We describe a patient who presented shortly after birth with hyperkinetic behaviour, myoclonia, respiratory insufficiency and hepatosplenomegaly. Gaucher-like storage cells were found in bone marrow. A liver biopsy showed massive lysosomal storage morphologically different to that in known lipid storage disorders. Biochemically, the patient had partial deficiencies of beta-galactocerebrosidase, beta-glucocerebrosidase and ceramidase in skin fibroblast extracts, but the sphingomyelinase activity was normal. Glucosyl ceramide and ceramide were elevated in liver tissue. Loading of cultured fibroblasts with radioactive sphingolipid precursors indicated a profound defect in ceramide catabolism. Immunological studies in fibroblasts showed a total absence of cross-reacting material to sphingolipid activator protein 2 (SAP-2). The patient died at 16 weeks of age. The fetus from his mother's next pregnancy was similarly affected. The possibility that the disorder results from a primary defect at the level of SAP-2 is discussed. We have named this unique disorder SAP deficiency.

Arachidonic acid (20:4(n-6)), which is released by cells responding to a wide range of stimuli, may play an important role in intracellular signaling. We now report that incubation of WB cells with 20:4(n-6) resulted in the appearance of several tyrosine-phosphorylated cytosolic proteins. Two of the phosphotyrosine-containing proteins, migrating in SDS-polyacrylamide gels of approximately 43 and 45 kDa, corresponded in mobility to phosphorylated species of the 42- and 44-kDa mitogen-activated protein kinase (MAPK) isoforms. Immunoblots of soluble fractions from unstimulated WB cells with anti-MAPK antibodies revealed the presence of the 42- and 44-kDa isoforms of MAPK. Upon incubation with 20:4(n-6), the mobility of both isoforms was retarded, consistent with their activation by phosphorylation. Chromatography of soluble fractions from these cells on Mono Q columns revealed early and late eluting peaks of myelin basic protein kinase activity, which contained the 42- and 44-kDa MAPK isoforms, respectively. Activation of MAPK was transient, peaking at 5 min, and was detectable at 5 microM 20:4(n-6). Further studies into the mechanisms by which MAPK was activated by 20:4(n-6) strongly suggested the involvement of protein kinase C (PKC). Not only did incubation of WB cells with 20:4(n-6) result in the translocation of PKC alpha, delta, and epsilon to a particulate fraction, it was found that the fatty acid failed to activate MAPK in cells pretreated for 26 h with phorbol 12-myristate 13-acetate, which depleted WB cells of PKC alpha, delta and epsilon. In addition, fatty acids of the n-3 series were effective activators of MAPK. The present study, to our knowledge, is the first to report that polyunsaturated fatty acids can cause the activation of MAPK.

Fatty acids with greater than 22 carbon atoms (very long chain fatty acids, VLCFA) are present in small amounts in most animal tissues. Saturated and monoenoic VLCFA are major components of brain, while the polyenoic VLCFA occur in significant amounts in certain specialized animal tissues such as retina and spermatozoa. Biosynthesis of VLCFA occurs by carbon chain elongation of shorter chain fatty acid precursors while beta-oxidation takes place almost exclusively in peroxisomes. Mitochondria are unable to oxidize VLCFA because they lack a specific VLCFA coenzyme A synthetase, the first enzyme in the beta-oxidation pathway. VLCFA accumulate in the tissues of patients with inherited abnormalities in peroxisomal assembly, and also in individuals with defects in enzymes catalyzing individual reactions along the beta-oxidation pathway. It is believed that the accumulation of VLCFA in patient tissues contributes to the severe pathological changes which are a feature of these conditions. However, little is known of the role of VLCFA in normal cellular processes, and of the molecular basis for their contribution to the disease process. The present review provides an outline of the current knowledge of VLCFA including their biosynthesis, degradation, possible function and involvement in human disease.

The polyunsaturated fatty acids docosahexaenoic acid (C22.,63), eicosapentaenoic acid, arachidonic acid, and linoleic acid caused marked in vitro growth inhibition of Plasmodium falciparum, assessed by a radiometric assay. In contrast, negligible parasite killing was seen with oleic acid or docosanoic acid. Parasite killing was significantly increased when oxidized forms of polyunsaturated fatty acids were used. Antioxidants greatly reduced the fatty acid-induced killing. Mice infected with P. berghei and treated for 4 d with C22:6,,.3 showed marked reduction in parasitemia. The anemia associated with the infection was also alleviated by treatment with C22A6,,3. The data provide new information that could be explored in order to develop new strategies in malaria treatment. (J. Clin. Invest. 1992. 89:961-967.)

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Although unesterified polyunsaturated fatty acids (PUFA) have been shown to elicit marked changes in neutrophil function, the associated signal transduction processes require clarification. In this study we examined the effect of PUFA on the sphingomyelin (SM)‐signalling cycle in human neutrophils. Treatment of neutrophils with eicosatetraenoic acid [ arachidonic acid, 20:4(n‐6)] caused a decrease in the mass of cellular SM and an increase in the level of ceramide. 20:4(n‐6)‐stimulated neutral sphingomyelinase (SMase) activity of the leucocytes in a time‐ and concentration‐dependent manner. Other unsaturated fatty acids, docosahexaenoic [22:6(n‐3)], eicosapentaenoic [20:5(n‐3)], octadecenoic [oleic, 18:1(n‐9)] and octadecadienoic [linoleic, 18:2(n‐6)] acids also had the capacity to activate neutral SMase; however, certain 20:4(n‐6) derivatives {20:4(n‐6) methyl ester [20:4(n‐6)ME], 15‐hydroperoxyeicosatetraenoic (15‐HPETE) and 15‐hydroxyeicosatetraenoic (15‐HETE) acids}, very‐long‐chain PUFA {tetracosatetraenoic [24:4(n‐6)] and octacosatetraenoic [28:4(n‐6)] acids} and saturated fatty acids [octadecanoic (stearic, 18:0) and eicosanoic (arachidic, 20:0) acids] had no significant effect. Activation of neutral SMase by 20:4(n‐6) appeared to involve metabolism via 20:4(n‐6)CoA (arachidonoyl CoA) and was not dependent on prostaglandin and leukotriene synthesis. All of the fatty acids and derivatives tested failed to activate acidic SMase of neutrophils. Ceramide was found to inhibit 20:4(n‐6)‐induced superoxide generation by the cells. It is envisaged that the PUFA‐induced ceramide production in neutrophils plays a role in the regulation of biological responses.

The high levels of very long chain fatty acids found in ram spermatozoa are located almost exclusively in one of two separable species of sphingomyelin. Mass spectral analysis, including fast atom bombardment of the purified sphingomyelin, has shown the fatty acids to have a carbon chain length of between 28 and 34, with between four and six double bonds, and to belong predominantly to the n-3 series.