Home LiteratureArticle Details
PMID: 10570187 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

A membrane lipid imbalance plays a role in the phenotypic expression of cystic fibrosis in cftr(-/-) mice.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 96 ·No. 24 ·1999-11-23 ·Pages 13995-4000

Freedman SD, Katz MH, Parker EM, Laposata M, Urman MY, Alvarez JG

Abstract

A deficiency in essential fatty acid metabolism has been reported in plasma from patients with cystic fibrosis (CF). However, its etiology and role in the expression of disease is unknown. The objective of this study was to determine whether alterations in fatty acid metabolism are specific to CF-regulated organs and whether they play a role in the expression of disease. A membrane lipid imbalance was found in ileum, pancreas, and lung from cftr(-/-) mice characterized by an increase in phospholipid-bound arachidonic acid and a decrease in phospholipid-bound docosahexaenoic acid (DHA). This lipid imbalance was observed in organs pathologically affected by CF including lung, pancreas, and ileum and was not secondary to impaired intestinal absorption or hepatic biosynthesis of DHA. As proof of concept, oral administration of DHA to cftr(-/-) mice corrected this lipid imbalance and reversed the observed pathological manifestations. These results strongly suggest that certain phenotypic manifestations of CF may result from remediable alterations in phospholipid-bound arachidonic acid and DHA levels.

MeSH Terms
Administration, Oral Animals Arachidonic Acid/metabolism,physiology Cystic Fibrosis/pathology Cystic Fibrosis Transmembrane Conductance Regulator/genetics,physiology Docosahexaenoic Acids/administration & dosage,metabolism Ileum/metabolism,pathology Intestinal Absorption Lipopolysaccharides/immunology,pharmacology Liver/metabolism Lung/metabolism,pathology Membrane Lipids/metabolism,physiology Mice Mice, Inbred C57BL Mice, Knockout Pancreas/metabolism,pathology Phenotype Phospholipids/metabolism,physiology Pneumonia Pseudomonas/immunology
Chemicals
Lipopolysaccharides Membrane Lipids Phospholipids Cystic Fibrosis Transmembrane Conductance Regulator Docosahexaenoic Acids Arachidonic Acid
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Freedman S D
Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Katz M H
Parker E M
Laposata M
Urman M Y
Alvarez J G
References (46)
46 references, click to expand
  1. Fatty acid supplementation in cystic fibrosis.
    Monogr Paediatr. 1979;10:1-4 PMID: 460262
  2. The effects of dietary lipids on gene expression and apoptosis.
    Proc Nutr Soc. 1998 Nov;57(4):543-50 PMID: 10096114
  3. Prostaglandins, arachidonic acid, and inflammation.
    Science. 1980 Nov 28;210(4473):978-84 PMID: 6254151
  4. Essential fatty acid status in cystic fibrosis and the effects of safflower oil supplementation.
    Am J Clin Nutr. 1981 Jan;34(1):1-7 PMID: 7446449
  5. Essential fatty acid deficiency in the rabbit as a model of nutritional impairment in cystic fibrosis. In vitro and in vivo effects on lung defense mechanisms.
    Am Rev Respir Dis. 1982 Sep;126(3):540-7 PMID: 7125341
  6. Cystic fibrosis and pseudomonas infection.
    Lancet. 1983 Jul 30;2(8344):257-8 PMID: 6135081
  7. Abnormal fatty acid turnover in the phospholipids of the red blood cell membranes of cystic fibrosis patients (in vitro study).
    Pediatr Res. 1984 Aug;18(8):704-9 PMID: 6472942
  8. Fatty acid abnormalities in cystic fibrosis.
    Pediatr Res. 1985 Jan;19(1):104-9 PMID: 3918287
  9. A new, rapid, method for preparation of dispersed pancreatic acini.
    Biochem J. 1985 Mar 1;226(2):621-4 PMID: 2581556
  10. Dietary essential fatty acids in cystic fibrosis.
    Pediatrics. 1977 Mar;59(3):428-32 PMID: 840562
  11. Membrane lipid composition and cellular function.
    J Lipid Res. 1985 Sep;26(9):1015-35 PMID: 3906008
  12. Increased mole fraction of arachidonic acid in bronchial phospholipids in patients with cystic fibrosis.
    Scand J Clin Lab Invest. 1986 Oct;46(6):511-8 PMID: 3775237
  13. The essential fatty acid deficient chicken as a model for cystic fibrosis.
    Am J Clin Nutr. 1986 Dec;44(6):816-24 PMID: 3466523
  14. Membrane docosahexaenoate is supplied to the developing brain and retina by the liver.
    Proc Natl Acad Sci U S A. 1989 Apr;86(8):2903-7 PMID: 2523075
  15. Regulation of chloride channels by protein kinase C in normal and cystic fibrosis airway epithelia.
    Science. 1989 Jun 16;244(4910):1353-6 PMID: 2472006
  16. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA.
    Science. 1989 Sep 8;245(4922):1066-73 PMID: 2475911
  17. Identification of the cystic fibrosis gene: genetic analysis.
    Science. 1989 Sep 8;245(4922):1073-80 PMID: 2570460
  18. Changes in phospholipid fatty acid composition of mouse cardiac organelles after feeding graded amounts of docosahexaenoate in presence of high levels of linoleate. Effect on cardiac ATPase activities.
    Ann Nutr Metab. 1989;33(3):125-42 PMID: 2529810
  19. A comparison of the effects of linolenic (18:3 omega 3) and docosahexaenoic (22:6 omega 3) acids on phospholipid bilayers.
    Chem Phys Lipids. 1990 May;54(2):79-88 PMID: 2142021
  20. Localization of the cystic fibrosis transmembrane conductance regulator in pancreas.
    J Clin Invest. 1991 Aug;88(2):712-6 PMID: 1713921
  21. Regulation of plasma membrane recycling by CFTR.
    Science. 1992 Apr 24;256(5056):530-2 PMID: 1373908
  22. Cystic fibrosis: molecular biology and therapeutic implications.
    Science. 1992 May 8;256(5058):774-9 PMID: 1375392
  23. An animal model for cystic fibrosis made by gene targeting.
    Science. 1992 Aug 21;257(5073):1083-8 PMID: 1380723
  24. Separation of acidic and neutral lipids by aminopropyl-bonded silica gel column chromatography.
    J Chromatogr. 1992 May 20;577(1):142-5 PMID: 1328266
  25. Docosahexaenoic acid increases permeability of lipid vesicles and tumor cells.
    Lipids. 1993 Feb;28(2):103-8 PMID: 8441334
  26. Relationship of a non-cystic fibrosis transmembrane conductance regulator-mediated chloride conductance to organ-level disease in Cftr(-/-) mice.
    Proc Natl Acad Sci U S A. 1994 Jan 18;91(2):479-83 PMID: 7507247
  27. Oral absorption of omega-3 fatty acids in patients with cystic fibrosis who have pancreatic insufficiency and in healthy control subjects.
    J Pediatr. 1994 Mar;124(3):400-8 PMID: 8120709
  28. Effects of fatty acids on gene expression mediated by a member of the nuclear receptor supergene family.
    Prog Clin Biol Res. 1994;387:21-8 PMID: 7972247
  29. Time- and voltage-dependent block of delayed rectifier potassium channels by docosahexaenoic acid.
    Mol Pharmacol. 1995 Feb;47(2):381-90 PMID: 7870048
  30. Effects of docosahexaenoic acid (DHA) on intestinal polyp development in Apc delta 716 knockout mice.
    Carcinogenesis. 1995 Nov;16(11):2605-7 PMID: 7586174
  31. Differential incorporation of fatty acids into and peroxidative loss of fatty acids from phospholipids of human spermatozoa.
    Mol Reprod Dev. 1995 Nov;42(3):334-46 PMID: 8579848
  32. Evidence that free polyunsaturated fatty acids modify Na+ channels by directly binding to the channel proteins.
    Proc Natl Acad Sci U S A. 1996 Apr 16;93(8):3542-6 PMID: 8622972
  33. Distribution of cAMP-activated chloride current and CFTR mRNA in the guinea pig heart.
    Circ Res. 1996 Aug;79(2):201-7 PMID: 8755996
  34. Pancreatic dysfunction in cystic fibrosis occurs as a result of impairments in luminal pH, apical trafficking of zymogen granule membranes, and solubilization of secretory enzymes.
    Pancreas. 1996 Jan;12(1):1-9 PMID: 8927611
  35. Phenotypic abnormalities in long-term surviving cystic fibrosis mice.
    Pediatr Res. 1996 Aug;40(2):233-41 PMID: 8827771
  36. The use of an intravenous fish oil emulsion enriched with omega-3 fatty acids in patients with cystic fibrosis.
    Nutrition. 1996 May;12(5):334-9 PMID: 8875517
  37. Docosahexaenoic acid block of neuronal voltage-gated K+ channels: subunit selective antagonism by zinc.
    Neuropharmacology. 1996;35(7):969-82 PMID: 8938727
  38. The biogenesis, traffic, and function of the cystic fibrosis transmembrane conductance regulator.
    Int Rev Cytol. 1997;172:193-241 PMID: 9102394
  39. Suppression of voltage-gated L-type Ca2+ currents by polyunsaturated fatty acids in adult and neonatal rat ventricular myocytes.
    Proc Natl Acad Sci U S A. 1997 Apr 15;94(8):4182-7 PMID: 9108126
  40. Effect of docosahexaenoic acid on mouse mitochondrial membrane properties.
    Lipids. 1997 May;32(5):497-506 PMID: 9168456
  41. Immuno and functional characterization of CFTR in submandibular and pancreatic acinar and duct cells.
    Am J Physiol. 1997 Aug;273(2 Pt 1):C442-55 PMID: 9277342
  42. Excessive inflammatory response of cystic fibrosis mice to bronchopulmonary infection with Pseudomonas aeruginosa.
    J Clin Invest. 1997 Dec 1;100(11):2810-5 PMID: 9389746
  43. Essential fatty acid deficiency in well nourished young cystic fibrosis patients.
    Eur J Pediatr. 1997 Dec;156(12):952-6 PMID: 9453380
  44. Dietary supplementation with eicosapentaenoic and docosahexaenoic acid inhibits growth of Morris hepatocarcinoma 3924A in rats: effects on proliferation and apoptosis.
    Int J Cancer. 1998 Mar 2;75(5):699-705 PMID: 9495237
  45. Effect of docosahexaenoic acid on intracellular calcium dynamics in vascular smooth muscle cells from normotensive and genetically hypertensive rats.
    Res Commun Mol Pathol Pharmacol. 1998 Oct;102(1):29-42 PMID: 9920344
  46. Intravenous linoleic acid supplementation in children with cystic fibrosis.
    Pediatrics. 1979 Aug;64(2):207-13 PMID: 382082
Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.96.24.13995
Published
1999-11-23
Pages
13995-4000
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC24179
Subset
IM
Grants
NIDDK NIH HHS · R01 DK052765 · United States
NIDDK NIH HHS · R01 DK-52765 · United States
External Links
PubMed source DOI: 10.1073/pnas.96.24.13995 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2