Abstract

Sphingosine and other long-chain bases are the backbones of sphingolipids, which are major components of membranes, lipoproteins, and milk. Sphingolipids participate in membrane structure and function, and are often associated with pathological states (eg., tumors and atherosclerotic plaques). Free long-chain bases may also serve as regulators of protein kinase C and processes dependent on this enzyme. Although the major enzymes of long-chain base metabolism were discovered over a decade ago, many important aspects of this pathway are still not known. In particular, there have been few studies with hepatocytes, even through liver makes sphingolipids for cellular membranes and lipoproteins and must handle large amounts of sphingolipids taken up from circulation. This proposal involves two complementary investigations central to understanding long-chain base metabolism: 1) the characterization of long-chain base formation and incorporation into hepatocyte membranes and lipoproteins, and 2) the analysis of long-chain base uptake and metabolism by these cells. These studies will provide new information about the regulation of this pathway and the relationship between the uptake of long-chain bases from circulation and their biosynthesis de novo. In addition, they will determine the occurrence of free long-chain bases in cells under different conditions, which could be important to understanding their potential role as regulators of protein kinase C.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM033369-08
Application #
3283010
Study Section
Physiological Chemistry Study Section (PC)
Project Start
1984-12-01
Project End
1993-06-30
Budget Start
1992-01-01
Budget End
1993-06-30
Support Year
8
Fiscal Year
1992
Total Cost
Indirect Cost

  Institution

Name
Emory University
Department
Type
Schools of Medicine
DUNS #
042250712
City
Atlanta
State
GA
Country
United States
Zip Code
30322

  Publications

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

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