Premium
FTY720/Fingolimod Reduces Steatosis in a Murine Model of Non‐Alcoholic Fatty Liver Disease
Author(s) -
Rohrbach Timothy D,
Asgharpour Amon,
Avni Dorit,
Cazanave Sophie C,
Bedossa Pierre,
Sanyal Arun J,
Spiegel Sarah D
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.870.7
Subject(s) - steatosis , sphingolipid , ceramide , fatty liver , nonalcoholic fatty liver disease , medicine , steatohepatitis , endocrinology , insulin resistance , sphingosine , cirrhosis , alcoholic liver disease , liver disease , pharmacology , biology , insulin , biochemistry , disease , apoptosis , receptor
Non‐alcoholic fatty liver disease (NAFLD) is a metabolic disease characterized by a spectrum of related liver disorders. Liver steatosis is an early initiator of NAFLD followed by the development of nonalcoholic steatohepatitis. Approximately 30% of adults in the United States are affected by NAFLD and although obesity and insulin resistance are risk factors for NAFLD, there is currently no approved therapy for this disease. To make matters worse, NAFLD can progress to liver cirrhosis and ultimately hepatocellular carcinoma. 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, an FDA approved 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 inhibits several sphingolipid metabolic enzymes. Therefore, in this study we investigated its effect in the C57BL/6 x 129S murine model of NAFLD. Mice were fed a high fat diet (42% kcal from fat) with sugar water (HFD+SW) for 16 weeks with concurrent oral administration of a clinically relevant dose of FTY720 (0.3 mg/kg). FTY720 significantly decreased liver lipid accumulation and steatosis. Mass spectrometry analysis confirmed that FTY720 was phosphorylated to its active form, FTY720‐phosphate. Although levels of S1P and monohexosylceramide were significantly decreased in blood by administration of FTY720, no major changes in ceramide were detected. Moreover, liver sphingolipid levels including ceramide, monohexosylceramide, sphingomyelin, dihydroceramide, dihydromonohexosylceramide, and dihydrosphingomyelin were all decreased (p < 0.05) by FTY720 treatment. Additionally, FTY720 treatment caused a significant decrease in activation of Akt known to play a critical role in steatosis. Taken together, these findings support the notion that targeting sphingolipid metabolism could lead to reduced hepatic steatosis. Support or Funding Information Supported by NIH T32 Training Grant 5T32DK007150‐39.