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Verfasst von:Lu, James [VerfasserIn]   i
 Hübner, Katrin [VerfasserIn]   i
 Nanjee, M. Nazeem [VerfasserIn]   i
 Brinton, Eliot A. [VerfasserIn]   i
 Mazer, Norman A. [VerfasserIn]   i
Titel:An in-silico model of lipoprotein metabolism and kinetics for the evaluation of targets and biomarkers in the reverse cholesterol transport pathway
Verf.angabe:James Lu, Katrin Hübner, M. Nazeem Nanjee, Eliot A. Brinton, Norman A. Mazer
E-Jahr:2014
Jahr:March 13, 2014
Umfang:26 S.
Fussnoten:Gesehen am 11.08.2020
Titel Quelle:Enthalten in: Public Library of SciencePLoS Computational Biology
Ort Quelle:San Francisco, Calif. : Public Library of Science, 2005
Jahr Quelle:2014
Band/Heft Quelle:10(2014) Artikel-Nummer e1003509, 26 Seiten
ISSN Quelle:1553-7358
Abstract:High-density lipoprotein (HDL) is believed to play an important role in lowering cardiovascular disease (CVD) risk by mediating the process of reverse cholesterol transport (RCT). Via RCT, excess cholesterol from peripheral tissues is carried back to the liver and hence should lead to the reduction of atherosclerotic plaques. The recent failures of HDL-cholesterol (HDL-C) raising therapies have initiated a re-examination of the link between CVD risk and the rate of RCT, and have brought into question whether all target modulations that raise HDL-C would be atheroprotective. To help address these issues, a novel in-silico model has been built to incorporate modern concepts of HDL biology, including: the geometric structure of HDL linking the core radius with the number of ApoA-I molecules on it, and the regeneration of lipid-poor ApoA-I from spherical HDL due to remodeling processes. The ODE model has been calibrated using data from the literature and validated by simulating additional experiments not used in the calibration. Using a virtual population, we show that the model provides possible explanations for a number of well-known relationships in cholesterol metabolism, including the epidemiological relationship between HDL-C and CVD risk and the correlations between some HDL-related lipoprotein markers. In particular, the model has been used to explore two HDL-C raising target modulations, Cholesteryl Ester Transfer Protein (CETP) inhibition and ATP-binding cassette transporter member 1 (ABCA1) up-regulation. It predicts that while CETP inhibition would not result in an increased RCT rate, ABCA1 up-regulation should increase both HDL-C and RCT rate. Furthermore, the model predicts the two target modulations result in distinct changes in the lipoprotein measures. Finally, the model also allows for an evaluation of two candidate biomarkers for in-vivo whole-body ABCA1 activity: the absolute concentration and the % lipid-poor ApoA-I. These findings illustrate the potential utility of the model in drug development.
DOI:doi:10.1371/journal.pcbi.1003509
URL:Bitte beachten Sie: Dies ist ein Bibliographieeintrag. Ein Volltextzugriff für Mitglieder der Universität besteht hier nur, falls für die entsprechende Zeitschrift/den entsprechenden Sammelband ein Abonnement besteht oder es sich um einen OpenAccess-Titel handelt.

Volltext ; Verlag: https://doi.org/10.1371/journal.pcbi.1003509
 Volltext: https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1003509
 DOI: https://doi.org/10.1371/journal.pcbi.1003509
Datenträger:Online-Ressource
Sprache:eng
Sach-SW:Biomarkers
 Cholesterol
 Cholesteryl esters
 Heterozygosity
 Homozygosity
 Lipids
 Lipoproteins
 Simulation and modeling
K10plus-PPN:1726741990
Verknüpfungen:→ Zeitschrift

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