Mathematically modelling the dynamics of cholesterol metabolism and ageing

Hdl Handle:
http://hdl.handle.net/10034/617945
Title:
Mathematically modelling the dynamics of cholesterol metabolism and ageing
Authors:
Morgan, Amy; Mooney, Kathleen M.; Wilkinson, Stephen J.; Pickles, Neil; Mc Auley, Mark T.
Abstract:
Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in the UK. This conditionbecomes increasingly prevalent during ageing; 34.1% and 29.8% of males and females respectively, over 75years of age have an underlying cardiovascular problem. The dysregulation of cholesterol metabolism isinextricably correlated with cardiovascular health and for this reason low density lipoprotein cholesterol(LDL-C) and high density lipoprotein cholesterol (HDL-C) are routinely used as biomarkers of CVD risk. Theaim of this work was to use mathematical modelling to explore how cholesterol metabolism is affectedby the ageing process. To do this we updated a previously published whole-body mathematical model ofcholesterol metabolism to include an additional 96 mechanisms that are fundamental to this biologicalsystem. Additional mechanisms were added to cholesterol absorption, cholesterol synthesis, reversecholesterol transport (RCT), bile acid synthesis, and their enterohepatic circulation. The sensitivity of themodel was explored by the use of both local and global parameter scans. In addition, acute cholesterolfeeding was used to explore the effectiveness of the regulatory mechanisms which are responsible formaintaining whole-body cholesterol balance. It was found that our model behaves as a hypo-responderto cholesterol feeding, while both the hepatic and intestinal pools of cholesterol increased significantly.The model was also used to explore the effects of ageing in tandem with three different cholesterolester transfer protein (CETP) genotypes. Ageing in the presence of an atheroprotective CETP genotype,conferring low CETP activity, resulted in a 0.6% increase in LDL-C. In comparison, ageing with a genotypereflective of high CETP activity, resulted in a 1.6% increase in LDL-C. Thus, the model has illustrated theimportance of CETP genotypes such as I405V, and their potential role in healthy ageing.
Affiliation:
University of Chester, Edgehill University
Citation:
Morgan, A. E., Mooney, K. M., Wilkinson, S. J., Pickles, N. A., & Mc Auley, M. T. (2016). Mathematically modelling the dynamics of cholesterol metabolism and ageing. Biosystems, 145, 19-32. doi: http://dx.doi.org/10.1016/j.biosystems.2016.05.001
Publisher:
Elsevier
Journal:
Biosystems
Publication Date:
30-Jul-2016
URI:
http://hdl.handle.net/10034/617945
DOI:
10.1016/j.biosystems.2016.05.001
Additional Links:
http://www.sciencedirect.com/science/article/pii/S0303264716300533
Type:
Article
Language:
en
ISSN:
0303-2647
Appears in Collections:
Chemical Engineering

Full metadata record

DC FieldValue Language
dc.contributor.authorMorgan, Amyen
dc.contributor.authorMooney, Kathleen M.en
dc.contributor.authorWilkinson, Stephen J.en
dc.contributor.authorPickles, Neilen
dc.contributor.authorMc Auley, Mark T.en
dc.date.accessioned2016-08-04T15:24:37Z-
dc.date.available2016-08-04T15:24:37Z-
dc.date.issued2016-07-30-
dc.identifier.citationMorgan, A. E., Mooney, K. M., Wilkinson, S. J., Pickles, N. A., & Mc Auley, M. T. (2016). Mathematically modelling the dynamics of cholesterol metabolism and ageing. Biosystems, 145, 19-32. doi: http://dx.doi.org/10.1016/j.biosystems.2016.05.001en
dc.identifier.issn0303-2647-
dc.identifier.doi10.1016/j.biosystems.2016.05.001-
dc.identifier.urihttp://hdl.handle.net/10034/617945-
dc.description.abstractCardiovascular disease (CVD) is the leading cause of morbidity and mortality in the UK. This conditionbecomes increasingly prevalent during ageing; 34.1% and 29.8% of males and females respectively, over 75years of age have an underlying cardiovascular problem. The dysregulation of cholesterol metabolism isinextricably correlated with cardiovascular health and for this reason low density lipoprotein cholesterol(LDL-C) and high density lipoprotein cholesterol (HDL-C) are routinely used as biomarkers of CVD risk. Theaim of this work was to use mathematical modelling to explore how cholesterol metabolism is affectedby the ageing process. To do this we updated a previously published whole-body mathematical model ofcholesterol metabolism to include an additional 96 mechanisms that are fundamental to this biologicalsystem. Additional mechanisms were added to cholesterol absorption, cholesterol synthesis, reversecholesterol transport (RCT), bile acid synthesis, and their enterohepatic circulation. The sensitivity of themodel was explored by the use of both local and global parameter scans. In addition, acute cholesterolfeeding was used to explore the effectiveness of the regulatory mechanisms which are responsible formaintaining whole-body cholesterol balance. It was found that our model behaves as a hypo-responderto cholesterol feeding, while both the hepatic and intestinal pools of cholesterol increased significantly.The model was also used to explore the effects of ageing in tandem with three different cholesterolester transfer protein (CETP) genotypes. Ageing in the presence of an atheroprotective CETP genotype,conferring low CETP activity, resulted in a 0.6% increase in LDL-C. In comparison, ageing with a genotypereflective of high CETP activity, resulted in a 1.6% increase in LDL-C. Thus, the model has illustrated theimportance of CETP genotypes such as I405V, and their potential role in healthy ageing.en
dc.language.isoenen
dc.publisherElsevieren
dc.relation.urlhttp://www.sciencedirect.com/science/article/pii/S0303264716300533en
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectAgeingen
dc.subjectcomputational modellingen
dc.titleMathematically modelling the dynamics of cholesterol metabolism and ageingen
dc.typeArticleen
dc.contributor.departmentUniversity of Chester, Edgehill Universityen
dc.identifier.journalBiosystemsen
dc.date.accepted2016-05-06-
or.grant.openaccessYesen
rioxxterms.funderinternalen
rioxxterms.identifier.projectinternalen
rioxxterms.versionSMURen
rioxxterms.licenseref.startdate2017-08-01-
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