Disturbed brain phospholipid and docosahexaenoic acid metabolism in calcium-independent phospholipase A2-VIA (iPLA2β)- knockout mice

Yewon Cheon, Hyung Wook Kim, Miki Igarashi, Hiren R. Modi, Lisa Chang, Kaizong Ma, Deanna Greenstein, Mary Wohltmann, John Turk, Stanley I. Rapoport, Ameer Y. Taha

Research output: Contribution to journalArticle

28 Scopus citations

Abstract

Calcium-independent phospholipase A2 group VIA (iPLA 2β) releases docosahexaenoic acid (DHA) from phospholipids in vitro. Mutations in the iPLA2β gene, PLA2G6, are associated with dystonia-parkinsonism and infantile neuroaxonal dystrophy. To understand the role of iPLA2β in brain, we applied our in vivo kinetic method using radiolabeled DHA in 4 to 5-month-old wild type (iPLA2β +/+) and knockout (iPLA2β-/-) mice, and measured brain DHA kinetics, lipid concentrations, and expression of PLA 2, cyclooxygenase (COX), and lipoxygenase (LOX) enzymes. Compared to iPLA2β+/+ mice, iPLA2β-/- mice showed decreased rates of incorporation of unesterified DHA from plasma into brain phospholipids, reduced concentrations of several fatty acids (including DHA) esterified in ethanolamine- and serine-glycerophospholipids, and increased lysophospholipid fatty acid concentrations. DHA turnover in brain phospholipids did not differ between genotypes. In iPLA2β -/- mice, brain levels of iPLA2β mRNA, protein, and activity were decreased, as was the iPLA2γ (Group VIB PLA 2) mRNA level, while levels of secretory sPLA2-V mRNA, protein, and activity and cytosolic cPLA2-IVA mRNA were increased. Levels of COX-1 protein were decreased in brain, while COX-2 protein and mRNA were increased. Levels of 5-, 12-, and 15-LOX proteins did not differ significantly between genotypes. Thus, a genetic iPLA2β deficiency in mice is associated with reduced DHA metabolism, profound changes in lipid-metabolizing enzyme expression (demonstrating lack of redundancy) and of phospholipid fatty acid content of brain (particularly of DHA), which may be relevant to neurologic abnormalities in humans with PLA2G6 mutations.

Original languageEnglish
Pages (from-to)1278-1286
Number of pages9
JournalBiochimica et Biophysica Acta - Molecular and Cell Biology of Lipids
Volume1821
Issue number9
DOIs
StatePublished - Sep 1 2012

Keywords

  • DHA
  • Incorporation
  • Lipid
  • Mouse
  • PLA2G6
  • Turnover

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