Abstract
Disturbances of lipoprotein metabolism are recognized as indicators of cardiometabolic disease risk. Lipoprotein size and composition, measured in a lipoprotein profile, are considered to be disease risk markers. However, the measured profile is a collective result of complex metabolic interactions, which complicates the identification of changes in metabolism. In this study we aim to develop a method which quantitatively relates murine lipoprotein size, composition and concentration to the molecular mechanisms underlying lipoprotein metabolism. We introduce a computational framework which incorporates a novel kinetic model of murine lipoprotein metabolism. The model is applied to compute a distribution of plasma lipoproteins, which is then related to experimental lipoprotein profiles through the generation of an in silico lipoprotein profile. The model was first applied to profiles obtained from wild-type C57Bl/6J mice. The results provided insight into the interplay of lipoprotein production, remodelling and catabolism. Moreover, the concentration and metabolism of unmeasured lipoprotein components could be determined. The model was validated through the prediction of lipoprotein profiles of several transgenic mouse models commonly used in cardiovascular research. Finally, the framework was employed for longitudinal analysis of the profiles of C57Bl/6J mice following a pharmaceutical intervention with a liver X receptor (LXR) agonist. The multifaceted regulatory response to the administration of the compound is incompletely understood. The results explain the characteristic changes of the observed lipoprotein profile in terms of the underlying metabolic perturbation and resultant modifications of lipid fluxes in the body. The Murine Lipoprotein Profiler (MuLiP) presented here is thus a valuable tool to assess the metabolic origin of altered murine lipoprotein profiles and can be applied in preclinical research performed in mice for analysis of lipid fluxes and lipoprotein composition.
Highlights
The transport of lipids between mammalian tissues is largely facilitated by lipoproteins
Altered lipoprotein metabolism is known to be associated with disease, for instance there is a well-known association between abnormal lipoproteinmediated cholesterol transport and atherosclerosis
This change in lipoprotein metabolism is reflected in altered lipoprotein size and lipid composition as illustrated by a lipoprotein profile
Summary
The transport of lipids between mammalian tissues is largely facilitated by lipoproteins. Lipoproteins are spherically organized protein-lipid compounds that, unlike the individual lipids, are soluble in blood. To achieve this vital property the outer shell of the lipoprotein is a surface layer consisting mainly of phospholipids (PL), free cholesterol (FC) and proteins. The body produces three classes of lipoproteins [1], [2] These classes differ with regard to size, lipid composition and protein content and have distinct origins [3], [4]. High density lipoproteins (HDL), the smallest class, exhibit a relatively high protein and cholesterol content and originate in the intestine and liver [3], [8], [9]. Further processing of circulating chylomicrons, VLDL and HDL, in turn, generates additional classes of lipoproteins which vary in size and composition and exhibit great metabolic diversity [7], [10], [11], [12], [13]
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