title: Disturbed brain phospholipid and docosahexaenoic acid metabolism in calcium-independent phospholipase A(2)-VIA (iPLA(2)β)-knockout mice.
abstract: Calcium-independent phospholipase A(2) group VIA (iPLA(2)β) releases docosahexaenoic acid (DHA) from phospholipids in vitro. Mutations in the iPLA(2)β gene, PLA2G6, are associated with dystonia-parkinsonism and infantile neuroaxonal dystrophy. To understand the role of iPLA(2)β in brain, we applied our in vivo kinetic method using radiolabeled DHA in 4 to 5-month-old wild type (iPLA(2)β(+/+)) and knockout (iPLA(2)β(-/-)) mice, and measured brain DHA kinetics, lipid concentrations, and expression of PLA(2), cyclooxygenase (COX), and lipoxygenase (LOX) enzymes. Compared to iPLA(2)β(+/+) mice, iPLA(2)β(-/-) 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 iPLA(2)β(-/-) mice, brain levels of iPLA(2)β mRNA, protein, and activity were decreased, as was the iPLA(2)γ (Group VIB PLA(2)) mRNA level, while levels of secretory sPLA(2)-V mRNA, protein, and activity and cytosolic cPLA(2)-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 iPLA(2)β 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.
authors.affiliation: National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA. cheony@mail.nih.gov
authors.forename: Yewon
authors.initials: Y
authors.lastname: Cheon
authors.forename: Hyung-Wook
authors.initials: HW
authors.lastname: Kim
authors.forename: Miki
authors.initials: M
authors.lastname: Igarashi
authors.forename: Hiren R
authors.initials: HR
authors.lastname: Modi
authors.forename: Lisa
authors.initials: L
authors.lastname: Chang
authors.forename: Kaizong
authors.initials: K
authors.lastname: Ma
authors.forename: Deanna
authors.initials: D
authors.lastname: Greenstein
authors.forename: Mary
authors.initials: M
authors.lastname: Wohltmann
authors.forename: John
authors.initials: J
authors.lastname: Turk
authors.forename: Stanley I
authors.initials: SI
authors.lastname: Rapoport
authors.forename: Ameer Y
authors.initials: AY
authors.lastname: Taha
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D001923:Brain Chemistry / Q000235:genetics; D051545:Cyclooxygenase 1 / Q000096:biosynthesis / Q000235:genetics; D004281:Docosahexaenoic Acids / Q000235:genetics / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics; D054522:Group VI Phospholipases A2; D006801:Humans; D050356:Lipid Metabolism; D008084:Lipoxygenase / Q000096:biosynthesis / Q000378:metabolism; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D054497:Phospholipases A2, Secretory / Q000096:biosynthesis / Q000235:genetics; D010743:Phospholipids / Q000235:genetics / Q000378:metabolism*
chemical_list: D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D010743:Phospholipids; D004281:Docosahexaenoic Acids; D008084:Lipoxygenase; D051545:Cyclooxygenase 1; C496512:Ptgs1 protein, mouse; D054522:Group VI Phospholipases A2; D054497:Phospholipases A2, Secretory; C516476:Pla2g6 protein, mouse