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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM033369-03
Application #
3283006
Study Section
Pathobiochemistry Study Section (PBC)
Project Start
1984-12-01
Project End
1988-01-19
Budget Start
1986-12-01
Budget End
1988-01-19
Support Year
3
Fiscal Year
1987
Total Cost
Indirect Cost
Name
Emory University
Department
Type
Schools of Medicine
DUNS #
042250712
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Riley, R T; Wang, E; Schroeder, J J et al. (1996) Evidence for disruption of sphingolipid metabolism as a contributing factor in the toxicity and carcinogenicity of fumonisins. Nat Toxins 4:3-15
Merrill Jr, A H; Wang, E; Vales, T R et al. (1996) Fumonisin toxicity and sphingolipid biosynthesis. Adv Exp Med Biol 392:297-306
Smith, E R; Merrill Jr, A H (1995) Differential roles of de novo sphingolipid biosynthesis and turnover in the ""burst"" of free sphingosine and sphinganine, and their 1-phosphates and N-acyl-derivatives, that occurs upon changing the medium of cells in culture. J Biol Chem 270:18749-58
Schroeder, J J; Crane, H M; Xia, J et al. (1994) Disruption of sphingolipid metabolism and stimulation of DNA synthesis by fumonisin B1. A molecular mechanism for carcinogenesis associated with Fusarium moniliforme. J Biol Chem 269:3475-81
Merrill Jr, A H; Wang, E; Gilchrist, D G et al. (1993) Fumonisins and other inhibitors of de novo sphingolipid biosynthesis. Adv Lipid Res 26:215-34
Merrill Jr, A H; Schroeder, J J (1993) Lipid modulation of cell function. Annu Rev Nutr 13:539-59
Borek, C; Merrill Jr, A H (1993) Sphingolipids inhibit multistage carcinogenesis and protein kinase C. Basic Life Sci 61:367-71
Merrill Jr, A H; van Echten, G; Wang, E et al. (1993) Fumonisin B1 inhibits sphingosine (sphinganine) N-acyltransferase and de novo sphingolipid biosynthesis in cultured neurons in situ. J Biol Chem 268:27299-306
Wu, W I; Lin, Y P; Wang, E et al. (1993) Regulation of phosphatidate phosphatase activity from the yeast Saccharomyces cerevisiae by sphingoid bases. J Biol Chem 268:13830-7
Wang, E; Ross, P F; Wilson, T M et al. (1992) Increases in serum sphingosine and sphinganine and decreases in complex sphingolipids in ponies given feed containing fumonisins, mycotoxins produced by Fusarium moniliforme. J Nutr 122:1706-16

Showing the most recent 10 out of 30 publications