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Journal of Lipid Research, Vol. 49, 1946-1954, September 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

A mechanism accounting for the low cellular level of linoleic acid in cystic fibrosis and its reversal by DHA^*

M. Rabie Al-Turkmani^*, Charlotte Andersson, Ragheed Alturkmani^*, Waddah Katrangi^*, Joanne E. Cluette-Brown^*, Steven D. Freedman and Michael Laposata^1,*

^* Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114
Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215

^* This study was funded by National Institutes of Health Grant R01 DK-52765 (S.D.F.) and The Cystic Fibrosis Foundation (Grant FREEDM06A0) (S.D.F.).

Published, JLR Papers in Press, May 14, 2008.

¹ To whom correspondence should be addressed. e-mail: michael.laposata{at}vanderbilt.edu

Specific fatty acid alterations have been described in the blood and tissues of cystic fibrosis (CF) patients. The principal alterations include decreased levels of linoleic acid (LA) and docosahexaenoic acid (DHA). We investigated the potential mechanisms of these alterations by studying the cellular uptake of LA and DHA, their distribution among lipid classes, and the metabolism of LA in a human bronchial epithelial cell model of CF. CF (antisense) cells demonstrated decreased levels of LA and DHA compared with wild type (WT, sense) cells expressing normal CFTR. Cellular uptake of LA and DHA was higher in CF cells compared with WT cells at 1 h and 4 h. Subsequent incorporation of LA and DHA into most lipid classes and individual phospholipids was also increased in CF cells. The metabolic conversion of LA to n-6 metabolites, including 18:3n-6 and arachidonic acid, was upregulated in CF cells, indicating increased flux through the n-6 pathway. Supplementing CF cells with DHA inhibited the production of LA metabolites and corrected the n-6 fatty acid defect. In conclusion, the evidence suggests that low LA level in cultured CF cells is due to its increased metabolism, and this increased LA metabolism is corrected by DHA supplementation.

Supplementary key words arachidonic acid • docosahexaenoic acid • fatty acid alterations • lipid classes • n-6 pathway • phospholipids • supplementation • uptake

Abbreviations: AA, arachidonic acid; CE, cholesteryl ester; CF, cystic fibrosis; CFTR, cystic fibrosis transmembrane conductance regulator; DHA, docosahexaenoic acid; FAME, fatty acid methyl ester; LA, linoleic acid; PC, phosphatidylcholine; PE, phosphatidylethanolamine; PI, phosphatidylinositol; PL, phospholipid; PS, phosphatidylserine; TG, triglyceride; WT, wild type

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