Evaluating computational models of cholesterol metabolism

Paalvast, Yared; Kuivenhoven, Jan Albert; Groen, Albert K.

doi:10.1016/j.bbalip.2015.05.008

Cited by 23 publications

(29 citation statements)

References 78 publications

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“…Furthermore, the size of the recycling compartment (which cannot be estimated from the presently available data) and its location in the outer retina have not been determined. The interplay between the two pathways of Ch efflux from the RPE to the BrM (via small ApoA-I-Ch particles and large ApoB-Ch particles) is also missing from the current model and should be further developed along the lines of models of Ch metabolism in the liver (71, 72). …”

Section: Discussionmentioning

confidence: 99%

An in silico model of retinal cholesterol dynamics (RCD model): insights into the pathophysiology of dry AMD

Zekavat

Lu²,

Maugeais

et al. 2017

Journal of Lipid Research

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We developed an in silico mathematical model of retinal cholesterol (Ch) dynamics (RCD) to quantify the physiological rate of Ch turnover in the rod outer segment (ROS), the lipoprotein transport mechanisms by which Ch enters and leaves the outer retina, and the rates of drusen growth and macrophage-mediated clearance in dry age-related macular degeneration. Based on existing experimental data and mechanistic hypotheses, we estimated the Ch turnover rate in the ROS to be 1–6 pg/mm2/min, dependent on the rate of Ch recycling in the outer retina, and found comparable rates for LDL receptor-mediated endocytosis of Ch by the retinal pigment epithelium (RPE), ABCA1-mediated Ch transport from the RPE to the outer retina, ABCA1-mediated Ch efflux from the RPE to the choroid, and the secretion of 70 nm ApoB-Ch particles from the RPE. The drusen growth rate is predicted to increase from 0.7 to 4.2 μm/year in proportion to the flux of ApoB-Ch particles. The rapid regression of drusen may be explained by macrophage-mediated clearance if the macrophage density reaches ∼3,500 cells/mm2. The RCD model quantifies retinal Ch dynamics and suggests that retinal Ch turnover and recycling, ApoB-Ch particle efflux, and macrophage-mediated clearance may explain the dynamics of drusen growth and regression.

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Section: Discussionmentioning

confidence: 99%

An in silico model of retinal cholesterol dynamics (RCD model): insights into the pathophysiology of dry AMD

Zekavat

Lu²,

Maugeais

et al. 2017

Journal of Lipid Research

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“…decreasing kinetic rates) and observing variations occurring in the system [4]. Several in silico models simulating cholesterol metabolism have been proposed so far, both for human and animal models [5]. In this work we started from an algorithm for cholesterol metabolism simulation published in literature by van de Pas and colleagues in 2012 [6].…”

Section: Introductionmentioning

confidence: 99%

In silico prediction of blood cholesterol levels from genotype data

Reggiani¹,

Carraro

Belligoli

et al. 2018

Preprint

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In this work we present a framework for blood cholesterol levels prediction from genotype data. The predictor is based on an algorithm for cholesterol metabolism simulation available in literature, implemented and optimized by our group in R language. Main weakness of the former simulation algorithm was the need of experimental data to simulate mutations in genes altering the cholesterol metabolism. This caveat strongly limited the application of the model in the clinical practice. In this work we present how this limitation could be bypassed thanks to an optimization of model parameters based on patients cholesterol levels retrieved from literature. Prediction performance has been assessed taking in consideration several scoring indices currently used for performance evaluation of machine learning methods. Our assessment shows how the optimization phase improved model performance, compared to the original version available in literature.

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“…One exception is that of the unpublished work of [12], which integrated a description of LDL endocytosis [13] with that of cholesterol biosynthesis [10]. This was favourably evaluated by [9] in assessing how well the model reproduced the known cellular response to statins, but no mathematical or computational analysis of the model was undertaken.…”

Section: Introductionmentioning

confidence: 99%

“…There exists a growing literature on the mathematical modelling of lipoprotein metabolism as recently reviewed in [9]. Such models have generally been formulated using the theory of linear and nonlinear ordinary differential equations and parameterised and tested, to varying degrees, against the experimental literature.…”

Section: Introductionmentioning

confidence: 99%

“…Such models have generally been formulated using the theory of linear and nonlinear ordinary differential equations and parameterised and tested, to varying degrees, against the experimental literature. The mathematical models reviewed in [9] were tested for their ability to correctly predict the response of each to statin therapy. They found that only a small proportion of models within the literature correctly predicted the well known effect of statins on increasing LDL uptake from the circulation.…”

Section: Introductionmentioning

confidence: 99%

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An Integrated Mathematical Model of Cellular Cholesterol Biosynthesis and Lipoprotein Metabolism

2018

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Abstract:Cholesterol regulation is an important aspect of human health. In this work we bring together and extend two recent mathematical models describing cholesterol biosynthesis and lipoprotein endocytosis to create an integrated model of lipoprotein metabolism in the context of a single hepatocyte. The integrated model includes a description of low density lipoprotein (LDL) receptor and cholesterol synthesis, delipidation of very low density lipoproteins (VLDLs) to LDLs and subsequent lipoprotein endocytosis. Model analysis shows that cholesterol biosynthesis produces the majority of intracellular cholesterol. The availability of free receptors does not greatly effect the concentration of intracellular cholesterol, but has a detrimental effect on extracellular VLDL and LDL levels. We test our model by considering its ability to reproduce the known biology of Familial Hypercholesterolaemia and statin therapy. In each case the model reproduces the known biological behaviour. Quantitative differences in response to statin therapy are discussed in the context of the need to extend the work to a more in vivo setting via the incorporation of more dietary lipoprotein related processes and the need for further testing and parameterisation of in silico models of lipoprotein metabolism.

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Evaluating computational models of cholesterol metabolism

Cited by 23 publications

References 78 publications

An in silico model of retinal cholesterol dynamics (RCD model): insights into the pathophysiology of dry AMD

An in silico model of retinal cholesterol dynamics (RCD model): insights into the pathophysiology of dry AMD

In silico prediction of blood cholesterol levels from genotype data

An Integrated Mathematical Model of Cellular Cholesterol Biosynthesis and Lipoprotein Metabolism

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