TY - JOUR
T1 - Disturbed brain phospholipid and docosahexaenoic acid metabolism in calcium-independent phospholipase A2-VIA (iPLA2β)- knockout mice
AU - Cheon, Yewon
AU - Kim, Hyung Wook
AU - Igarashi, Miki
AU - Modi, Hiren R.
AU - Chang, Lisa
AU - Ma, Kaizong
AU - Greenstein, Deanna
AU - Wohltmann, Mary
AU - Turk, John
AU - Rapoport, Stanley I.
AU - Taha, Ameer Y.
N1 - Funding Information:
The work conducted by Y. Cheon, H-W. Kim, M. Igarashi, H. R. Modi, L. Chang, K. Ma, S. I. Rapoport and A. Y. Taha was supported by the Intramural Research Program of the National Institute on Aging and that by D. Greenstein by the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health . The work conducted by M. Wohltmann and J. Turk was supported by NIH grants R37-DK34388 , P41-RR00954 , P60-DK20579 , and P30-DK56341 . We appreciate the editorial assistance of the NIH Fellows Editorial Board.
PY - 2012/9
Y1 - 2012/9
N2 - 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.
AB - 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.
KW - DHA
KW - Incorporation
KW - Lipid
KW - Mouse
KW - PLA2G6
KW - Turnover
UR - http://www.scopus.com/inward/record.url?scp=84863987499&partnerID=8YFLogxK
U2 - 10.1016/j.bbalip.2012.02.003
DO - 10.1016/j.bbalip.2012.02.003
M3 - Article
C2 - 22349267
AN - SCOPUS:84863987499
SN - 1388-1981
VL - 1821
SP - 1278
EP - 1286
JO - Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids
JF - Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids
IS - 9
ER -