title: Mathematically modelling the dynamics of cholesterol metabolism and ageing.
abstract: Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in the UK. This condition becomes increasingly prevalent during ageing; 34.1% and 29.8% of males and females respectively, over 75 years of age have an underlying cardiovascular problem. The dysregulation of cholesterol metabolism is inextricably 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. The aim of this work was to use mathematical modelling to explore how cholesterol metabolism is affected by the ageing process. To do this we updated a previously published whole-body mathematical model of cholesterol metabolism to include an additional 96 mechanisms that are fundamental to this biological system. Additional mechanisms were added to cholesterol absorption, cholesterol synthesis, reverse cholesterol transport (RCT), bile acid synthesis, and their enterohepatic circulation. The sensitivity of the model was explored by the use of both local and global parameter scans. In addition, acute cholesterol feeding was used to explore the effectiveness of the regulatory mechanisms which are responsible for maintaining whole-body cholesterol balance. It was found that our model behaves as a hypo-responder to 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 cholesterol ester 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 genotype reflective of high CETP activity, resulted in a 1.6% increase in LDL-C. Thus, the model has illustrated the importance of CETP genotypes such as I405V, and their potential role in healthy ageing.
authors.affiliation: Department of Chemical Engineering, University of Chester, Thornton Science Park, Chester, CH2 4NU, United Kingdom. Electronic address: amy.morgan@chester.ac.uk.
authors.forename: A E
authors.initials: AE
authors.lastname: Morgan
authors.affiliation: Faculty of Health and Social Care, Edge Hill University, Ormskirk, Lancashire, L39 4QP, United Kingdom.
authors.forename: K M
authors.initials: KM
authors.lastname: Mooney
authors.affiliation: Department of Chemical Engineering, University of Chester, Thornton Science Park, Chester, CH2 4NU, United Kingdom.
authors.forename: S J
authors.initials: SJ
authors.lastname: Wilkinson
authors.affiliation: Department of Biological Sciences, University of Chester, Parkgate Road, Chester, CH1 4BJ, United Kingdom.
authors.forename: N A
authors.initials: NA
authors.lastname: Pickles
authors.affiliation: Department of Chemical Engineering, University of Chester, Thornton Science Park, Chester, CH2 4NU, United Kingdom. Electronic address: m.mcauley@chester.ac.uk.
authors.forename: M T
authors.initials: MT
authors.lastname: Mc Auley
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism*; D005260:Female; D006801:Humans; D050356:Lipid Metabolism / Q000502:physiology*; D008297:Male; D008962:Models, Theoretical
chemical_list: D002784:Cholesterol
keywords: Ageing; Cholesterol; Cholesterol ester transfer protein (CETP); High density lipoprotein cholesterol (HDL-C); Low density lipoprotein cholesterol (LDL-C)