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. 2019 May;285(5):562-577.
doi: 10.1111/joim.12877. Epub 2019 Mar 12.

Investigation of human apoB48 metabolism using a new, integrated non-steady-state model of apoB48 and apoB100 kinetics

E Björnson  1 , C J Packard  2 , M Adiels  1 , L Andersson  1 , N Matikainen  3   4   5 , S Söderlund  3   4 , J Kahri  3   4 , C Sihlbom  6 , A Thorsell  6 , H Zhou  7 , M-R Taskinen  3   4 , J Borén  1
Affiliations

Investigation of human apoB48 metabolism using a new, integrated non-steady-state model of apoB48 and apoB100 kinetics

E Björnson et al. J Intern Med. 2019 May.

Abstract

Background: Triglyceride-rich lipoproteins and their remnants have emerged as major risk factors for cardiovascular disease. New experimental approaches are required that permit simultaneous investigation of the dynamics of chylomicrons (CM) and apoB48 metabolism and of apoB100 in very low-density lipoproteins (VLDL).

Methods: Mass spectrometric techniques were used to determine the masses and tracer enrichments of apoB48 in the CM, VLDL1 and VLDL2 density intervals. An integrated non-steady-state multicompartmental model was constructed to describe the metabolism of apoB48- and apoB100-containing lipoproteins following a fat-rich meal, as well as during prolonged fasting.

Results: The kinetic model described the metabolism of apoB48 in CM, VLDL1 and VLDL2 . It predicted a low level of basal apoB48 secretion and, during fat absorption, an increment in apoB48 release into not only CM but also directly into VLDL1 and VLDL2 . ApoB48 particles with a long residence time were present in VLDL, and in subjects with high plasma triglycerides, these lipoproteins contributed to apoB48 measured during fasting conditions. Basal apoB48 secretion was about 50 mg day-1 , and the increment during absorption was about 230 mg day-1 . The fractional catabolic rates for apoB48 in VLDL1 and VLDL2 were substantially lower than for apoB48 in CM.

Discussion: This novel non-steady-state model integrates the metabolic properties of both apoB100 and apoB48 and the kinetics of triglyceride. The model is physiologically relevant and provides insight not only into apoB48 release in the basal and postabsorptive states but also into the contribution of the intestine to VLDL pool size and kinetics.

Keywords: apolipoprotein B48; kinetics; model; remnants; stable isotope.

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Conflict of interest statement

The authors report no duality of interest.

Figures

Figure 1
Figure 1
Model fits to experimental data for subject 3 – a representative subject. All tracer‐to‐tracee ratio data (for leucine and glycerol enrichment) in the different fractions are depicted in sub figures a–i, followed by concentration data depicted in subfigures j–s. For model fits to all subjects, see Appendix S1. Plasma leucine enr (enrichment) is plotted in semilogarithmic scale. APE, atom percent excess; TTR, tracer‐to‐tracee ratio.
Figure 2
Figure 2
Model fits to plasma apoB48 and plasma apoB48 enrichment during fasting conditions for the four subjects. Since data were not available in the CM, VLDL 1 and VLDL 2 fraction, the model was fitted to only the total plasma measurements. Total plasma apoB48 concentration is shown in the top row (a–d) for each subject, and total plasma apoB48 enrichment is shown in the bottom row (e–h) for each subject. Modelling of the previous day is indicated with grey background.
Figure 3
Figure 3
The final integrated model structure. Compartments 1‐6 represents apoB100 in VLDL 1 and VLDL 2 fraction; compartments 7–12 represents apoB100‐TG in VLDL 1 and VLDL 2 fraction; compartments 13–19 represents apoB48 in CM, VLDL 1 and VLDL 2 fraction; compartments 20–26 represents apoB48‐TG in CM, VLDL 1 and VLDL 2 fraction. Plasma leucine and plasma glycerol are represented by compartments 27–29 and 38–39, respectively. Blue arrows indicate where postprandial fluxes of apoB48/apoB48‐TG enter the model. The above structure represents a simplified schematic version of the full model (see Figure S2).
Figure 4
Figure 4
(a) Fluxes of apoB48 in CM, VLDL 1 and VLDL 2 and fluxes of apoB100 in VLDL 1 and VLDL 2; (b) Concentrations of apoB48 in CM, VLDL 1 and VLDL 2 and concentration of apoB100 in VLDL 1 and VLDL 2; (c) ApoB48‐TG flux in CM, VLDL 1 and VLDL 2 and apoB100‐TG flux in VLDL 1 and VLDL 2; (d) ApoB48‐TG concentration in CM, VLDL 1 and VLDL 2. Solid lines indicate model predictions and coloured circles indicate experimental data. Modelling of the previous day is indicated with grey background. The concentration and flux (in terms of mass) of apoB100 is higher than that of apoB48 in the VLDL 1/2 fractions. Total apoB48 flux into the CM fraction is higher than the basal apoB48 flux, and postprandial apoB48 flux also constitutes a significant portion of the total postprandial apoB48 flux. The total triglyceride flux into the CM fraction is the biggest source of triglyceride flux. However, VLDL 1‐TG concentration is higher than CM‐TG concentration because of the high CM‐TG FCR.
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