Abstract
Fatty acid analysis of phospholipid compositions of lung and pancreas cells from a cystic fibrosis transmembrane regulator (CFTR) negative mouse (cftr−/−)suggested that a decreased concentration of docosahexaenoate (22:6n-3) and increased arachidonate (20:4n-6) may be related to the disease process in cystic fibrosis (CF). Consequently, we have determined compositions of the major phospholipids of lung, pancreas, liver, and plasma from a different mouse model of CF, the cftrtm1HGU/tm1HGU mouse, compared with ZTM:MF-1 control mice. Electrospray ionization mass spectrometry permitted the quantification of all of the individual molecular species of phosphatidylcholine (PtdCho), phosphatidylethanolamine (PtdEtn), phosphatidylglycerol (PtdGly), phosphatidylserine (PtdSer), and phosphatidylinositol (PtdIns). There was no deficiency of 22:6n-3 in any phospholipid class from lung, pancreas, or liver from mice with the cftrtm1HGU/tm1HGU. Instead, the concentration of 20:4n-6 was significantly decreased in plasma PtdCho species and in pancreas and lung species of PtdEtn, PtdSer, and PtdIns. These results demonstrate the variability of membrane phospholipid compositions in different mouse models of CF and suggest that in cftrtm1HGU/tm1HGU mice, the apparent deficiency was of 20:4n-6- rather than of 22:6n-3–containing phospholipid species. They highlight a need for detailed phospholipid molecular species analysis of cells expressing mutant CFTR from children with CF before the therapeutic effects of administering high doses of 22:6n-3–containing oils to children with CF can be fully evaluated.
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Abbreviations
- 20:4n-6:
-
arachidonate
- 22:6n-3:
-
docosahexaenoate
- 18:2n-6:
-
linoleate
- 18:0:
-
stearate
- 16:0:
-
palmitate
- CF:
-
cystic fibrosis
- CFTR:
-
cystic fibrosis transmembrane regulator
- ESI-MS:
-
electrospray ionization mass spectrometry
- EFA:
-
essential fatty acid
- PtdCho:
-
phosphatidylcholine
- PtdEtn:
-
phosphatidylethanolamine
- PtdGly:
-
phosphatidylglycerol
- PtdIns:
-
phosphatidylinositol
- PtdSer:
-
phosphatidylserine
References
Farrell PM, Mischler EH, Engle MJ, Brown DJ, Lau SM 1985 Fatty-acid abnormalities in cystic-fibrosis. Pediatr Res 19: 104–109
Christophe AB, Warwick WJ, Holman RT 1994 Serum fatty acid profiles in cystic fibrosis patients and their parents. Lipids 29: 569–575
Rogiers V, Crokaert R, Vis H 1980 Altered phospholipid composition and changed fatty acid pattern of the various phospholipid fractions of red cell membranes of cystic fibrosis patients with pancreatic insufficiency. Clin Chim Acta 105: 105–115
Hubbard VS, Dunn DG 1980 Fatty acid compositions of erythrocyte phospholipids from patients with cystic fibrosis. Clin Chim Acta 102: 115–118
Rogiers V, Vercruysse A, Dab I, Baran D 1983 Abnormal fatty-acid pattern of the plasma-cholesterol ester fraction in cystic-fibrosis patients with and without pancreatic insufficiency. Eur J Pediatr 141: 39–42
Kang JX, Man SFP, Brown NE, Labrecque PA, Clandinin MT 1992 The chloride channel blocker anthracene 9-carboxylate inhibits fatty acid incorporation into phospholipid in cultured human airway epithelial cells. Biochem J 285: 725–729
Bhura-Bandali FN, Suh M, Man SFP, Clandinin MT 2000 The F508 mutation in the cystic fibrosis transmembrane conductance regulator alters control of essential fatty acid utilization in epithelial cells. J Nutr 130: 2870–2875
Rogiers V, Dab I, Michotte Y, Vercruysse A, Crokaert R, Vis HL 1984 Abnormal fatty acid turnover in the phospholipids of the red blood cell membranes of cystic fibrosis patients (in vitro study). Pediatr Res 18: 704–709
Ulane MM, Butler JDB, Peri A, Miele L, Ulane RE, Hubbard VS 1994 Cystic fibrosis and phosphatidylcholine biosynthesis. Clin Chim Acta 230: 109–116
Bernhard W, Bertling A, Dombrowsky H, Vieten G, Rau GA, von der Hardt H, Freihorst J 2001 Metabolism of surfactant phosphatidylcholine molecular species in cftrtm1HGU/tm1HGU mice compared to MF-1 mice. Exp Lung Res 27: 349–366
Freedman SD, Katz MH, Parker EM, Laposata M, Urman MY, Alvarez JG 1999 A membrane lipid imbalance plays a role in the phenotypic expression of cystic fibrosis in cftr−/−- mice. Proc Natl Acad Sci U S A 96: 13995–14000
Dorin JR, Dickinson P, Alton EWF, Smith SN, Geddes DM, Stevenson BJ, Kimber WL, Fleming S, Clarke AR, Hooper ML, Anderson L, Beddington RSP, Porteous DJ 1992 Cystic-fibrosis in the mouse by targeted insertional mutagenesis. Nature 359: 211–215
Dorin JR, Stevenson BJ, Fleming S, Alton EWFW, Dickinson P, Porteous DJ 1994 Long-term survival of the exon-10 insertional cystic-fibrosis mutant mouse is a consequence of low-level residual wild-type CFTR gene-expression. Mamm Genome 5: 465–472
Bronsveld I, Mekus F, Bijman J, Ballman M, de Jonge DR, Laabs U, Halley DJ, Ellemunter H, Mastella G, Thomas S, Veeze HJ, Tummler B 2001 Chloride conductance and genetic background modulates the cystic fibrosis phenotype of Delta F508 homozygous twins and siblings. J Clin Invest 108: 1705–1715
Postle AD 1998 Composition and role of phospholipids in the body. In: Sadler M, Caballero B, Strain S (eds) Encyclopedia of Human Nutrition. Academic Press, London, 1193–1201.
Brügger B, Erben G, Sandhoff R, Wieland FT, Lehmann WD 1997 Quantitative analysis of biological membrane lipids at the low picomole level by nano-electrospray ionization tandem mass spectrometry. Proc Natl Acad Sci U S A 94: 2339–2344
Han X, Gross RW 1995 Structural determination of picomole amounts of phospholipids via electrospray ionization tandem mass spectrometry. J Am Soc Mass Spectrom 6: 1202–1210
Hunt AN, Clarke GT, Attard GS, Postle AD 2001 Highly saturated endonuclear phosphatidylcholine is synthesized in situ and colocated with CDP-choline pathway enzymes. J Biol Chem 276: 8492–8499
Bernhard W, Wang J-Y, Tschernig T, Tuemmler B, Hedrich HJ, von der Hardt H 1997 Lung surfactant in a cystic fibrosis animal model: increased alveolar phospholipid pool size without altered composition and surface tension function in cftrm1HGU/m1HGU mice. Thorax 52: 723–730
Bligh EG, Dyer WS 1959 A rapid method of total lipid extraction and purification. Can J Biochem 37: 911–923
Scott BL, Bazan NG 1989 Membrane docosahexaenoate is supplied to the developing brain and retina by the liver. Proc Natl Acad Sci U S A 86: 2903–2907
Davidson DJ, Dorin JR, McLachlan G, Ranaldi V, Lamb D, Doherty C, Govan J, Porteous DJ 1995 Lung disease in the cystic-fibrosis mouse exposed to bacterial pathogens. Nat Genet 9: 351–357
Hubbard VS, Dunn DG, Di Sant'Agnese PA 1977 Abnormal fatty-acid composition of plasma-lipids in cystic fibrosis: a primary or a secondary defect?. Lancet 31: 1302–1304
Rosenlund ML, Kim HK, Kritchevsky D 1974 Essential fatty acids in cystic fibrosis. Nature 251: 719
El Boustani OS, Causse JE, Descomps B, Monnier L, Mendy F, Crastes de Paulet A 1989 Direct in vivo characterization of delta 5 desaturase activity in humans by deuterium labeling: effect of insulin. Metabolism 38: 315–321
Sato S, Ward CL, Krouse ME, Wine JJ, Kopito RR 1995 Glycerol reverses the misfolding phenotype of the most common cystic fibrosis mutation. J Biol Chem 271: 635–638
Cheng SH, Fang SL, Zabner J, Marshall J, Piraino S, Schiavi SC, Jefferson DM, Welsh MJ, Smith AE 1995 Functional activation of the cystic fibrosis trafficking mutant delta-F508-CFTR by overexpression. Am J Physiol 124: L615–L624
Keicher U, Koletzko B, Reinhardt D 1995 Omega-3 fatty acids suppress the enhanced production of 5-lipoxygenase products from polymorph neutrophil granulocytes in cystic fibrosis. Eur J Clin Invest 25: 915–919
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This study was supported by a project grant from the British Lung Foundation (H.D.) and by an equipment grant to purchase the mass spectrometer and for salary support from the Wellcome Trust (G.T.C.).
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Dombrowsky, H., Clark, G., Rau, G. et al. Molecular Species Compositions of Lung and Pancreas Phospholipids in the cftrtm1HGU/tm1HGU Cystic Fibrosis Mouse. Pediatr Res 53, 447–454 (2003). https://doi.org/10.1203/01.PDR.0000049937.30305.8A
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DOI: https://doi.org/10.1203/01.PDR.0000049937.30305.8A
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