Altered phosphoinositide fatty acid composition, mass and metabolism in brain essential fatty acid deficiency

This study describes the specific alterations in phosphoinositide mass and fatty acid composition observed in brain essential fatty acid deficiency (EFAD). These investigations were motivated by the observation that alterations in volatile anesthetic potency were associated with changes in brain arachidonyl-phosphatidylinositol (PI) content, and were aimed at defining whether EFAD might alter the generation of chemical second messengers via the PI cycle. Analyses of cerebral cortical phosphoinositide mass and fatty acid composition showed that EFAD results in specific and preferential depletion of arachidonate (20:4(n - 6); 5,8,11,14-eicosatetraenoic acid) from cerebral cortical polyphosphoinositides, and that this depletion is reversed by parenteral supplementation with linoleic acid (18:2(n - 6); 9,12-octadecadienoic acid). These analyses also showed that, while phosphoinositides containing 20:3(n - 9) (5,8,11-eicosatrienoic acid) accumulated in EFAD, linoleate supplementation decreased 20:3(n - 9)-PI and 20:3(n - 9)-phosphatidylinositol 4-phosphate (PIP), but resulted in accumulation of 20:3(n - 9)-phosphatidylinositol 4,5-bisphosphate (PIP2). Comparison of the fatty acid composition of brain polyphosphoinositides and 1,2-diacylglycerols between treatment groups showed that diacylglycerols contain a lower molar percentage of 20:3(n - 9) and a higher percentage of arachidonate than the corresponding polyphosphoinositides. The combined results of these studies suggest the existence of fatty acid substrate specificity for the hydrolysis of PIP2 by phospholipase C. The biological relevance of these findings is suggested by a strong correlation between the mass of cerebral cortical arachidonyl-PIP2 and the potency of the anesthetic halothane.