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

Abstract

Supplementary key words lipogenesis • sphingolipids • sphingosine-1phosphateNonalcoholic fatty liver disease (NAFLD) encompasses a spectrum of disease states defined by hepatic steatosis occurring in the absence of alcohol abuse (1). Steatosis is the initial stage of NAFLD, in which lipid droplets form and accumulate in the liver (2). This stage can be self-limiting; however, steatosis can progress to more aggressive liver injury, inflammation, and fibrosis in the form of nonalcoholic steatohepatitis (NASH) (3). NASH can progress to cirrhosis, end-stage liver disease, or hepatocellular carcinoma (4). Caloric excess, associated with obesity, insulin resistance, and dyslipidemia, has been implicated in the development of NAFLD (5), and it is estimated that about a third of the US population has NAFLD (6). Approximately 30% to 50% of NAFLD patients have NASH at the time of diagnosis (7) and, unfortunately, however, there are currently no approved therapies (8).The oversupply of nutrients due to obesogenic diet consumption alters many aspects of cellular metabolism, including the biosynthesis of lipids (9). Several lipid mediators typically associated with lipotoxicity, such as diacylglycerols, free fatty acids, oxysterols, and more recently, sphingolipids, have been linked to the progression of steatosis to NASH (9-11). It has been suggested that the bioactive sphingolipid ceramide contributes to insulin 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 a...

FTY720 ameliorates GvHD by blocking T lymphocyte migration to target organs and by skin fibrosis inhibition

“…[13] FTY720 inhibited expression of the cytokines that have been shown to play a role in liver fibrosis in the mice model of diet-induced non-alcoholic fatty liver disease while FTY720 only had a minimal effect on inflammation. [14] Early administration of FTY720 inhibited the severity and fibrosis in murine sclerodermatous chronic GvHD through decreasing soluble collagen and dermal thickness. [15] In a recent study, FTY720 was found to directly and specifically target various phenotypes of hypertrophic scarring fibroblasts (HSFs), suppressing the expression of fibrotic markers such as α-smooth muscle actin (α-SMA) and collagen, effectively suppressing HSF activation [16].…”

Multiple Sclerosis: Melatonin, Orexin, and Ceramide Interact with Platelet Activation Coagulation Factors and Gut-Microbiome-Derived Butyrate in the Circadian Dysregulation of Mitochondria in Glia and Immune Cells

“…The BMI in MS modulates ceramide-induced DNA methylation and disease course, via increased levels of monocytes [78]. Gut-derived butyrate is significantly decreased in obesity, and is an important driver of the alterations in the gut–liver axis that underpin obesity, non-alcoholic fatty liver disease, and wider metabolic dysregulation [79], all of which may be suppressed by fingolimod, suggesting unrecognized gut microbiome, butyrate/HDAC inhibitory-like effects of this drug [80,81].…”

“…Other data on MS pathophysiology may also be framed within this model, including the role of ceramide and gut dysbiosis in glucose dysregulation, insulin resistance, and the lipid alterations that are common in MS [148], with ceramide decreasing high-density lipoprotein (HDL) cholesterol and increasing very low-density lipoprotein (vLDL) cholesterol [149]. This model also provides a framework for incorporating the effects of medication in the treatment of MS, e.g., fingolimod inhibits aSMase and ceramide [80], including ceramide-induced emergent obesity in MS [150], and, like butyrate, increases gangliosides via HDAC inhibitory effects [85]. Although they have optimizing effects in mitochondria, orexin and melatonin can have distinct and sometimes opposing effects on glia and immune cells [151,152], which seems to contribute to the circadian variation in glia and immune cell activity [153].…”

A novel S1PR4 functional antagonist prevents nonalcoholic steatohepatitis by deactivating the NLRP3 inflammasome without causing lymphopenia

“…Targeting S1PRs was shown to be a promising strategy for treating NASH after the recent preclinical success of FTY720 16 , a drug for multiple sclerosis 17 . FTY720 (Fingolimod; 2-amino-2-[2-(4-noctylphenyl)ethyl]-1, 3-propanediol hydrochloride), a non-selective modulator of S1PRs (S1PR1, 3, 4, and 5), has been shown to prevent the development of alcoholic liver disease 18 , NAFLD 19 and NASH 16 in murine models. However, a widespread use of FTY720 in NASH has been hampered by its lymphopenic effects.…”