Advanced Glycation End Products Inhibition Restores Sphingolipid Rheostat in Mice Liver and Prevents Diet-Induced Insulin Resistance

The maintenance of sphingolipid rheostat by interconversion of ceramide (Cer), sphingosine (Sph), and sphingosine-1-phosphate (S1P) is relevant for the control of several metabolic pathways. In particular, accumulation of Cer and S1P in response to cellular stress interferes with insulin signalling and mitochondrial metabolism. Emerging evidence has highlighted a role for Advanced Glycation End Products (AGEs) in the imbalance of the sphingolipid rheostat. We and others have recently demonstrated the accumulation of AGEs in tissues of diet-induced insulin-resistant mice and their involvement in altered lipid synthesis and mitochondrial dysfunction. We, thus, investigated the impact of a high trans fat diet on the sphingolipid rheostat in mice liver and whether the administration of the anti-AGEs compound pyridoxamine could prevent insulin resistance onset by restoring the Cer/Sph/S1P equilibrium. C57Bl/6J mice were fed a standard diet (SD) or a 60% trans fat diet (HFD) for 10 weeks. Two subgroups received pyridoxamine (150 mg/kg/day) in the drinking water. The pyridoxamine administration efficiently prevented insulin resistance, obesity, AGEs accumulation and RAGE hyperexpression induced by the HFD. HFD also induced a dramatic reduction of the liver Sph levels, paralleled by the increase in Cer levels, assessed by an UPLC/TQMS system, and the induction of the S1P receptors. Interestingly, pyridoxamine administration prevented the Cer increase by reducing Cer synthase expression and significantly inhibited S1P receptors by reducing S1P kinase levels, completely reverting Sph depletion. The present data indicate for the first time that the inhibition of AGEs is effective in the maintenance of the sphingolipid rheostat through the modulation of the involved enzymes, and this could contribute to the prevention of insulin resistance observed in the pyridoxamine-treated HFD mice. Therefore, it could be of relevance to further investigate on the predictive value of Cer/Sph/S1P imbalance for insulin resistance onset and on pyridoxamine supplementation as preventive strategy.