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• W2149139434 abstract "Lipoprotein kinetic parameters are determined from mass spectrometry data after administering mass isotopes of amino acids, which label proteins endogenously. The standard procedure is to model the isotopic content of the labeled precursor amino acid and of proteins of interest as tracer-to-tracee ratio (TTR). It is shown here that even though the administered tracer alters amino acid mass and turnover, apolipoprotein synthesis is unaltered and hence the apolipoprotein system is in a steady state, with the total (labeled plus unlabeled) masses and fluxes remaining constant. The correct model formulation for apolipoprotein kinetics is shown to be in terms of tracer enrichment, not of TTR. The needed mathematical equations are derived. A theoretical error analysis is carried out to calculate the magnitude of error in published results using TTR modeling. It is shown that TTR modeling leads to a consistent underestimation of the fractional synthetic rate. In constant-infusion studies, the bias error percent is shown to equal approximately the plateau enrichment, generally <10%. It is shown that, in bolus studies, the underestimation error can be larger. Thus, for mass isotope studies with endogenous tracers, apolipoproteins are in a steady state and the data should be fitted by modeling enrichments. Lipoprotein kinetic parameters are determined from mass spectrometry data after administering mass isotopes of amino acids, which label proteins endogenously. The standard procedure is to model the isotopic content of the labeled precursor amino acid and of proteins of interest as tracer-to-tracee ratio (TTR). It is shown here that even though the administered tracer alters amino acid mass and turnover, apolipoprotein synthesis is unaltered and hence the apolipoprotein system is in a steady state, with the total (labeled plus unlabeled) masses and fluxes remaining constant. The correct model formulation for apolipoprotein kinetics is shown to be in terms of tracer enrichment, not of TTR. The needed mathematical equations are derived. A theoretical error analysis is carried out to calculate the magnitude of error in published results using TTR modeling. It is shown that TTR modeling leads to a consistent underestimation of the fractional synthetic rate. In constant-infusion studies, the bias error percent is shown to equal approximately the plateau enrichment, generally <10%. It is shown that, in bolus studies, the underestimation error can be larger. Thus, for mass isotope studies with endogenous tracers, apolipoproteins are in a steady state and the data should be fitted by modeling enrichments. Beginning in the 1970s, apolipoprotein kinetics were routinely studied with exogenous tracers, for instance by isolating VLDL or LDL from a subject, radioiodinating it, and injecting it back into the subject (1Langer T. Strober W. Levy R.I. The metabolism of low density lipoprotein in familial type II hyperlipoproteinemia.J. Clin. Invest. 1972; 51: 1528-1536Crossref PubMed Google Scholar, 2Phair R.D. Hammond M.G. Bowden J.A. Fried M. Fisher W.R. Berman M. Preliminary model for human lipoprotein metabolism in hyperlipoproteinemia.Fed. Proc. 1975; 34: 2263-2270PubMed Google Scholar, 3Kissebah A.H. Alfarsi S. Adams P.W. Wynn V. The metabolic fate of plasma lipoproteins in normal subjects and in patients with insulin resistance and endogenous hypertriglyceridaemia.Diabetologia. 1976; 12: 501-509Crossref PubMed Google Scholar, 4Packard C.J. Third J.L. Shepherd J. Lorimer A.R. Morgan H.G. Lawrie T.D. Low density lipoprotein metabolism in a family of familial hypercholesterolemic patients.Metabolism. 1976; 25: 995-1006Abstract Full Text PDF PubMed Google Scholar). Endogenous labeling, with a labeled precursor of the metabolite of interest, has the virtue of labeling the synthetic pathways and not altering tracer metabolic properties, as might happen with exogenous labeling. Whole body cholesterol metabolism was studied with tritiated water (5Kekki M. Miettinen T.A. Wahlstrom B. Measurement of cholesterol synthesis in kinetically defined pools using fecal steroid analysis and double labeling technique in man.J. Lipid Res. 1977; 18: 99-114Abstract Full Text PDF PubMed Google Scholar), and tritiated leucine has been used to study lipoprotein kinetics (6Beltz W.F. Kesaniemi Y.A. Miller N.H. Grundy S.M. Zech L.A. Studies on the metabolism of apolipoprotein B in hypertriglyceridemic subjects using simultaneous administration of tritiated leucine and radioiodinated very low density lipoprotein.J. Lipid Res. 1990; 31: 361-374Abstract Full Text PDF PubMed Google Scholar, 7Stacpoole P.W. von Bermann K. Kilgore L.L. Zech L.A. Fisher W.R. Nutritional regulation of cholesterol synthesis and apolipoprotein B kinetics: studies in patients with familial hypercholesterolemia and normal subjects treated with a high carbohydrate, low fat diet.J. Lipid Res. 1991; 32: 1837-1848Abstract Full Text PDF PubMed Google Scholar, 8Fisher W.R. Venkatakrishnan V. Fisher E.S. Stacpoole P.W. Zech L.A. The 3H-leucine tracer: its use in kinetic studies of plasma lipoproteins.Metabolism. 1997; 46: 333-342Abstract Full Text PDF PubMed Scopus (12) Google Scholar). Highly sensitive gas chromatography-mass spectrometry and refinements thereof, and the availability of synthetic amino acids and other molecules that are multiply labeled with mass isotopes, have altered the field to the point that endogenous labeling with mass isotopes is now the norm in human turnover studies (9Barrett P.H. Chan D.C. Watts G.F. Design and analysis of lipoprotein tracer kinetics studies in humans.J. Lipid Res. 2006; 47: 1607-1619Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar). An important aspect of mass isotopes is that the amount of tracer introduced is not negligible in relation to the amount in plasma of the tracee. Cobelli, Toffolo, and Foster (10Cobelli C. Toffolo G. Foster D.M. Tracer-to-tracee ratio for analysis of stable isotope tracer data—link with radioactive kinetic formalism.Am. J. Physiol. Endocrinol. Metab. 1992; 262: E968-E975Crossref PubMed Google Scholar) and Foster et al. (11Foster D.M. Barrett P.H.R. Toffolo G. Beltz W.F. Cobelli C. Estimating the fractional synthetic rate of plasma apolipoproteins and lipids from stable-isotope data.J. Lipid Res. 1993; 34: 2193-2205Abstract Full Text PDF PubMed Google Scholar) considered this problem and advocated the use of tracer-to-tracee ratio (TTR) in place of the previously standard use of tracer enrichment in atoms percent excess or moles percent excess (12Cryer 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, 13Schauder P. Arends J. Schafer G. Langer K. Bier D.M. Incorporation of N-15-glycine into VLDL and LDL—in vivo synthesis of apolipoprotein-B in post-absorptive and fasting individuals [in German].Klin. Wochenschr. 1989; 67: 280-285Crossref PubMed Scopus (0) Google Scholar, 14Cohn J.S. Wagner D.A. Cohn S.D. Miller 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 Google Scholar, 15Cortner J.A. Le N-A. Coates P.M. Bennett M.J. Cryer D.R. Determinants of fasting plasma triglyceride levels: metabolism of hepatic and intestinal lipoproteins.Eur. J. Clin. Invest. 1992; 22: 158-165Crossref PubMed Google Scholar). Since then, nearly all investigators have used TTR in analyzing mass isotope data to calculate lipoprotein turnover parameters. In what follows, we revisit this issue and derive the mathematical relationships needed for the analysis of tracer data from endogenous labeling. In particular, we show that the apolipoprotein system is in a steady state and that the correct formulation is in terms of tracer enrichment or concentration, not TTR. We show that compartmental models and the usual fractional synthetic rate (FSR) equations are valid provided that they are written for tracer enrichments but not for TTRs. The error in using TTR is shown for constant-infusion studies to be in the range of the plateau tracer enrichment, usually 5–10%; the error is shown to be higher for bolus studies. The word “enrichment” (E) is used here solely to denote tracer concentration, defined as the amount of tracer divided by the sum of the amounts of tracer and tracee (16Matthews D.E. Motil K.J. Rohrbaugh D.K. Burke J.F. Young V.R. Bier D.M. Measurement of leucine metabolism in man from a primed, continuous infusion of L-[1-3C]leucine.Am. J. Physiol. Endocrinol. Metab. 1980; 238: E473-E479Crossref PubMed Google Scholar). The word is used sometimes to denote TTR, but not here. That mass isotope tracers have nonnegligible mass has been recognized from early on. Matthews et al. (16Matthews D.E. Motil K.J. Rohrbaugh D.K. Burke J.F. Young V.R. Bier D.M. Measurement of leucine metabolism in man from a primed, continuous infusion of L-[1-3C]leucine.Am. J. Physiol. Endocrinol. Metab. 1980; 238: E473-E479Crossref PubMed Google Scholar) adjusted for it by assuming that the total flux is increased by a constant tracer infusion, so that a tracer balance can be written as:(Q+i)Ep=iEiEq. 1 where Q is the tracee flux, i is the constant infusion rate of the tracer, Ep is the plasma enrichment of the traced molecule (amino acid in Ref. 16Matthews D.E. Motil K.J. Rohrbaugh D.K. Burke J.F. Young V.R. Bier D.M. Measurement of leucine metabolism in man from a primed, continuous infusion of L-[1-3C]leucine.Am. J. Physiol. Endocrinol. Metab. 1980; 238: E473-E479Crossref PubMed Google Scholar), and Ei is the infusion enrichment. With a radiotracer, because of its negligible mass, there would be no i on the left side of the equation, and the right side would be the infusion rate of radioactivity. The question relevant to lipoprotein turnover is whether every component of the flux changes similarly. Foster et al. (11Foster D.M. Barrett P.H.R. Toffolo G. Beltz W.F. Cobelli C. Estimating the fractional synthetic rate of plasma apolipoproteins and lipids from stable-isotope data.J. Lipid Res. 1993; 34: 2193-2205Abstract Full Text PDF PubMed Google Scholar) assume that incorporation into specific proteins follows the same pattern. This approach is shown by them to lead to simple equations for protein kinetics. The tracee masses and fluxes are constant, and linear differential equations can be written for TTR, the equations identical in form to those written for radiotracers. Figure 1 shows the essential part of their model (Fig. 1 in Ref. 11Foster D.M. Barrett P.H.R. Toffolo G. Beltz W.F. Cobelli C. Estimating the fractional synthetic rate of plasma apolipoproteins and lipids from stable-isotope data.J. Lipid Res. 1993; 34: 2193-2205Abstract Full Text PDF PubMed Google Scholar) for leucine incorporation into VLDL apolipoprotein B (apoB), leaving out other pathways. Before tracer infusion, there is Uleu of unlabeled leucine, being incorporated into VLDL apoB with a rate constant of kleu; UB is the tracee mass of VLDL apoB. During the tracer study, by the assumption of tracee steady state, Uleu, kleu, and UB do not change; at any time t, there is mleu(t) of tracer, being incorporated into labeled VLDL apoB with the same rate constant as the tracee, kleu. [Since an apoB molecule has multiple leucine molecules, a labeled leucine combines with unlabeled leucine in the same apoB molecule, so this model is not precise, but it is easily rectified by combining the two apoB pools into one. None of the results below are affected, and the figure is drawn to be close to Fig. 1 in Foster et al. (11Foster D.M. Barrett P.H.R. Toffolo G. Beltz W.F. Cobelli C. Estimating the fractional synthetic rate of plasma apolipoproteins and lipids from stable-isotope data.J. Lipid Res. 1993; 34: 2193-2205Abstract Full Text PDF PubMed Google Scholar).] Thus, the constant tracee flux assumption predicts that, compared with the steady state before the study, more leucine should be incorporated into VLDL apoB during the tracer study and the total amount of VLDL apoB should increase correspondingly. If the TTR of leucine in VLDL apoB approaches 5%, which is typical, then, under the constant tracee flux assumption, VLDL apoB mass should be higher by 5% at the end of the constant infusion. There are two reasons why the assumption of constant tracee masses and fluxes may be invalid. One is that the assumption of constant tracee flux, applied simultaneously to multiple amino acids, leads to a contradiction. The other is that there is evidence that apolipoprotein synthesis is unaltered by tracer infusion. These reasons are elaborated on below. Consider a study with a primed constant infusion of a tracer of leucine and a simultaneous bolus injection of a tracer of glycine, as in Parhofer et al. (17Parhofer K.G. Barrett P.H.R. Bier D.M. Schonfeld G. Determination of kinetic parameters of apolipoprotein B metabolism using amino acids labeled with stable isotopes.J. Lipid Res. 1991; 32: 1311-1323Abstract Full Text PDF PubMed Google Scholar). Figure 2A shows three amino acids that go into the synthesis of apoB. The assumption that the tracee remains in a steady state can be applied to each of the three amino acids. The incorporation from each tracee pool is shown as constant, whereas the incorporation from each tracer pool varies with time, denoted by (t). Figure 2B shows the hypothetical total rate of incorporation of each precursor (tracer plus tracee) resulting from the assumption of tracee steady state. The values before tracer infusion are at the mol%s of the three amino acids in apoB. The total incorporation rate of leucine increases to a higher steady state, that of glycine increases sharply and declines with the clearance of the glycine tracer, and that of alanine remains unchanged. Thus, if the tracee fluxes are constant, the relative amounts of leucine, glycine, and alanine in newly synthesized apoB begin at the known values for apoB, but soon after the tracer study begins, newly synthesized apoB has 14% leucine and 9% glycine, the percentages changing every moment, a stoichiometric impossibility as this would mean a changing amino acid composition of the protein.Fig. 2.Schemata of three amino acid precursors, and their rates of incorporation into a specific apolipoprotein in a hypothetical study with a primed constant infusion of a tracer of leucine and a simultaneous bolus injection of a tracer of glycine. Under the assumption of tracee steady state, A shows the precursor pools, with the small pools representing tracers. If the tracee (unlabeled) masses Uleu, Ugly, and Uala are constant, the rates of incorporation vary with time, as given by the formulas under the arrows and as shown in B. The numbers along the y axis are in arbitrary units. The curves begin at the leucine, glycine, and alanine contents of apolipoprotein B before tracer infusion. Soon after 0 h, leucine is at 14 instead of 12.5, and glycine is at 9 instead of 4.5, resulting in a changing stoichiometry of the apoB product, an impossibility. C shows the tracer-to-tracee ratio (TTR) data from Fig. 4 of Parhofer et al. (17Parhofer K.G. Barrett P.H.R. Bier D.M. Schonfeld G. Determination of kinetic parameters of apolipoprotein B metabolism using amino acids labeled with stable isotopes.J. Lipid Res. 1991; 32: 1311-1323Abstract Full Text PDF PubMed Google Scholar), presented here, under the assumption of tracee steady state, as the change in total mass of VLDL apoB. If tracee apoB were constant, total apoB increased by nearly 4% to a new steady level, according to the leucine TTR data, whereas the glycine TTR data would suggest that total apoB increased quickly by nearly 4% and then declined. The dashed horizontal line indicates that an untraced amino acid should be interpreted as no change in VLDL apoB. Thus, the assumption of a tracee steady state is contradicted by the data of Parhofer et al. (17Parhofer K.G. Barrett P.H.R. Bier D.M. Schonfeld G. Determination of kinetic parameters of apolipoprotein B metabolism using amino acids labeled with stable isotopes.J. Lipid Res. 1991; 32: 1311-1323Abstract Full Text PDF PubMed Google Scholar). AA, amino acid.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Fig. 2.Schemata of three amino acid precursors, and their rates of incorporation into a specific apolipoprotein in a hypothetical study with a primed constant infusion of a tracer of leucine and a simultaneous bolus injection of a tracer of glycine. Under the assumption of tracee steady state, A shows the precursor pools, with the small pools representing tracers. If the tracee (unlabeled) masses Uleu, Ugly, and Uala are constant, the rates of incorporation vary with time, as given by the formulas under the arrows and as shown in B. The numbers along the y axis are in arbitrary units. The curves begin at the leucine, glycine, and alanine contents of apolipoprotein B before tracer infusion. Soon after 0 h, leucine is at 14 instead of 12.5, and glycine is at 9 instead of 4.5, resulting in a changing stoichiometry of the apoB product, an impossibility. C shows the tracer-to-tracee ratio (TTR) data from Fig. 4 of Parhofer et al. (17Parhofer K.G. Barrett P.H.R. Bier D.M. Schonfeld G. Determination of kinetic parameters of apolipoprotein B metabolism using amino acids labeled with stable isotopes.J. Lipid Res. 1991; 32: 1311-1323Abstract Full Text PDF PubMed Google Scholar), presented here, under the assumption of tracee steady state, as the change in total mass of VLDL apoB. If tracee apoB were constant, total apoB increased by nearly 4% to a new steady level, according to the leucine TTR data, whereas the glycine TTR data would suggest that total apoB increased quickly by nearly 4% and then declined. The dashed horizontal line indicates that an untraced amino acid should be interpreted as no change in VLDL apoB. Thus, the assumption of a tracee steady state is contradicted by the data of Parhofer et al. (17Parhofer K.G. Barrett P.H.R. Bier D.M. Schonfeld G. Determination of kinetic parameters of apolipoprotein B metabolism using amino acids labeled with stable isotopes.J. Lipid Res. 1991; 32: 1311-1323Abstract Full Text PDF PubMed Google Scholar). AA, amino acid.View Large Image Figure ViewerDownload Hi-res image Download (PPT) This can also been seen in the composition of the product, VLDL apoB. Under the assumption of constant tracee mass, the TTR in VLDL apoB leucine or glycine is equivalent to the change in total VLDL apoB. If leucine TTR is 4% at some time, then VLDL apoB at that moment is 4% higher than before the study. Likewise, if glycine TTR in VLDL apoB is 2%, then VLDL apoB is up by 2% at that moment. For an amino acid such as alanine, there is no tracer and so total VLDL apoB should be unchanging. Figure 2C shows the VLDL apoB TTR data from Parhofer et al. (17Parhofer K.G. Barrett P.H.R. Bier D.M. Schonfeld G. Determination of kinetic parameters of apolipoprotein B metabolism using amino acids labeled with stable isotopes.J. Lipid Res. 1991; 32: 1311-1323Abstract Full Text PDF PubMed Google Scholar), with the TTR values presented here, under the tracee constancy assumption, as changes in total VLDL apoB mass. The horizontal line indicates that an untraced amino acid such as alanine would imply no change in VLDL apoB. The three curves in Fig. 2C show very different behaviors for total VLDL apoB. Thus, the data of Parhofer et al. (17Parhofer K.G. Barrett P.H.R. Bier D.M. Schonfeld G. Determination of kinetic parameters of apolipoprotein B metabolism using amino acids labeled with stable isotopes.J. Lipid Res. 1991; 32: 1311-1323Abstract Full Text PDF PubMed Google Scholar) are inconsistent with the tracee steady state assumption. The data of Demant et al. (18Demant 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. Endocrinol. Metab. 1996; 270: E1022-E1036Crossref PubMed Google Scholar), with simultaneous leucine bolus and phenylalanine constant infusion, would also support this conclusion. Indeed, any double-tracer study in which the TTRs of the two tracers in VLDL apoB are not identical contradicts the assumption of tracee steady state. The other reason for the likely invalidity of a constant tracee flux to apolipoproteins is that there is no evidence that infusion of a single amino acid affects apolipoprotein synthesis. Apolipoprotein synthesis is regulated by many factors affecting transcription, mRNA stability, translation, and posttranslational degradation, but a single amino acid availability is not known to be such a factor. Cohn et al. (14Cohn J.S. Wagner D.A. Cohn S.D. Miller 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 Google Scholar) and Lichtenstein et al. (19Lichtenstein A.H. Cohn J.S. Hachey D. Millar J.S. Ordovas J.M. Schaefer E.J. Comparison of deuterated leucine, valine, and lysine in the measurement of human apolipoprotein A-I and B-100 kinetics.J. Lipid Res. 1990; 31: 1693-1701Abstract Full Text PDF PubMed Google Scholar) measured VLDL apoB a number of times during a 15 h constant-infusion study. No time trend in VLDL apoB mass was seen, whereas VLDL apoB TTR increased to ∼6%. This constancy has been replicated in a number of studies by that group (20Lichtenstein A.H. Hachey D. Millar J.S. Jenner L.J. Booth L. Ordovas J.M. Schaefer E.J. Measurement of human apolipoprotein B-48 and B-100 kinetics in triglyceride-rich lipoproteins using [5,5,5-2H3]leucine.J. Lipid Res. 1992; 33: 907-914Abstract Full Text PDF PubMed Google Scholar, 21Welty F.K. Lichtenstein A.H. Barrett P.H.R. Dolnikowski G.G. Ordovas J.M. Schaefer E.J. Decreased production and increased catabolism of apolipoprotein B-100 in apolipoprotein B-67/B-100 heterozygotes.Arterioscler. Thromb. Vasc. Biol. 1997; 17: 881-888Crossref PubMed Google Scholar, 22Welty F.K. Lichtenstein A.H. Barrett P.H.R. Dolnikowski G.G. Schaefer E.J. Human apolipoprotein (apo) B-48 and apoB-100 kinetics with stable isotopes.Arterioscler. Thromb. Vasc. Biol. 1999; 19: 2966-2974Crossref PubMed Google Scholar, 23Welty F.K. Lichtenstein A.H. Barrett P.H.R. Dolnikowski G.G. Schaefer E.J. Interrelationships between human apolipoprotein A-I and apolipoproteins B-48 and B-100 kinetics using stable isotopes.Arterioscler. Thromb. Vasc. Biol. 2004; 24: 1703-1707Crossref PubMed Scopus (36) Google Scholar), in which multiple VLDL apoB fractions were obtained during the study. Other studies (24Ikewaki K. Nishiwaki M. Sakamoto T. Ishikawa T. Fairwell T. Zech L.A. Nagano M. Nakamura H. Brewer H.B. Rader D.J. Increased catabolic rate of low-density lipoproteins in humans with cholesteryl ester transfer protein-deficiency.J. Clin. Invest. 1995; 96: 1573-1581Crossref PubMed Google Scholar, 25Pietzsch J. Wiedemann B. Julius U. Nitzsche S. Gehrisch S. Bergmann S. Leonhardt W. Jaross W. Hanefeld M. Increased clearance of low density lipoprotein precursors in patients with heterozygous familial defective apolipoprotein B-100: a stable isotope approach.J. Lipid Res. 1996; 37: 2074-2087Abstract Full Text PDF PubMed Google Scholar, 26Latour M.A. Patterson B.W. Pulai J. Chen Z.J. Schonfeld G. Metabolism of apolipoprotein B-100 in a kindred with familial hypobetalipoproteinemia without a truncated form of apoB.J. Lipid Res. 1997; 38: 592-599Abstract Full Text PDF PubMed Google Scholar, 27Elias N. Patterson B.W. Schonfeld G. Decreased production rates of VLDL triglycerides and apoB-100 in subjects heterozygous for familial hypobetalipoproteinemia.Arterioscler. Thromb. Vasc. 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Lack of evidence for reduced plasma apo B48 catabolism in patients with heterozygous familial hypercholesterolemia carrying the same null LDL receptor gene mutation.Atherosclerosis. 2004; 172: 367-373Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar, 31Magkos F. Wright D.C. Patterson B.W. Mohammed B.S. Mittendorfer B. Lipid metabolism response to a single, prolonged bout of endurance exercise in healthy young men.Am. J. Physiol. Endocrinol. Metab. 2006; 290: E355-E362Crossref PubMed Scopus (84) Google Scholar) have also found no change in apolipoprotein concentrations during constant-infusion studies. There appear to be no reports of an increase in VLDL apoB mass during a constant-infusion study. Davis and coworkers (32Davis T.A. Fiorotto M.L. Burrin D.G. Reeds P.J. Nguyen H.V. Beckett P.R. Vann R.C. O'Connor P.M.J. Stimulation of protein synthesis by both insulin and amino acids is unique to skeletal muscle in neonatal pigs.Am. J. Physiol. Endocrinol. Metab. 2002; 282: E880-E890Crossref PubMed Scopus (167) Google Scholar) have shown in pigs that, once the neonatal phase is over, amino acid infusion or protein intake increases muscle protein synthesis, but the effect on liver protein synthesis is quite modest, as was found earlier in rats (33Mosoni L. Houlier M.L. Mirand P.P. Bayle G. Grizard J. Effect of amino acids alone or with insulin on muscle and liver protein synthesis in adult and old rats.Am. J. Physiol. Endocrinol. Metab. 1993; 264: E614-E620Crossref PubMed Google Scholar, 34Anthony T.G. Anthony J.C. Yoshizawa F. Kimball S.R. Jefferson L.S. Oral administration of leucine stimulates ribosomal protein mRNA translation but not global rates of protein synthesis in the liver of rats.J. Nutr. 2001; 131: 1171-1176Crossref PubMed Scopus (95) Google Scholar). Of particular relevance to apolipoproteins, Motil et al. (35Motil K.J. Opekun A.R. Montandon C.M. Berthold H.K. Davis T.A. Klein P.D. Reeds P.J. Leucine oxidation changes rapidly after dietary protein intake is altered in adult women but lysine flux is unchanged as is lysine incorporation into VLDL-apolipoprotein B-100.J. Nutr. 1994; 124: 41-51Crossref PubMed Scopus (35) Google Scholar) studied two different protein intakes in five women and found that leucine oxidation increased with protein intake but lysine incorporation into apoB did not. These animal and human studies are consistent with cell culture studies showing that a significant fraction of newly synthesized apoB is degraded, with secretion determined largely by lipid availability (36Fisher E.A. Ginsberg H.N. Complexity in the secretory pathway: the assembly and secretion of apolipoprotein B-containing lipoproteins.J. Biol. Chem. 2002; 277: 17377-17380Abstract Full Text Full Text PDF PubMed Scopus (354) Google Scholar). Intracellular apoB degradation has been estimated by compartmental modeling to be ∼90% in HepG2 cells (37Wilcox L.J. Barrett P.H. Huff M.W. Differential regulation of apolipoprotein B secretion from HepG2 cells by two HMG-CoA reductase inhibitors, atorvastatin and simvastatin.J. Lipid Res. 1999; 40: 1078-1089Abstract Full Text Full Text PDF PubMed Google Scholar, 38Wilcox L.J. Barrett P.H. Newton R.S. Huff M.W. ApoB100 secretion from HepG2 cells is decreased by the ACAT inhibitor CI-1011: an effect associated with enhanced intracellular degradation of apoB.Arterioscler. Thromb. Vasc. Biol. 1999; 19: 939-949Crossref PubMed Google Scholar) and >30% in primary hepatocytes (39Twisk J. Gillian-Daniel D.L. Tebon A. Wang L. Barrett P.H. Attie A.D. The role of the LDL receptor in apolipoprotein B secretion.J. Clin. Invest. 2000; 105: 521-532Crossref PubMed Google Scholar). Thus, there is no reason to expect that a tracer amino acid infusion alters apolipoprotein synthesis. Assuming that apolipoprotein synthesis is unaltered by tracer infusion avoids the contradiction implied by the constant tracee flux assumption and is consistent with the published data cited above. We next show that the introduction of tracer alters tracee incorporation (as opposed to the total of tracer and tracee) into apolipoproteins. Consider Fig. 3, which shows, for amino acid 1, the tracer with mass m1(t) and tracee with mass U1(t) at the site of synthesis of the apolipoprotein of interest. The rate of incorporation into the protein remains at f1S before and after tracer is introduced, where S is the protein synthesis and f1 is the fraction from amino acid 1. Since the tracer and tracee are indistinguishable, the tracer incorporation rate is obtained simply by multiplying f1S by the trac" @default.
• W2149139434 created "2016-06-24" @default.
• W2149139434 creator A5024233450 @default.
• W2149139434 date "2006-12-01" @default.
• W2149139434 modified "2023-10-17" @default.
• W2149139434 title "Studying apolipoprotein turnover with stable isotope tracers: correct analysis is by modeling enrichments" @default.
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