Preferential hydrolysis of truncated oxidized glycerophospholipids by lysosomal phospholipase A2

J Lipid Res. 2017 Feb;58(2):339-349. doi: 10.1194/jlr.M070730. Epub 2016 Dec 19.

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.

Keywords: catabolic pathway; lysosome; positional specificity; truncated oxidized phospholipid.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acylation
  • Amiodarone / pharmacology
  • Animals
  • CHO Cells
  • Cricetulus
  • Fatty Acids / metabolism
  • Glycerophospholipids / metabolism*
  • Hydrogen-Ion Concentration
  • Hydrolysis / drug effects
  • Liposomes / metabolism
  • Lysosomes / drug effects
  • Lysosomes / enzymology
  • Oxidation-Reduction
  • Phosphatidylcholines / metabolism*
  • Phosphatidylcholines / pharmacology
  • Phospholipases A2 / genetics
  • Phospholipases A2 / metabolism*
  • Sphingosine / analogs & derivatives*
  • Sphingosine / metabolism

Substances

  • Fatty Acids
  • Glycerophospholipids
  • Liposomes
  • N-acetylsphingosine
  • Phosphatidylcholines
  • Phospholipases A2
  • 1,2-oleoylphosphatidylcholine
  • Amiodarone
  • Sphingosine