title: In silico modeling of the dynamics of low density lipoprotein composition via a single plasma sample.
abstract: Lipoproteins play a key role in the development of CVD, but the dynamics of lipoprotein metabolism are difficult to address experimentally. This article describes a novel two-step combined in vitro and in silico approach that enables the estimation of key reactions in lipoprotein metabolism using just one blood sample. Lipoproteins were isolated by ultracentrifugation from fasting plasma stored at 4°C. Plasma incubated at 37°C is no longer in a steady state, and changes in composition may be determined. From these changes, we estimated rates for reactions like LCAT (56.3 µM/h), β-LCAT (15.62 µM/h), and cholesteryl ester (CE) transfer protein-mediated flux of CE from HDL to IDL/VLDL (21.5 µM/h) based on data from 15 healthy individuals. In a second step, we estimated LDL's HL activity (3.19 pools/day) and, for the very first time, selective CE efflux from LDL (8.39 µM/h) by relying on the previously derived reaction rates. The estimated metabolic rates were then confirmed in an independent group (n = 10). Although measurement uncertainties do not permit us to estimate parameters in individuals, the novel approach we describe here offers the unique possibility to investigate lipoprotein dynamics in various diseases like atherosclerosis or diabetes.
authors.affiliation: Institute of Clinical Chemistry and Laboratory Medicine, University of Freiburg, Germany martin.jansen@uniklinik-freiburg.de.
authors.forename: Martin
authors.initials: M
authors.lastname: Jansen
authors.affiliation: Medical Center, and Department of Mathematical Stochastics, University of Freiburg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Pfaffelhuber
authors.affiliation: Institute of Clinical Chemistry and Laboratory Medicine, University of Freiburg, Germany.
authors.forename: Michael M
authors.initials: MM
authors.lastname: Hoffmann
authors.affiliation: Institute of Clinical Chemistry and Laboratory Medicine, University of Freiburg, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Puetz
authors.affiliation: Institute of Clinical Chemistry and Laboratory Medicine, University of Freiburg, Germany.
authors.forename: Karl
authors.initials: K
authors.lastname: Winkler
mesh_terms: D000328:Adult; D000465:Algorithms; D053480:Cholesterol Ester Transfer Proteins / Q000502:physiology; D003198:Computer Simulation; D004951:Esterification; D005260:Female; D006801:Humans; D006868:Hydrolysis; D008077:Lipoproteins, LDL / Q000097:blood*; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D007862:Phosphatidylcholine-Sterol O-Acyltransferase / Q000502:physiology; D014280:Triglycerides / Q000502:physiology; D055815:Young Adult
chemical_list: C506642:CETP protein, human; D053480:Cholesterol Ester Transfer Proteins; D008077:Lipoproteins, LDL; D014280:Triglycerides; D007862:Phosphatidylcholine-Sterol O-Acyltransferase
keywords: lecithin:cholesterol acyltransferase; lipase/hepatic; lipid transfer proteins; lipoproteins/kinetics; low density lipoprotein/metabolism