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ToxSci Advance Access originally published online on September 7, 2006
Toxicological Sciences 2006 94(2):388-397; doi:10.1093/toxsci/kfl102
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© The Author 2006. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Ceramide Synthase Inhibition by Fumonisin B1 Treatment Activates Sphingolipid-Metabolizing Systems in Mouse Liver

Quanren He1, Hirofumi Suzuki, Neelesh Sharma and Raghubir P. Sharma

Department of Physiology and Pharmacology, College of Veterinary Medicine, The University of Georgia, Athens, Georgia 30602-7389

Received July 20, 2006; accepted August 29, 2006

Sphingolipids are important components of cell structure and cell signaling. Both external and internal stimuli can alter levels of cellular sphingolipids by regulating enzyme activities associated with sphingolipid metabolism. Fumonisin B1, mycotoxin produced by Fusarium verticillioides, is a reportedly specific inhibitor of ceramide synthase. In order to test our hypothesis whether ceramide synthase inhibition by fumonisin B1 alters other sphingolipid-metabolizing enzymes, we investigated the changes in free sphingoid bases and sphingomyelin (SM) and activities of key enzymes for their metabolism, sphingomyelinase (SMase), serine palmitoyltransferase (SPT), and sphingosine kinase (SPHK) in mouse liver. The hepatic free sphingoid bases increased significantly following five daily treatments with fumonisin B1 in mice. The activity of acidic SMase was enhanced by fumonisin B1, accompanied with a decrease in liver SM content. The expression and activities of SPT and SPHK1 in liver increased significantly following fumonisin B1 treatment. Another hepatotoxicant acetaminophen caused liver regeneration similar to fumonisin B1 but did not produce similar effects on liver sphingolipid-metabolizing enymes, suggesting that activation of sphingolipid metabolism was not a consequence of hepatocye regeneration. Data suggest that ceramide synthase inhibition by fumonisin B1 treatment stimulates sphingolipid-metabolizing systems to maintain a balance of cellular sphingolipids.

Key Words: sphingomyelinase; fumonisin; sphingolipid; sphingosine kinase; serine palmitoyltransferase.


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