Nonalcoholic fatty liver disease (NAFLD), a leading cause of liver dysfunction, 
is a metabolic disease that begins with steatosis. Sphingolipid metabolites, 
particularly ceramide and sphingosine-1-phosphate (S1P), have recently received 
attention for their potential roles in insulin resistance and hepatic steatosis. 
FTY720/fingolimod, a prodrug for the treatment of multiple sclerosis, is 
phosphorylated in vivo to its active phosphorylated form by sphingosine kinase 2 
and has been shown to interfere with the actions of S1P and to inhibit ceramide 
biosynthesis. Therefore, in this study we investigated the effects of FTY720 in 
a diet-induced animal model of NAFLD (DIAMOND) that recapitulates the hallmarks 
of the human disease. The oral administration of FTY720 to these mice fed a 
high-fat diet and sugar water improved glucose tolerance and reduced steatosis. 
In addition to decreasing liver triglycerides, FTY720 also reduced hepatic 
sphingolipid levels, including ceramides, monohexosylceramides, and 
sphingomyelins, particularly the C16:0 and C24:1 species, as well as S1P and 
dihydro-S1P. FTY720 administration decreased diet-induced fatty acid synthase 
(FASN) expression in DIAMOND mice without affecting other key enzymes in 
lipogenesis. FTY720 had no effect on the expression of SREBP-1c, which 
transcriptionally activates FASN. However, in agreement with the notion that the 
active phosphorylated form of FTY720 is an inhibitor of histone deacetylases, 
FTY720-P accumulated in the liver, and histone H3K9 acetylation was markedly 
increased in these mice. Hence, FTY720 might be useful for attenuating FASN 
expression and triglyceride accumulation associated with steatosis.