The deltaF508 mutation in the cystic fibrosis transmembrane conductance regulator alters control of essential fatty acid utilization in epithelial cells
2000
Bhura-Bandali, F.N. | Suh, M. | Man, S.F.P. | Clandinin, M.T.
Essential fatty acid (EFA) incorporation into phospholipid is influenced by chloride channels, suggesting that the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) may regulate aspects of EFA metabolism. The objective of this study was to determine whether the deltaF508 mutation in the CFTR lowers 18:2(n-6) levels in phospholipid. Control cells, CF cells and CF cells transfected with the "normal" CFTR gene or the deltaF508 CFTR gene were cultured for 3-5 d and used to determine [1-14C]18:2(n-6) incorporation into cell lipids. CF cells exhibited low 18:2(n-6) levels in phospholipid, reduced [1-14C]18:2(n-6) incorporation into phospholipid (50% of control) and greater [1-14C]18:2(n-6) incorporation into the triacylglycerol fraction (400% of control; P < 0.05). Kinetic modeling of time course data for [1-14C]18:2(n-6) incorporation revealed a loss of metabolic control over the intracellular partitioning of 18:2(n-6) between phospholipid and triacylglycerol pools in CF cells. Expression of the normal CFTR gene in transfected CF cells increased chloride efflux and the incorporation of [1-14C]18:2(n-6) into phospholipid and triacylglycerol fractions. The increased incorporation of [1-14C]18:2(n-6) into phospholipid was attributed to significantly increased incorporation of [1-14C]18:2(n-6) into phosphatidylcholine and phosphatidylinositol. In CF cells expressing the defective deltaF508 CFTR gene, conversion of [1-14C]18:2(n-6) to 20:4(n-6) by desaturation-chain elongation was 1.8-fold greater (P < 0.05) than observed for CF cells transfected with the normal gene. The observations suggest that CF results in a defect in the utilization of 18:2(n-6), which is attributed in part to the defective CFTR.
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