title: Preferential hydrolysis of truncated oxidized glycerophospholipids by lysosomal phospholipase A2.
abstract: Truncated oxidized glycerophospholipids (ox-PLs) are bioactive lipids resulting from oxidative stress. The catabolic pathways for truncated ox-PLs are not fully understood. Lysosomal phospholipase A2 (LPLA2) with phospholipase A and transacylase activities is a key enzyme in phospholipid homeostasis. The present study assessed whether LPLA2 could hydrolyze truncated ox-PLs. Incubation of LPLA2 with liposomes consisting of 1,2-O-octadecenyl-sn-glycero-3-phosphocholine (DODPC)/1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) or truncated oxidized phosphatidylcholine (ox-PC)/N-acetylsphingosine (NAS) under acidic conditions resulted in the preferential deacylation at the sn-1 position of the truncated ox-PCs. Additionally, the release of free fatty acid from the truncated ox-PCs preferentially occurred compared with the NAS-acylation. Incubation of LPLA2 with the liposomes consisting of DODPC/DOPC/truncated ox-PC/NAS resulted in the same preferential fatty acid release from the truncated ox-PC. The cationic amphiphilic drug, amiodarone, did not inhibit such fatty acid release, indicating that truncated ox-PCs partition from the lipid membrane into the aqueous phase and react with free LPLA2. Consistent with this mechanism, the hydrolysis of some truncated ox-PCs, but not DOPC, by LPLA2 was detected at neutral pH. Additionally, LPLA2-overexpressed Chinese hamster ovary cells efficiently catabolized truncated ox-PC and were protected from growth inhibition. These findings support the existence of a novel catabolic pathway for truncated ox-PLs via LPLA2.
authors.affiliation: Department of Ophthalmology, School of Medicine, Sapporo Medical University, Sapporo, Japan abeakira@sapmed.ac.jp.
authors.forename: Akira
authors.initials: A
authors.lastname: Abe
authors.affiliation: Department of Ophthalmology, School of Medicine, Sapporo Medical University, Sapporo, Japan.
authors.forename: Miki
authors.initials: M
authors.lastname: Hiraoka
authors.affiliation: Department of Ophthalmology, School of Medicine, Sapporo Medical University, Sapporo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ohguro
authors.affiliation: Life Sciences Institute and Departments of Pharmacology, Biological Chemistry, University of Michigan, Ann Arbor, MI.
authors.forename: John J
authors.initials: JJ
authors.lastname: Tesmer
authors.affiliation: Internal Medicine, University of Michigan Medical School, University of Michigan, Ann Arbor, MI.
authors.forename: James A
authors.initials: JA
authors.lastname: Shayman
mesh_terms: D000215:Acylation; D000638:Amiodarone / Q000494:pharmacology; D000818:Animals; D016466:CHO Cells; D003412:Cricetulus; D005227:Fatty Acids / Q000378:metabolism; D020404:Glycerophospholipids / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis / Q000187:drug effects; D008081:Liposomes / Q000378:metabolism; D008247:Lysosomes / Q000187:drug effects / Q000201:enzymology; D010084:Oxidation-Reduction; D010713:Phosphatidylcholines / Q000378:metabolism* / Q000494:pharmacology; D054467:Phospholipases A2 / Q000235:genetics / Q000378:metabolism*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism
chemical_list: D005227:Fatty Acids; D020404:Glycerophospholipids; D008081:Liposomes; C064769:N-acetylsphingosine; D010713:Phosphatidylcholines; D054467:Phospholipases A2; C017251:1,2-oleoylphosphatidylcholine; D000638:Amiodarone; D013110:Sphingosine
keywords: catabolic pathway; lysosome; positional specificity; truncated oxidized phospholipid