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

Department of Pathology, The Vanderbilt Clinic, Nashville, TN 37232

Corresponding Author: 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 cystic fibrosis. CF (antisense) cells demonstrated decreased levels of LA and DHA compared to wild type (WT, sense) cells expressing normal CFTR. Cellular uptake of LA and DHA was higher in CF cells compared to WT cells at 1 hour and 4 hours. 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.

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