such as isolevuglandins (IsoLG) results in the modification of phosphatidylethanolamine (PE). We therefore sought to determine (i) whether PE modification by isolevuglandins (IsoLG-PE) occurred in vivo, (ii) whether IsoLG-PE stimulated the inflammatory responses of macrophages, and (iii) the identity of receptors mediating the inflammatory effects of IsoLG-PE. Results: IsoLG-PE levels were elevated in plasma of patients with familial hypercholesterolemia and in the livers of mice fed a high-fat diet to induce obesity and hepatosteatosis. IsoLG-PE potently stimulated nuclear factor kappa B (NFjB) activation and expression of inflammatory cytokines in macrophages. The effects of IsoLG-PE were blocked by the soluble form of the receptor for advanced glycation endproducts (sRAGE) and by RAGE antagonists. Furthermore, macrophages derived from the bone marrow of Ager null mice failed to express inflammatory cytokines in response to IsoLG-PE to the same extent as macrophages from wild-type mice. Innovation: These studies are the first to identify IsoLG-PE as a mediator of macrophage activation and a specific receptor, RAGE, which mediates its biological effects. Conclusion: PE modification by IsoLG forms RAGE ligands that activate macrophages, so that the increased IsoLG-PE generated by high circulating cholesterol levels or high-fat diet may play a role in the inflammation associated with these conditions. Antioxid. Redox Signal. 22, 1633-1645.

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“…Levels rapidly declined over six hours, supporting the existence of phospholipases that catabolize N -modified PE (Guo et al, 2013). Treatment of HEK293 cells with siRNA specific for N -acyl PE hydrolyzing phospholipase D (NAPE-PLD) elevated levels of N -IsoLG-PE compared to cells treated with control siRNA, suggesting that NAPE-PLD is one of the principal enzymes that hydrolyzes N -IsoLG-PE.…”

Section: Class Iv: Oxidatively N-modified Phospholipids (Pl)mentioning

confidence: 82%

Lipid peroxidation generates biologically active phospholipids including oxidatively N-modified phospholipids

Davies

Guo

2014

Chemistry and Physics of Lipids

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Peroxidation of membranes and lipoproteins converts “inert” phospholipids into a plethora of oxidatively modified phospholipids (oxPL) that can act as signaling molecules. In this review, we will discuss four major classes of oxPL: mildly oxygenated phospholipids, phospholipids with oxidatively truncated acyl chains, phospholipids with cyclized acyl chains, and phospholipids that have been oxidatively N-modified on their headgroups by reactive lipid species. For each class of oxPL we will review the chemical mechanisms of their formation, the evidence for their formation in biological samples, the biological activities and signaling pathways associated with them, and the catabolic pathways for their elimination. We will end by briefly highlighting some of the critical questions that remain about the role of oxPL in physiology and disease.

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Isolevuglandin-modified phosphatidylethanolamine is metabolized by NAPE-hydrolyzing phospholipase D

Cited by 14 publications

References 20 publications

Chemistry and analysis of HNE and other prominent carbonyl-containing lipid oxidation compounds

Chemistry and analysis of HNE and other prominent carbonyl-containing lipid oxidation compounds

Isolevuglandin-Type Lipid Aldehydes Induce the Inflammatory Response of Macrophages by Modifying Phosphatidylethanolamines and Activating the Receptor for Advanced Glycation Endproducts

Lipid peroxidation generates biologically active phospholipids including oxidatively N-modified phospholipids

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