Experiments are proposed to characterize sphingolipid biosynthesis and its regulation by cells in culture. These studies will focus on the metabolism of the long-chain base moiety of the sphingolipids and the relationship between the regulation of long-chain base synthesis and the levels of sphingomyelin and other lipids in the cells. Factors that are predicted to influence long-chain base metabolism are 1) the demand for more sphingolipids by growing cells or cells with rapid lipid synthesis and/or turnover; 2) the uptake of long-chain bases from the medium (probably via lipoproteins) which, if they are reutilized, might inhibit their biosynthesis de novo; 3) the treatment of the cells with glucocorticoids, which increase sphingomyelin synthesis; and 4) suicide inhibitors for serine palmitoyltransferase, the initial and committed reaction of long-chain base formation. Each of these will be tested by measuring the effects of such variables on long-chain base synthesis and degradation, the lipid composition of the cells, and the activities of the enzymes of long-chain base synthesis. For most of these investigations, rat liver and isolated hepatocytes and Chinese hamster ovary cells will be studied. To enable the interpretation of the effects of lipoproteins on long-chain base metabolism, the extent to which these molecules are taken up and reutilized by the cells will also be assessed. These studies will add substantially to our understanding of sphingolipid metabolism and its regulation. Such understanding could be important to the treatment of diseases caused by excessive accumulation of sphingolipids, and to the understanding of diseases for which sphingolipid levels are elevated (such as some tumors, atherosclerosis, some mental diseases, muscular dystrophy, inter alia) but for which the cause of this elevation is not understood.
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