In vivo and in silico dynamics of the development of Metabolic Syndrome.

Yvonne J W Rozendaal,Peter A J Hilbers,Jan A Kuivenhoven,Patrick C N Rensen,Zhuang Li,Natal A W Van Riel,Albert K Groen,Yared Paalvast,Ko Willems Van Dijk,Lauren L Tambyrajah,Yanan Wang

doi:10.1371/journal.pcbi.1006145

Abstract

The Metabolic Syndrome (MetS) is a complex, multifactorial disorder that develops slowly over time presenting itself with large differences among MetS patients. We applied a systems biology approach to describe and predict the onset and progressive development of MetS, in a study that combined in vivo and in silico models. A new data-driven, physiological model (MINGLeD: Model INtegrating Glucose and Lipid Dynamics) was developed, describing glucose, lipid and cholesterol metabolism. Since classic kinetic models cannot describe slowly progressing disorders, a simulation method (ADAPT) was used to describe longitudinal dynamics and to predict metabolic concentrations and fluxes. This approach yielded a novel model that can describe long-term MetS development and progression. This model was integrated with longitudinal in vivo data that was obtained from male APOE*3-Leiden.CETP mice fed a high-fat, high-cholesterol diet for three months and that developed MetS as reflected by classical symptoms including obesity and glucose intolerance. Two distinct subgroups were identified: those who developed dyslipidemia, and those who did not. The combination of MINGLeD with ADAPT could correctly predict both phenotypes, without making any prior assumptions about changes in kinetic rates or metabolic regulation. Modeling and flux trajectory analysis revealed that differences in liver fluxes and dietary cholesterol absorption could explain this occurrence of the two different phenotypes. In individual mice with dyslipidemia dietary cholesterol absorption and hepatic turnover of metabolites, including lipid fluxes, were higher compared to those without dyslipidemia. Predicted differences were also observed in gene expression data, and consistent with the emergence of insulin resistance and hepatic steatosis, two well-known MetS co-morbidities. Whereas MINGLeD specifically models the metabolic derangements underlying MetS, the simulation method ADAPT is generic and can be applied to other diseases where dynamic modeling and longitudinal data are available.

Highlights

The simultaneous presentation of obesity, dyslipidemia, insulin resistance and hypertension is generally referred to as the Metabolic Syndrome (MetS) [1,2,3,4,5]
Hereto we integrated prior knowledge on the complex metabolic systems that underlie the pathophysiology of MetS with experimental observations on the actual metabolic status over time: in vivo data of the onset and progressive development of MetS have been collected from 11-week-old male end we use male APOEÃ3-Leiden (E3L).CETP mice that were fed diets differing in fat and cholesterol content and were followed for three months
These diets comprised of a low-fat diet (LFD; 20% of energy from fat; n = 8), high-fat diet (HFD; 60% of energy from fat; n = 12) and a high-fat diet with additional dietary cholesterol (HFD+C; 0.25% cholesterol; n = 8)

Summary

Introduction

The simultaneous presentation of obesity, dyslipidemia, insulin resistance and hypertension is generally referred to as the Metabolic Syndrome (MetS) [1,2,3,4,5]. Together, these factors impose increased risk for the development of co-morbidities including cardiovascular disease, type 2 diabetes and non-alcoholic fatty liver disease [6,7]. Clinical research on MetS is mostly cross-sectional in nature and tends to focus on either lipid or glucose metabolism, while both make up MetS. Knowledge on the interplay between these different metabolic components during the relatively slow progression into disease is limited, but which a systems biology approach could provide

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Conclusion