Preferential hydrolysis of truncated oxidized glycerophospholipids by lysosomal phospholipase A2

Abstract

generation and elimination of ROS affects cellular structure and function. Within lipid membranes and particles, unsaturated and polyunsaturated acyl groups conjugated at the sn-2 position of phospholipids (PLs) are susceptible to ROS inducing nonenzymatic fragmentation of the unsaturated acyl chains. As a result, various truncated oxidized glycerophospholipids (ox-PLs) are formed with an oxidized short or medium chain terminating in an aldehyde or carboxylic acid at the sn-2 position (2). The truncated ox-PLs produced under oxidative stress derive mainly from phosphatidylcholine (PC) and mediate inflammatory, apoptotic, and innate immune responses via cellular receptor-dependent or -independent pathways (3).For example, 1-palmitoyl-2-(5′-oxo-valeroyl)-sn-glycero-3-phosphocholine (POVPC) and 1-palmitoyl-2-glutaryl-snglycero-3-phosphocholine (PGPC) are found in oxidized LDL and act on intracellular signaling systems associated with platelet activating factor (PAF) receptors (4), scavenger receptors (5), and Toll-like receptors (6). Truncated ox-PLs perturb the lipid bilayer and its physical properties (7,8). Azelaoyl-PCs, including 1-palmitoyl-2-azelaoyl-snglycero-3-phosphocholine (PAzPC), can disrupt lipid membranes, inducing cytotoxicity in a receptor-independent manner (9, 10) and enhancing the interaction between Bax and mitochondrial membranes in an apoptotic pathway (11). The 1-palmitoyl-2-(9′-oxo-nonanoyl)-snglycero-3-phosphocholine (PONPC) accelerates the fibrillation of gelsolin associated with familial Finnish type Reactive oxygen species (ROS), generated enzymatically or nonenzymatically, modify proteins, nucleic acids, and lipids (1). Oxidative stress induced by an imbalance between

Macrophage phenotype and bioenergetics are controlled by oxidized phospholipids identified in lean and obese adipose tissue

“…Similar to the findings of Podrez et al ( 70 ), we found micromolar levels of OxPL species in murine whole blood, and a significant increase in response to high-fat feeding. As has been previously reported, HFD feeding induces PLA2 activity in blood ( 71 ) and it has been found that PLA2 preferentially cleaves the sn -2 moiety from truncated OxPL ( 72 ), offering an explanation for the increased level of LysoPC at the cost of carbonyl-PC species. Additionally, it was previously demonstrated that during obesity adipocytes significantly up-regulate two isoforms of secretory PLA2, specifically PLA2G5 and PLA2G2E ( 73 ).…”

Filamentous Aggregation of Sequestosome-1/p62 in Brain Neurons and Neuroepithelial Cells upon Tyr-Cre-Mediated Deletion of the Autophagy Gene Atg7

“…Our demonstration of elevated amounts of the oxidized phospholipids PAzPC and SAzPC in Atg7 f/f Tyr-Cre brains indicates that the turnover of these substances is altered. The differential effects of autophagy inhibition on different classes of oxidized phospholipids (PAzPC and SAzPC versus Lyso-PPC, Lyso-SPC, PLPC, and SLPC in the Atg7 f/f Tyr-Cre brain), which are similar to those observed in Atg7 f/f K14-Cre skin cells [ 58 ], may be caused by the delivery of substrates to lysosomal phospholipase A2 [ 59 ]. Augmentation of oxidatively modified phospholipids in cellular membranes affects their polarity and permeability, which has been specifically demonstrated for PLPC-derived PazPC [ 60 ].…”

An Increase of Oxidized Phospholipids and the Role of Macrophages in Intraocular Inflammation

“…Recently, we found that LPLA2 preferentially hydrolyzed truncated OxPCs in vitro. 11 This study also showed that LPLA2-overexpressed CHO cells more efficiently catabolize PAzPC in the cultured system than CHO cells. To determine whether LPLA2 is connected with the metabolic pathway of truncated OxPCs by AMs, mouse AMs were prepared from both wild-type and LPLA2 deficient C57BL6 mice Alveolar macrophages of LPLA2 deficient mice develop phospholipidosis due to the reduction of phospholipid digestion.…”