Abstract
Recent research adds to a growing body of literature on the essential role of ceramides in glucose homeostasis and insulin signaling, while the mechanistic interplay between various components of ceramide metabolism remains to be quantified. We present an extended model of C16:0 ceramide production through both the de novo synthesis and the salvage pathways. We verify our model with a combination of published models and independent experimental data. In silico experiments of the behavior of ceramide and related bioactive lipids in accordance with the observed transcriptomic changes in obese/diabetic murine macrophages at 5 and 16 weeks support the observation of insulin resistance only at the later phase. Our analysis suggests the pivotal role of ceramide synthase, serine palmitoyltransferase and dihydroceramide desaturase involved in the de novo synthesis and the salvage pathways in influencing insulin resistance versus its regulation.
Highlights
Working with an extended model of the one presented by Gupta et al.[5] to include the interplay between ceramide and sphingosine, the main result is the ability of our model to explain mechanistically the interplay between sphingolipid metabolism, ceramide, and insulin resistance
We experimented on our model by focusing on two cases: (i) the availability of CERS6, and (ii) the groups of enzymes that are identified as significantly differentially-expressed in obese mice
We investigated the response to variation in CERS6 fold change (FC), as this enzyme plays a central role in the de novo production of ceramide, catalyzing dihydroceramide starting from sphinganine, and in the salvage production, recycling ceramide from sphingosine
Summary
Working with an extended model of the one presented by Gupta et al.[5] to include the interplay between ceramide and sphingosine, the main result is the ability of our model to explain mechanistically the interplay between sphingolipid metabolism, ceramide, and insulin resistance. The sphingolipids related to insulin action, ceramide, glucosylcermide (GluCer) and S1P are balanced: GluCer and S1P, are either stable or decreasing, ceramide increases and the mechanisms of insulin resistance due to Akt activity remain unaffected These observations are in agreement with[10]: after 5 weeks, ob/ob mice show signs of early insulin resistance, compared with wild-type mice, show well-controlled glycemia. Simulations suggest that ob/ob mice metabolism is highly affected after 16 weeks with a general up-regulation of sphingolipids, including the ones involved in insulin signaling (Fig. 2d). This suggests potential impairment of insulin signaling and the development of insulin resistance and glucose intolerance. Our results demonstrate that while the concentrations of enzymes like ceramide-activated protein phosphatase (CAPP), ceramide kinase (CERK), sphingosine-1-phosphate lyase (SGPL1) and sphingosine-1-phosphate phosphatase (SGPP1) have strong effect on specific sphingolipids, other enzymes like CERS, ceramide glucosyltransferase (UGCG), dihydroceramide desaturase (DEGS), sphingomyelin synthase (SMS), ceramidase (ASAH), sphingomyelinase (SMA) and serine palmitoyltransferase (SPT) have a more diffuse effect throughout the model
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