Mechanistic interplay between ceramide and insulin resistance

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.

Resveratrol protects against hepatic insulin resistance in a rat's model of non‐alcoholic fatty liver disease by down‐regulation of GPAT‐1 and DGAT2 expression and inhibition of PKC membranous translocation

“…Thus ceramide is not considered in the pathogenesis of hepatic IR or mechanism of RES protective effect in the model used in the current study. 21 In this study, HFD-fed rats had stable plasma glucose levels but higher fasting insulin levels, suggesting the development of IR. These results have also been shown by other authors using the same animal model.…”

“…Authors who have used the 3‐day HFD animal model to investigate hepatic IR found no alteration in ceramide content in these rodents. Thus ceramide is not considered in the pathogenesis of hepatic IR or mechanism of RES protective effect in the model used in the current study …”

Optimization Algorithms for Computational Systems Biology

“…This problem is often formulated in the form of least squares, as in models related to diabetes [10,19,20], biological pathways [21][22][23][24], and pharmacokinetics/pharmacodynamics [25,26]. Least squares problems may arise in statistical regression as well [27][28][29][30][31][32].…”

Stochastic simulation algorithms for computational systems biology: Exact, approximate, and hybrid methods

“…During the last two decades, different models have been proposed to mechanistically explore different aspects of the sphingolipid metabolism (Alvarez‐Vasquez et al, ; Gupta et al, ; Kaddi, Niesner, et al, ; Kaddi, Reali et al, ; Reali et al, ; Wronowska, Charzyńska, Nienałtowski, & Gambin, ). Here, we analyze two models that have been simulated using three different approaches, and each approach has led to different discoveries.…”

“…In literature, different models have been devoted to studying sphingolipid metabolism and in particular of ceramide. Here, we analyze how the use of three simulation algorithms have supported the different findings on two of these models (Gupta, Maurya, Merrill, Glass, & Subramaniam, 2011;Reali, Morine, et al, 2017;Thanh et al, 2018).…”