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.

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National Institute of General Medical Sciences (NIGMS)
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Physiological Chemistry Study Section (PC)
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Emory University
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