Computational modeling of sphingolipid metabolism

Abstract

BackgroundAs suggested by the origin of the word, sphingolipids are mysterious molecules with various roles in antagonistic cellular processes such as autophagy, apoptosis, proliferation and differentiation. Moreover, sphingolipids have recently been recognized as important messengers in cellular signaling pathways. Notably, sphingolipid metabolism disorders have been observed in various pathological conditions such as cancer and neurodegeneration.ResultsThe existing formal models of sphingolipid metabolism focus mainly on de novo ceramide synthesis or are limited to biochemical transformations of particular subspecies. Here, we propose the first comprehensive computational model of sphingolipid metabolism in human tissue. Contrary to the previous approaches, we use a model that reflects cell compartmentalization thereby highlighting the differences among individual organelles.ConclusionsThe model that we present here was validated using recently proposed methods of model analysis, allowing to detect the most sensitive and experimentally non-identifiable parameters and determine the main sources of model variance. Moreover, we demonstrate the usefulness of our model in the study of molecular processes underlying Alzheimer’s disease, which are associated with sphingolipid metabolism.Electronic supplementary materialThe online version of this article (doi:10.1186/s12918-015-0176-9) contains supplementary material, which is available to authorized users.

Quantitative Systems Pharmacology Model for Alzheimer Disease Indicates Targeting Sphingolipid Dysregulation as Potential Treatment Option

“…Specifically, we were interested in the response of various dysregulated lipids in the brain, as well as Aβ as a relevant disease marker in AD, to sphingosine receptor agonists. We used published quantitative models for specific biological pathways from the literature as the basis for our model development . The model structure was then carefully altered and amended for additional interactions between different pathways to reflect our understanding of the pathobiology.…”

“…Quantitative Systems Pharmacology (QSP) models are one tool to tackle this seemingly intractable complex problem. [3][4][5] AD is good substrate for a QSP approach as useful mechanistic models, [6][7][8][9][10] as well as statistical and pharmacokinetic/pharmacodynamic PK/PD models, 11,12 of some aspects of AD exist. There is a substantial database of clinical data observations, including pharmacology and biomarker data, that can be used to calibrate and validate QSP models.…”

Mechanistic interplay between ceramide and insulin resistance

“…Other approaches have been tested in the literature, such as in ref. 36, where the authors proposed a model for sphingolipid metabolism that includes compartments. However, their results are neither compared with experimental data, nor quantitatively justified.…”

“…Moreover, the model in ref. 36, despite the lack of experimental verification, includes more than 120 free parameters, which introduces additional challenges in terms of interpretation of the results. In contrast, our model includes only 29 parameters, which are instantiated by using experimental data, and verified by independent data and sensitivity analysis.…”

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.…”