FTY720/fingolimod decreases hepatic steatosis and expression of fatty acid synthase in diet-induced nonalcoholic fatty liver disease in mice

• DOI: 10.1194/jlr.m093799
• Publication Date: 2019-05-20T19:29:02Z
• Authors: Timothy D. Rohrbach; Amon Asgharpour; Melissa A. Maczis; David Montefusco; L. Ashley Cowart; Pierre Bedossa; Arun J. Sanyal; Sarah Spiegel
• Keywords: Steatosis; Lipogenesis; Sphingolipid; Sphingomyelin phosphodiesterase; Ceramide synthase

Nonalcoholic fatty liver disease (NAFLD), a leading cause of dysfunction, is metabolic that begins with steatosis. Sphingolipid metabolites, particularly ceramide and sphingosine-1-phosphate (S1P), have recently received attention for their potential roles in insulin resistance hepatic FTY720/fingolimod, prodrug the treatment multiple sclerosis, phosphorylated vivo to its active form by sphingosine kinase 2 has been shown interfere actions S1P inhibit biosynthesis. Therefore, this study we investigated effects FTY720 diet-induced animal model NAFLD (DIAMOND) recapitulates hallmarks human disease. The oral administration these mice fed high-fat diet sugar water improved glucose tolerance reduced In addition decreasing triglycerides, also sphingolipid levels, including ceramides, monohexosylceramides, sphingomyelins, C16:0 C24:1 species, as well dihydro-S1P. decreased acid synthase (FASN) expression DIAMOND without affecting other key enzymes lipogenesis. had no effect on SREBP-1c, which transcriptionally activates FASN. However, agreement notion an inhibitor histone deacetylases, FTY720-P accumulated liver, H3K9 acetylation was markedly increased mice. Hence, might be useful attenuating FASN triglyceride accumulation associated Erratum: FTY720/fingolimod decreases steatosis nonalcoholic miceJournal Lipid ResearchVol. 61Issue 2PreviewVOL 60 (2019) PAGES 1311–1322 Full-Text PDF Open Access (NAFLD) encompasses spectrum states defined occurring absence alcohol abuse (1Satapathy S.K. Sanyal A.J. Epidemiology natural history disease.Semin. 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Isogenic derived C57BL/6J 129S1/SvImJ backgrounds (B6/129) kindly provided Dr. Sandra Erickson (UCSF) maintained inbreeding previously described housed under 12-h light/12-h dark cycle 21–23°C facility. All procedures Animal Care Use Committee Virginia Commonwealth University. Genome-wide mapping revealed striking differences control female male (36Norheim Hui Kulahcioglu Mehrabian Cantor R.M. Pan Parks B.W. Lusis Genetic hormonal 58: 178-187Abstract (34) Female because severity HFD-induced precludes interrogation pathogenesis sex-independent manner. standard chow (CD; Harlan TD.7012) until reaching 12 weeks age unless indicated otherwise. Mice then high-fat, high-carbohydrate (Harlan TD.88137) 42% kcal milk 0.1% cholesterol (Western diet; WD) 16 weeks. Drinking contained amount fructose (23.1 g/l) (18.9 (sugar water; SW) Both food ad libitum. (0.3 mg/kg; Cayman Chemical #10006292) vehicle (saline) administered gavage three times week throughout 16-week HFD. 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