Ceramide synthase inhibition by fumonisin B1 treatment activates sphingolipid-metabolizing systems in mouse liver

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 B-1, 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 B-1 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 B-1 in mice. The activity of acidic SMase was enhanced by fumonisin B-1, accompanied with a decrease in liver SM content. The expression and activities of SPT and SPHK1 in liver increased significantly following fumonisin B-1 treatment. Another hepatotoxicant acetaminophen caused liver regeneration similar to fumonisin B-1 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 B-1 treatment stimulates sphingolipid-metabolizing systems to maintain a balance of cellular sphingolipids.