Document Type
Article
Department/Program
General Education
Journal Title
Journal of Lipid Research
Pub Date
2-2020
Publisher
ASBMB Publications
Volume
63
Issue
3
Journal Article URL
https://doi.org/10.1194/jlr.M093799
First Page
1311
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.
Abstract
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.
Keywords: lipogenesis; sphingolipids; sphingosine-1-phosphate.
Recommended Citation
Rohrbach, Timothy D.; Asgharpour, Amon; Maczis, Melizza A.; Montefusco, David; Cowart, Ashley; Bedossa, Pierre; Sanyal, Arun J.; and Spiegel, Sarah, "FTY720/fingolimod decreases hepatic steatosis and expression of fatty acid synthase in diet-induced nonalcoholic fatty liver disease in mice" (2020). Richard Bland Faculty Works. 13.
https://scholarworks.wm.edu/rbc_facwork/13
DOI
https://doi.org/10.1194/jlr.M093799
