A Cybernetic Approach to Modeling Lipid Metabolism in Mammalian Cells

Abstract

The goal-oriented control policies of cybernetic models have been used to predict metabolic phenomena such as the behavior of gene knockout strains, complex substrate uptake patterns, and dynamic metabolic flux distributions. Cybernetic theory builds on the principle that metabolic regulation is driven towards attaining goals that correspond to an organism’s survival or displaying a specific phenotype in response to a stimulus. Here, we have modeled the prostaglandin (PG) metabolism in mouse bone marrow derived macrophage (BMDM) cells stimulated by Kdo2-Lipid A (KLA) and adenosine triphosphate (ATP), using cybernetic control variables. Prostaglandins are a well characterized set of inflammatory lipids derived from arachidonic acid. The transcriptomic and lipidomic data for prostaglandin biosynthesis and conversion were obtained from the LIPID MAPS database. The model parameters were estimated using a two-step hybrid optimization approach. A genetic algorithm was used to determine the population of near optimal parameter values, and a generalized constrained non-linear optimization employing a gradient search method was used to further refine the parameters. We validated our model by predicting an independent data set, the prostaglandin response of KLA primed ATP stimulated BMDM cells. We show that the cybernetic model captures the complex regulation of PG metabolism and provides a reliable description of PG formation.

Whither chemical engineering?

“…The success with modeling regulatory effects in bacterial metabolism provides considerable incentive to extend the approach to eukaryotic systems in spite of the latter's greatly added complexity. Some beginnings have been made by Aboulmouna et al 71 with cybernetic modeling of regulation in macrophage cells which are concerned with the organism's immune response. This system is riddled with uncertainties from various sources.…”

“…Some beginnings have been made by Aboulmouna et al 71 with cybernetic modeling of regulation in macrophage cells which are concerned with the organism's immune response. This system is riddled with uncertainties from various sources.…”

Whither Chemical Engineering?

“…Some beginnings have been made by Aboulmouna et al 69 with cybernetic modeling of regulation in macrophage cells which are concerned with the organism's immune response. This system is riddled with uncertainties from various sources.…”

Special Issue on Feature Papers for Celebrating the Fifth Anniversary of the Founding of Processes

“…The first paper shows the development of a systems model for investigating patient outcomes from liver surgery and determining the processes responsible for liver failure [5]. The extension of the cybernetic modeling approach to lipid metabolism in mouse bone marrow-derived macrophage cells is the focus of the second paper [6]. The third paper addresses the metabolic modeling of cell-free protein expression through adaptation of a genome-scale metabolic model and direct incorporation of metabolite measurements [7].…”