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Interventions in S1P Metabolism as Modifiers of Susceptibility and Treatability of Metabolic Disorders
Melissa K. Nowak 1, Sarah Weske 1, Philipp Wollnitzke 1, Bodo Levkau 11 Institute for Molecular Medicine III, Heinrich Heine University, Düsseldorf, Germany
Background: Obesity, non-alcoholic fatty liver disease (NAFLD) and diabetes constitute a worldwide rising health problem often referred to as the metabolic syndrome. Several studies have proposed that dysregulation of sphingosine-1-phosphate (S1P) signaling is involved in metabolic disorders including diabetes and NAFLD. S1P is generated by two specific kinases, sphingosine kinase 1 and 2 (Sphk1 and Sphk2) and irreversibly degraded by the S1P lyase (Sgpl) that have all been shown to exert metabolically relevant functions in the liver, adipose tissue and pancreas.
Aims: We addressed the question how Sphk1, Sphk2 and Sgpl affect hepatic and peripheral insulin sensitivity under normal and high caloric conditions and what effects they may have on the metabolic disorders.
Methods: C57BL/6J control mice, Sphk1-, and Sphk2 knockout mice were fed a high fat diet (60% kcal fat) for 12 weeks and compared to each other and their normal chow counterparts. The effect on established metabolic disease was investigated by therapeutic application of the selective Sphk2 inhibitor ABC294640 and the Sgpl inhibitor 5-deoxypyridoxine, respectively. Data were collected on glucose and insulin tolerance, plasma lipids and liver functional parameters. Livers were analyzed by histology, RNA-Seq, whole tissue kinase activity profiling, Seahorse™ profiling, and targeted lipidomics. Murine primary hepatocytes were employed for in vitro studies.
Results: Wild-type and Sphk1-KO but not Sphk2-KO became increasingly obese and displayed NAFLD under high fat diet, with Sphk1-KO proving to be more and Sphk2-KO less susceptible to obesity and hepatosteatosis. In contrast to wild-type mice, Sphk2-KO showed less diet-induced body weight gain, better glucose tolerance, higher insulin sensitivity and improved liver function, whereas Sphk1-KO fared worse in all of these parameters as compared to wild type. RNAseq data displayed a plethora of differentially regulated genes among cohorts with emphasis on lipid and glucose metabolism. Initiation of pharmacological inhibition of Sphk2 with ABC294640 in already obese mice lead to substantial weight loss and improved glucose tolerance over the following 3 weeks despite continued high fat feeding. This could be recapitulated by pharmacological Sgpl inhibition that was also begun after manifestation of disease and maintained under high fat diet.
Conclusion: Overall, our results indicate a crucial role of S1P in the development of metabolic disorders. We are currently investigating the mechanism by which S1P prevents onset and reverses already established metabolic disease. Pharmacological interventions in S1P metabolism may present a promising approach to treating metabolic disorders.