FTY720/Fingolimod Decreases Hepatic Steatosis and Expression of Fatty Acid Synthase in Diet-Induced Non-Alcoholic Fatty Liver Disease in Mice.

FTY720/Fingolimod Decreases Hepatic Steatosis and Expression of Fatty Acid Synthase in Diet-Induced Non-Alcoholic Fatty Liver Disease in Mice.

Publication date: May 20, 2019

Non-alcoholic 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 pro-drug for 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. 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 (FAS) expression in DIAMOND mice without affecting other key enzymes in lipogenesis. FTY720 had no effect on 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 to attenuate FASN expression and triglyceride accumulation associated with steatosis.

Rohrbach, T.D., Asgharpour, A., Maczis, M.A., Montefusco, D., Cowart, L.A., Bedossa, P., Sanyal, A.J., and Spiegel, S. FTY720/Fingolimod Decreases Hepatic Steatosis and Expression of Fatty Acid Synthase in Diet-Induced Non-Alcoholic Fatty Liver Disease in Mice. 18056. 2019 J Lipid Res.

Concepts Keywords
Acetylation Ceramide
Biosynthesis Sphingosine kinase
Ceramide Sphingolipid
Ceramides Fatty liver disease
Deacetylases Fingolimod
FAS Sphingosine-1-phosphate
Fat Medical specialties
Fatty Acid Synthase Organic compounds
Fatty Liver Branches of biology
Fingolimod Lipids
FTY720 Liver dysfunction
Glucose
Hepatic
Hepatic Steatosis
Histone
Inhibitor
Insulin Resistance
Liver
Mice
Multiple Sclerosis
Phosphate
Phosphorylated
S1P
Species
Sphingolipid
Sphingomyelins
Sphingosine
SREBP
Steatosis
Sugar
Triglyceride
Triglycerides
Vivo

Semantics

Type Source Name
disease DOID Obesity
disease MESH Obesity
gene UNIPROT FASN
gene UNIPROT FAS
drug DRUGBANK Ceramide NP
drug DRUGBANK D-glucose
drug DRUGBANK Dextrose unspecified form
drug DRUGBANK Water
gene UNIPROT CD36
gene UNIPROT FAT1
drug DRUGBANK Palmitic Acid
pathway BSID ceramide biosynthesis
pathway BSID Ceramide biosynthesis
disease DOID multiple sclerosis
disease MESH multiple sclerosis
pathway BSID Insulin resistance
disease MESH insulin resistance
gene UNIPROT MBTPS1
drug DRUGBANK Sphingosine
disease DOID metabolic disease
disease MESH metabolic disease
disease MESH liver dysfunction
disease DOID Non-Alcoholic Fatty Liver Disease
disease MESH Non-Alcoholic Fatty Liver Disease
drug DRUGBANK Fingolimod

Original Article

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