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• W1984177683 abstract "The use of stable isotopes in conjunction with compartmental modeling analysis has greatly facilitated studies of the metabolism of the apolipoprotein B (apoB)-containing lipoproteins in humans. The aim of this study was to develop a multicompartment model that allows us to simultaneously determine the kinetics of apoB and triglyceride (TG) in VLDL1 and VLDL2 after a bolus injection of [2H3]leucine and [2H5]glycerol and to follow the catabolism and transfer of the lipoprotein particles. Here, we describe the model and present the results of its application in a fasting steady-state situation in 17 subjects with lipid values representative of a Western population. Analysis of the correlations showed that plasma TG was determined by the VLDL1 and VLDL2 apoB and TG fractional catabolic rate. Furthermore, the model showed a linear correlation between VLDL1 TG and apoB production. A novel observation was that VLDL TG entered the circulation within 21 min after its synthesis, whereas VLDL apoB entered the circulation after 33 min.These observations are consistent with a sequential assembly model of VLDL and suggest that the TG is added to a primordial apoB-containing particle in the liver. The use of stable isotopes in conjunction with compartmental modeling analysis has greatly facilitated studies of the metabolism of the apolipoprotein B (apoB)-containing lipoproteins in humans. The aim of this study was to develop a multicompartment model that allows us to simultaneously determine the kinetics of apoB and triglyceride (TG) in VLDL1 and VLDL2 after a bolus injection of [2H3]leucine and [2H5]glycerol and to follow the catabolism and transfer of the lipoprotein particles. Here, we describe the model and present the results of its application in a fasting steady-state situation in 17 subjects with lipid values representative of a Western population. Analysis of the correlations showed that plasma TG was determined by the VLDL1 and VLDL2 apoB and TG fractional catabolic rate. Furthermore, the model showed a linear correlation between VLDL1 TG and apoB production. A novel observation was that VLDL TG entered the circulation within 21 min after its synthesis, whereas VLDL apoB entered the circulation after 33 min. These observations are consistent with a sequential assembly model of VLDL and suggest that the TG is added to a primordial apoB-containing particle in the liver. Regulation of the metabolism of VLDL subfractions has been an area of active interest that received fresh impetus from the introduction of stable isotope-based techniques in the late 1980s (1Cryer D.R. Matsushima T. Marsh J.B. Yudkoff M. Coates P.M. Cortner J.A. Direct measurement of apolipoprotein B synthesis in human very low density lipoprotein using stable isotopes and mass spectrometry.J. Lipid Res. 1986; 27: 508-516Abstract Full Text PDF PubMed Google Scholar, 2Cohn J.S. Wagner D.A. Cohn S.D. Millar J.S. Schaefer E.J. Measurement of very low density and low density lipoprotein apolipoprotein (apo) B-100 and high density lipoprotein apo A-I production in human subjects using deuterated leucine. Effect of fasting and feeding.J. Clin. Invest. 1990; 85: 804-811Crossref PubMed Scopus (156) Google Scholar). The use of tracer models has generated direct information on lipoprotein synthetic rates, which previously could only be inferred from the turnover of radiolabeled lipoproteins. One common approach is to inject a bolus of radioactive tracer, such as [3H,14C]glycerol, and determine the subsequent monoexponential slope of the decline in plasma VLDL-specific radioactivity. A disadvantage of this approach is that it can underestimate the true VLDL turnover rate because it does not account for recycling of the injected bolus of tracer (3Patterson B.W. Mittendorfer B. Elias N. Satyanarayana R. Klein S. Use of stable isotopically labeled tracers to measure very low density lipoprotein-triglyceride turnover.J. Lipid Res. 2002; 43: 223-233Abstract Full Text Full Text PDF PubMed Google Scholar). Multicompartmental modeling improves the accuracy by attempting to account for tracer recycling (3Patterson B.W. Mittendorfer B. Elias N. Satyanarayana R. Klein S. Use of stable isotopically labeled tracers to measure very low density lipoprotein-triglyceride turnover.J. Lipid Res. 2002; 43: 223-233Abstract Full Text Full Text PDF PubMed Google Scholar, 4Zech L.A. Grundy S.M. Steinberg D. Berman M. Kinetic model for production and metabolism of very low density lipoprotein triglycerides. Evidence for a slow production pathway and results for normolipidemic subjects.J. Clin. Invest. 1979; 63: 1262-1273Crossref PubMed Scopus (86) Google Scholar, 5Melish J. Le N.A. Ginsberg H. Steinberg D. Brown W.V. Dissociation of apoprotein B and triglyceride production in very-low-density lipoproteins.Am. J. Physiol. 1980; 239: E354-E362Crossref PubMed Google Scholar, 6Harris W.S. Connor W.E. Illingworth D.R. Rothrock D.W. Foster D.M. Effects of fish oil on VLDL triglyceride kinetics in humans.J. Lipid Res. 1990; 31: 1549-1558Abstract Full Text PDF PubMed Google Scholar, 7Barrett P.H. Baker N. Nestel P.J. Model development to describe the heterogeneous kinetics of apolipoprotein B and triglyceride in hypertriglyceridemic subjects.J. Lipid Res. 1991; 32: 743-762Abstract Full Text PDF PubMed Google Scholar, 8Patterson B.W. Methods for measuring lipid metabolism in vivo.Curr. Opin. Clin. Nutr. Metab. Care. 2002; 5: 475-479Crossref PubMed Scopus (7) Google Scholar). Such studies have revealed that VLDL1 apolipoprotein B-100 (apoB-100) production and VLDL2 apoB-100 production are independently regulated (9Malmstrom R. Packard C.J. Caslake M. Bedford D. Stewart P. Yki-Jarvinen H. Shepherd J. Taskinen M.R. Defective regulation of triglyceride metabolism by insulin in the liver in NIDDM.Diabetologia. 1997; 40: 454-462Crossref PubMed Scopus (276) Google Scholar, 10Malmstrom R. Packard C.J. Watson T.D. Rannikko S. Caslake M. Bedford D. Stewart P. Yki-Jarvinen H. Shepherd J. Taskinen M.R. Metabolic basis of hypotriglyceridemic effects of insulin in normal men.Arterioscler. Thromb. Vasc. Biol. 1997; 17: 1454-1464Crossref PubMed Scopus (166) Google Scholar, 11Packard C.J. Shepherd J. Lipoprotein heterogeneity and apolipoprotein B metabolism.Arterioscler. Thromb. Vasc. Biol. 1997; 17: 3542-3556Crossref PubMed Scopus (333) Google Scholar), indicating that regulatory steps in the assembly of VLDL govern the lipid content of the secreted particles. However, it is still unclear how the liver regulates the triglyceride (TG) content of VLDL particles to produce large VLDL1 or small VLDL2. VLDL assembly is thought to involve at least two steps in which nascent VLDL particles are formed and then TG is added, resulting in larger particles (12Boren J. Rustaeus S. Olofsson S.O. Studies on the assembly of apolipoprotein B-100- and B-48-containing very low density lipoproteins in McA-RH7777 cells.J. Biol. Chem. 1994; 269: 25879-25888Abstract Full Text PDF PubMed Google Scholar, 13Olofsson S.O. Asp L. Boren J. The assembly and secretion of apolipoprotein B-containing lipoproteins.Curr. Opin. Lipidol. 1999; 10: 341-346Crossref PubMed Scopus (187) Google Scholar). Several studies have analyzed VLDL TG turnover kinetics using stable isotopically labeled glycerol or palmitate tracers and mathematical modeling. However, VLDL subclasses were not analyzed in those studies, and VLDL apoB was not included in the models (3Patterson B.W. Mittendorfer B. Elias N. Satyanarayana R. Klein S. Use of stable isotopically labeled tracers to measure very low density lipoprotein-triglyceride turnover.J. Lipid Res. 2002; 43: 223-233Abstract Full Text Full Text PDF PubMed Google Scholar, 14Lemieux S. Patterson B.W. Carpentier A. Lewis G.F. Steiner G. A stable isotope method using a [(2)H(5)]glycerol bolus to measure very low density lipoprotein triglyceride kinetics in humans.J. Lipid Res. 1999; 40: 2111-2117Abstract Full Text Full Text PDF PubMed Google Scholar, 15Carpentier A. Patterson B.W. Leung N. Lewis G.F. Sensitivity to acute insulin-mediated suppression of plasma free fatty acids is not a determinant of fasting VLDL triglyceride secretion in healthy humans.Diabetes. 2002; 51: 1867-1875Crossref PubMed Scopus (38) Google Scholar). To enhance our understanding of the pathways leading to VLDL1 and VLDL2 and of the metabolic fate of these particles, we developed for the first time a multicompartmental mathematical model that allows the kinetics of TG and apoB-100 in VLDL1 and VLDL2 to be simultaneously assessed after a bolus injection of glycerol and leucine. Here, we describe the model and present the results of its application in 17 subjects with lipid values representative of a Western population. Seventeen healthy subjects were recruited for this study. The purpose, nature, and potential risks of the study were explained to all subjects before their written consent was obtained. The study protocols were approved by the Ethical Committee of the Helsinki University Central Hospital. All materials were from Sigma Chemical Co. (Poole, Dorset, UK) unless otherwise stated. All subjects were admitted at 7:30 AM to the metabolic ward of the Helsinki University Central Hospital after a 12 h overnight fast. An indwelling cannula was inserted into an antecubital vein for infusions. A second cannula was inserted retrogradely into a heated hand vein to obtain arterialized venous blood for sampling. A saline infusion was started. Thirty minutes later, leucine (5,5,5-D3), 7 mg/kg body weight, and glycerol (1,1,2,3,3-D5), 500 mg (Isotec, Miamisburg, OH), were injected as a bolus. For the measurement of free [2H3]leucine concentrations in plasma, blood samples were taken before the tracer injection and at 2, 4, 6, 8, 10, 12, 15, 20, 30, and 45 min and 1, 2, 3, 4, 6, and 8 h. For the measurement of [2H3]leucine and [2H5]glycerol in VLDL1 and VLDL2, blood samples were taken before the injection of tracers and at 15, 30, 45, 60, 75, 90, 120, and 150 min and 3, 4, 5, 6, 7, and 8 h. The particle composition and apoB mass of the VLDL1 and VLDL2 fractions were determined 30 min before and 0, 4, and 8 h after the injection. The subjects continued to fast until 5 PM, when the last blood sample was taken. VLDL1 and VLDL2 were isolated from 8.4 ml of plasma as described (16Lindgren F.T. Jensen L.C. Hatch F.T. The isolation and quantitative analysis of serum lipoproteins.in: Nelson G.J. Blood Lipids and Lipoproteins: Quantitation, Composition, and Metabolism. John Wiley & Sons, New York1972: 181-274Google Scholar). The apoB and TG pool sizes were analyzed from samples obtained at 0, 4, and 8 h and prepared as described (16Lindgren F.T. Jensen L.C. Hatch F.T. The isolation and quantitative analysis of serum lipoproteins.in: Nelson G.J. Blood Lipids and Lipoproteins: Quantitation, Composition, and Metabolism. John Wiley & Sons, New York1972: 181-274Google Scholar). Pool sizes for apoB and TG were calculated as the product of plasma volume (4.5% of body weight) and the plasma concentration of apoB and TG in VLDL1 and VLDL2. The leucine content of the apoB pool was calculated from the apoB amino acid residue composition. The glycerol content was calculated from the TG concentration using a molar weight of 885 g/mol for TG and 92 g/mol for glycerol and assuming that 1 mol of TG equals 1 mol of glycerol. TG and cholesterol concentrations in total plasma and in all lipoprotein fractions were determined by automated enzymatic methods (Cobas Mira analyzer; Hoffman-La Roche, Basel, Switzerland). ApoB was analyzed in the plasma lipoprotein fractions as described (17Mero N. Syvanne M. Eliasson B. Smith U. Taskinen M.R. Postprandial elevation of apoB-48-containing triglyceride-rich particles and retinyl esters in normolipemic males who smoke.Arterioscler. Thromb. Vasc. Biol. 1997; 17: 2096-2102Crossref PubMed Scopus (63) Google Scholar). Serum glucose, insulin, free fatty acids, and alanine transaminase were analyzed as described (18Vakkilainen J. Porkka K.V. Nuotio I. Pajukanta P. Suurinkeroinen L. Ylitalo K. Viikari J.S. Ehnholm C. Taskinen M.R. Glucose intolerance in familial combined hyperlipidaemia. EUFAM Study Group.Eur. J. Clin. Invest. 1998; 28: 24-32Crossref PubMed Scopus (28) Google Scholar). Protein concentrations in lipoprotein fractions were measured by the method of Kashyap, Hynd, and Robinson (19Kashyap M.L. Hynd B.A. Robinson K. A rapid and simple method for measurement of total protein in very low density lipoproteins by the Lowry assay.J. Lipid Res. 1980; 21: 491-495Abstract Full Text PDF PubMed Google Scholar). The samples were precipitated with isopropanol, delipidated with ethanol-diethyl ether, dried, and hydrolyzed with 6 M HCl at 110°C for 22–24 h (16Lindgren F.T. Jensen L.C. Hatch F.T. The isolation and quantitative analysis of serum lipoproteins.in: Nelson G.J. Blood Lipids and Lipoproteins: Quantitation, Composition, and Metabolism. John Wiley & Sons, New York1972: 181-274Google Scholar). The samples were then prepared for analysis of leucine enrichment (20Egusa G. Brady D.W. Grundy S.M. Howard B.V. Isopropanol precipitation method for the determination of apolipoprotein B specific activity and plasma concentrations during metabolic studies of very low density lipoprotein and low density lipoprotein apolipoprotein B.J. Lipid Res. 1983; 24: 1261-1267Abstract Full Text PDF PubMed Google Scholar), and the [2H3]leucine enrichments in protein hydrolysates and plasma amino acids were performed as described (21Demant T. Packard C.J. Demmelmair H. Stewart P. Bedynek A. Bedford D. Seidel D. Shepherd J. Sensitive methods to study human apolipoprotein B metabolism using stable isotope-labeled amino acids.Am. J. Physiol. 1996; 270: E1022-E1036Crossref PubMed Google Scholar). Enrichments were determined by GC-MS with a quadrupole GC-MS instrument (MD 800; Fisons, Manchester, UK). The samples were precipitated with isopropanol and delipidated twice with ethanol-diethyl ether as described (20Egusa G. Brady D.W. Grundy S.M. Howard B.V. Isopropanol precipitation method for the determination of apolipoprotein B specific activity and plasma concentrations during metabolic studies of very low density lipoprotein and low density lipoprotein apolipoprotein B.J. Lipid Res. 1983; 24: 1261-1267Abstract Full Text PDF PubMed Google Scholar). The supernatants were combined, and the volume was increased to 20 ml with isopropanol. To remove phospholipids, 2 g of activated zeolite (product no. 96096; Fluka Biochemika, Buchs, Switzerland) was added to each tube and mixed for 20 min. After centrifugation, the supernatants were evaporated under N2 at 80°C. Isopropanol (1 ml) was added to each tube, transferred into a 1.5 ml vial, and dried on a heating block at 80°C. The glycerol samples were stored at −80°C. The amount of diacylglycerol and monoacylglycerols not extracted in the supernatant was not determined. This has been reported to be a minor contaminant, accounting for 2–10% of the total plasma TG (22Witter R.F. Whitner V.S. Determination of serum triglycerides.in: Nelson G.J. Blood Lipids and Lipoproteins: Quantification, Composition, and Metabolism. John Wiley & Sons, New York1972: 75-105Google Scholar). Immediately before analysis, the glycerol extracts were saponified with 250 μl of 2% KOH in ethanol, incubated at 60°C for 2 h, and dried under N2 at 70°C for 2 h. In three subjects, glycerol was isolated as described by Patterson et al. (23Patterson B.W. Zhao G. Elias N. Hachey D.L. Klein S. Validation of a new procedure to determine plasma fatty acid concentration and isotopic enrichment.J. Lipid Res. 1999; 40: 2118-2124Abstract Full Text Full Text PDF PubMed Google Scholar). Briefly, plasma proteins were precipitated with ice-cold acetone, equal volumes of hexane and water were added to the supernatant, and the upper phase (hexane) was dried in a centrifugal evaporator. Glycerol was derivatized to its 1,2,3-triacetate ester by adding equal volumes of pyridine and acetic anhydride (24Beylot M. Martin C. Beaufrere B. Riou J. Mornex R. Determination of steady state and nonsteady-state glycerol kinetics in humans using deuterium-labeled tracer.J. Lipid Res. 1987; 28: 414-422Abstract Full Text PDF PubMed Google Scholar). Enrichments were determined with a quadrupole GC-MS instrument (Trio-1000; Fisons) under electron ionization conditions within 24 h after saponification. Samples (1–3 μl) were injected automatically into a 30 m × 0.25 mm (inner diameter) × 0.25 μm DB5MS capillary column fitted with a 2 m plain silica guard column (J&W, Folsom, CA), which was run isothermally at 195°C, using a split ratio of 1:50, helium as the carrier gas, and a head pressure of 70 kPa (10 pounds per square inch). The glycerol derivative eluted at ∼3.5 min. Under these conditions, the derivative fragments between carbons 1 and 2 or 2 and 3 of the glycerol backbone resulted in the formation of two symmetrical fragments of m/z 145 and two symmetrical fragments of m/z 73 for the unlabeled derivative (24Beylot M. Martin C. Beaufrere B. Riou J. Mornex R. Determination of steady state and nonsteady-state glycerol kinetics in humans using deuterium-labeled tracer.J. Lipid Res. 1987; 28: 414-422Abstract Full Text PDF PubMed Google Scholar). The penta-deuterated derivative formed a tri-deuterated fragment at m/z 148 and a bi-deuterated fragment at m/z 75. Monitoring the larger fragment (m/z 148) allowed measurements to be made against a very low natural background, resulting in greater sensitivity than monitoring the smaller ion fragment. Ion mass fragments at m/z 147 and 148 were monitored in the selective ion recording mode. Ion peaks areas were integrated and quantified in arbitrary units with the LabBase GC-MS data management system (Fisons). To calculate isotope enrichments, the average value of the m/z 147:145 ratio was determined in the baseline sample. This value was multiplied by the m/z 148:147 ratio, and the resulting m/z 148:145 values were expressed as molar percentage excess (mpe) by the following formula: mpe=[(IRt/IRb)/(1+(IRt/IRb))]×100 where IRt is the m/z 148:145 peak area ratio for the enriched sample at time t and IRb is the equivalent ratio for the baseline (0 h) sample. Monitoring of the m+3 and m+2 peaks permitted greater loading of the GC-MS apparatus and enhanced our ability to detect low enrichments with good precision, as we do for leucine enrichment in apoB (21Demant T. Packard C.J. Demmelmair H. Stewart P. Bedynek A. Bedford D. Seidel D. Shepherd J. Sensitive methods to study human apolipoprotein B metabolism using stable isotope-labeled amino acids.Am. J. Physiol. 1996; 270: E1022-E1036Crossref PubMed Google Scholar). Standards with enrichments of 0.00–1.00 mpe were included at the beginning and end of each batch of samples and used to correct the calculated mpe values with the calculated recovery rate of the standards. Care was taken to ensure similar total ion counts in the standards and all samples. In three subjects, the m/z 148, 147, 146, and 145 peaks was measured to compare the glycerol enrichment by assessing the d5-glycerol tracer as an entire moiety in GC-MS analysis and by the technique described above. The measurements of enrichment of free leucine in plasma, VLDL1, and VLDL2, enrichment of glycerol in VLDL1 and VLDL2, the pool sizes of leucine and glycerol (i.e., derived from apoB and TG) in VLDL1 and VLDL2, and the known injected amounts of labeled leucine and glycerol were used to determine kinetic parameters using the modeling software SAAMII (SAAM Institute, Seattle, WA) and Matlab. By simultaneously modeling apoB and TG kinetics, it was possible to determine the TG/apoB ratio of newly produced VLDL1 and VLDL2 particles and to follow in detail the transfer and removal of lipids. The data were analyzed with two linear compartmental models. The proposed apoB/TG model can be envisioned as a two layer model, connected at certain points, and is based on the apoB model originally described by Packard et al. (25Packard C.J. Gaw A. Demant T. Shepherd J. Development and application of a multicompartmental model to study very low density lipoprotein subfraction metabolism.J. Lipid Res. 1995; 36: 172-187Abstract Full Text PDF PubMed Google Scholar), which has been used in several studies (9Malmstrom R. Packard C.J. Caslake M. Bedford D. Stewart P. Yki-Jarvinen H. Shepherd J. Taskinen M.R. Defective regulation of triglyceride metabolism by insulin in the liver in NIDDM.Diabetologia. 1997; 40: 454-462Crossref PubMed Scopus (276) Google Scholar, 10Malmstrom R. Packard C.J. Watson T.D. Rannikko S. Caslake M. Bedford D. Stewart P. Yki-Jarvinen H. Shepherd J. Taskinen M.R. Metabolic basis of hypotriglyceridemic effects of insulin in normal men.Arterioscler. Thromb. Vasc. Biol. 1997; 17: 1454-1464Crossref PubMed Scopus (166) Google Scholar, 25Packard C.J. Gaw A. Demant T. Shepherd J. Development and application of a multicompartmental model to study very low density lipoprotein subfraction metabolism.J. Lipid Res. 1995; 36: 172-187Abstract Full Text PDF PubMed Google Scholar, 26Packard C.J. Demant T. Stewart J.P. Bedford D. Caslake M.J. Schwertfeger G. Bedynek A. Shepherd J. Seidel D. Apolipoprotein B metabolism and the distribution of VLDL and LDL subfractions.J. Lipid Res. 2000; 41: 305-318Abstract Full Text Full Text PDF PubMed Google Scholar, 27Griffin B.A. Packard C.J. Metabolism of VLDL and LDL subclasses.Curr. Opin. Lipidol. 1994; 5: 200-206Crossref PubMed Scopus (61) Google Scholar, 28Malmstrom R. Packard C.J. Caslake M. Bedford D. Stewart P. Shepherd J. Taskinen M.R. Effect of heparin-stimulated plasma lipolytic activity on VLDL APO B subclass metabolism in normal subjects.Atherosclerosis. 1999; 146: 381-390Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar, 29Malmstrom R. Packard C.J. Caslake M. Bedford D. Stewart P. Yki-Jarvinen H. Shepherd J. Taskinen M.R. Effects of insulin and acipimox on VLDL1 and VLDL2 apolipoprotein B production in normal subjects.Diabetes. 1998; 47 ([Erratum. 1998. Diabetes. 47: 1532.]): 779-787Crossref PubMed Scopus (161) Google Scholar). Basically, the model consists of four parts: plasma leucine, plasma glycerol, the assembly of lipoprotein, and lipoprotein plasma kinetics. Free plasma leucine was modeled as a four-compartment catenary system (Fig. 1). Compartment 1 is the plasma compartment, where the leucine is injected. Compartments 3 and 4 are protein pools, which give a slow release of leucine. Compartment 2 is an intracellular compartment from which the leucine is transferred into the liver's apoB synthetic machinery. The transfer coefficients between compartments 1 and 2 are equal, giving equilibrium. To further decrease the number of unknowns, k3,4 is set at 0.1 k4,3 (i.e., the transfer from compartment 4 to 3 is one-tenth of the transfer from compartment 3 to 4) (26Packard C.J. Demant T. Stewart J.P. Bedford D. Caslake M.J. Schwertfeger G. Bedynek A. Shepherd J. Seidel D. Apolipoprotein B metabolism and the distribution of VLDL and LDL subfractions.J. Lipid Res. 2000; 41: 305-318Abstract Full Text Full Text PDF PubMed Google Scholar). Other approaches such as a forcing function, determined from measurements, could also be used. TG assembly was modeled with a modified variant of a model described by Zech et al. (4Zech L.A. Grundy S.M. Steinberg D. Berman M. Kinetic model for production and metabolism of very low density lipoprotein triglycerides. Evidence for a slow production pathway and results for normolipidemic subjects.J. Clin. Invest. 1979; 63: 1262-1273Crossref PubMed Scopus (86) Google Scholar). The plasma compartment (i.e., compartment 13) is connected to an extrahepatic pool (compartment 12). The fractional transfer coefficients are fixed by the population means as described by Zech et al. (4Zech L.A. Grundy S.M. Steinberg D. Berman M. Kinetic model for production and metabolism of very low density lipoprotein triglycerides. Evidence for a slow production pathway and results for normolipidemic subjects.J. Clin. Invest. 1979; 63: 1262-1273Crossref PubMed Scopus (86) Google Scholar): k12,13 = 12, k13,12 = 5, and k0,13 = 19 [h–1] (Fig. 1). This restriction could be relaxed by measurements of enrichment of free glycerol in plasma and to either choose parameters to fit the data or use a forcing function determined by the data. To justify the approach of population means, we have made measurements of plasma glycerol and compared the kinetic parameters determined by the two models. The TG conversion (compartment 14) has influx from compartment 13, and a slow path for conversion is implemented as compartment 21 interchanging materials with compartment 14. Compared with the model by Zech et al. (4Zech L.A. Grundy S.M. Steinberg D. Berman M. Kinetic model for production and metabolism of very low density lipoprotein triglycerides. Evidence for a slow production pathway and results for normolipidemic subjects.J. Clin. Invest. 1979; 63: 1262-1273Crossref PubMed Scopus (86) Google Scholar), the slow pathway was modeled by compartment 21 instead of a compartment with influx from compartment 13 and outfluxes into compartments 5 and 8. The reason for choosing the current model is the reduced complexity of the model. Both models allow for a slow production pathway (most noticeable after 8 h), but the current implementation does not allow for a small amount of material to rapidly pass through the slow pathway. In theory, information regarding the extent of tracer recycling in the liver through compartment 21 could be obtained by following VLDL kinetics over a prolonged period (e.g., 24 h). In the latter stages, the input of tracer into VLDL would be dominated by internally recycled material via compartment 21 (i.e., material stored in compartment 21 and released back to compartment 14). Over the 8 h of the current experiments, there was limited ability to define this “tail” of the VLDL curve with precision (4Zech L.A. Grundy S.M. Steinberg D. Berman M. Kinetic model for production and metabolism of very low density lipoprotein triglycerides. Evidence for a slow production pathway and results for normolipidemic subjects.J. Clin. Invest. 1979; 63: 1262-1273Crossref PubMed Scopus (86) Google Scholar, 30Zech L.A. Boston R.C. Foster D.M. The methodology of compartmental modeling as applied to the investigation of lipoprotein metabolism.Methods Enzymol. 1986; 129: 366-384Crossref PubMed Scopus (6) Google Scholar). The synthesis of apoB and lipoproteins was modeled by two delays, a seven-compartment delay initially set to 0.5 h for apoB and a five-compartment delay initially set to 0.3 h for TG (Fig. 1). In the underlying apoB model (Fig. 1), a particle is thought of as moving downward (i.e., to a higher density lipoprotein) as it moves from one compartment to another. The TG/apoB decreases as the density increases. Hence, for an apoB particle to move downward in the model, its carrier lipoprotein must lose TG. Focusing on the apoB model (Fig. 1), the hydrolysis chain is modeled by a four-compartment chain (compartments 5, 6, 8, and 10) and two slowly decaying compartments (7 and 9). VLDL1 consists of compartments 5, 6, and 7, and VLDL2 consists of compartments 8, 10, and 9. Direct removal of apoB (and hence whole particles) is allowed from compartments 6, 7, 9, and 10. Particles in compartment 10 can be removed both by direct removal and by transfer to intermediate density lipoprotein (IDL). However, it is not possible to separate these without sampling IDL apoB enrichments and measuring the pool size. VLDL TG kinetics is often modeled by a single compartment (i.e., having monoexponential decay), but our goal was to use the same model used for apoB. This made it possible to extract quantities such as the TG/apoB ratio of newly produced particles. Using different models for apoB and TG would have made it impossible to compare the transfer rates of apoB and TG. Mathematically, a compartment is defined as an amount of material with homogeneous kinetics. Therefore, all particles in an apoB compartment should be thought of as having similar kinetics, and their average TG/apoB ratio is the ratio of the pools. However, there are variations of composition and size within VLDL subfractions, and the true distribution of lipoprotein particles is continuous. Thus, a small VLDL1 particle might be smaller than a large VLDL2 particle, and consequently the TG/apoB ratio of some VLDL1 particles may be lower than that of some VLDL2. The TG model shares the structure of the apoB model, in which each apoB compartment (5, 6, etc.) has a corresponding TG compartment number (15, 16, etc.). There are several ways to connect the TG model to the apoB model. Here, we present an intuitive approach in which the TG is removed in the transition between two compartments. We denote the TG/apoB ratio in a compartment by Ai, so the TG mass in a compartment is Q(i+10) = Ai × Qi. Furthermore, the fraction of the TG that is removed during the transition is denoted (1 − fj,i). More precisely, the TG/apoB ratio of a particle that leaves compartment i is Ai, the amount of TG per apoB that is removed from that particle is (1 − fj,i)Ai, and the TG/apoB ratio of the particle when it enters the destination compartment, j, is fj,i × Ai. Therefore, the fractional transfer coefficients for the TG compartments are defined as follows: kj+10,i+10=fj,ikj,i,k0,i+10=k0,i+∑j=510(1−fj,i)kj,iwhere i, j, = 5, … 10. The steady-state assumption posits that A5 equals the ratio of the TG and apoB fluxes into compartments 15 and 5. Furthermore A6 = A5 × f6,5, A7 = A5 × f7,5, A8 = A6 × f8,6, etc. VLDL2 particles synthesized in the liver and derived from VLDL1 should have the same TG/apoB ratio. This is determined by defining the fraction of TG going into VLDL1, d15, as follows: d15=d5d5+f8,6f6,5(1−d5)where d5 is the fraction of ap" @default.
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• W1984177683 date "2005-01-01" @default.
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• W1984177683 title "A new combined multicompartmental model for apolipoprotein B-100 and triglyceride metabolism in VLDL subfractions" @default.
• W1984177683 cites W11746928 @default.
• W1984177683 cites W1927803805 @default.
• W1984177683 cites W2000362605 @default.
• W1984177683 cites W2012708342 @default.
• W1984177683 cites W2013067322 @default.
• W1984177683 cites W2019277096 @default.
• W1984177683 cites W2023791516 @default.
• W1984177683 cites W2052008556 @default.
• W1984177683 cites W2065481372 @default.
• W1984177683 cites W2095500795 @default.
• W1984177683 cites W2100577034 @default.
• W1984177683 cites W2102578670 @default.
• W1984177683 cites W2117950105 @default.
• W1984177683 cites W2122433263 @default.
• W1984177683 cites W2150855617 @default.
• W1984177683 cites W2155129096 @default.
• W1984177683 cites W2166384071 @default.
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