doi: 10.1161/hq0901.094489
© 2001 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Differential Metabolism of Human VLDL According to Content of ApoE and ApoC-III
From the Department of Nutrition (K.T., K.I., H.J., F.M.S.), Harvard School of Public Health; the Department of Obstetrics and Gynecology (B.W.W.), Brigham and Women’s Hospital; and Channing Laboratory (F.M.S.), Department of Medicine, Harvard Medical School, Brigham and Women’s Hospital, Boston, Mass. Dr Tomiyasu is now at Tokorozawa City, Saitama, and Dr Ikewaki is now at Department of Cardiology, Jikei University School of Medicine, Tokyo, Japan.
Reprints requests to Frank M. Sacks, MD, Department of Nutrition, Harvard School of Public Health, 665 Huntington Ave, Boston, MA 02115. E-mail fsacks{at}hsph.harvard.edu
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Abstract |
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Abstract—— We studied the metabolism of very low density lipoprotein (VLDL) and intermediate density lipoprotein (IDL) particles that did or did not have apolipoprotein E (apoE) in 12 normolipidemic women by endogenously labeling plasma apolipoprotein B. The plasma was separated into bound (E+) and unbound (E-) fractions by use of a monoclonal antibody (1D7), and the fractions were ultracentrifuged to yield E+ and E- subfractions of light and dense VLDL and IDL. VLDL E+ and IDL E+ were produced mainly by the liver. VLDL E+ and IDL E+ had lower fractional catabolic rates and much higher apolipoprotein C-III (apoC-III) content than did the corresponding E- particles. Most light VLDL apoE+ underwent lipolysis to dense VLDL E+ with reduced apoC-III content, which was removed from the circulation without conversion to IDL. In contrast, most light VLDL apoE-, poor in apoC-III, was removed from the circulation, and a smaller proportion underwent lipolysis to dense VLDL E-. Most dense VLDL E- underwent lipolysis to IDL E-. The rate constant for lipolysis of dense VLDL to IDL was greater for E- than for E+, and the rate constant for clearance from plasma was greater for dense VLDL E+ than for E-. In conclusion, metabolism of human VLDL particles is influenced by their content of apoE, further modulated by the coexistence of apoC-III.
Key Words: lipoproteins • metabolism • apolipoprotein B • apolipoprotein E • apolipoprotein C-III
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Introduction |
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Some VLDLs and IDLs contain apoE.1–7 ApoE can modulate the metabolism of VLDL and IDL because it has epitopes that bind to receptors2,8,9 and heparin proteoglycans,10,11 increasing the uptake of VLDL by cells.5,12 ApoE is required for the normal clearance of VLDL and IDL from plasma.13 It is responsible for
30% to 50% of the binding of human VLDL particles by cells, and apoB is responsible for the rest.3–5 However, in normolipidemic humans, it is not known to what extent functional apoE molecules (E3 or E4), when present on VLDL and IDL, affect their metabolism in vivo. Therefore, we studied the metabolism of VLDL and IDL, which were isolated according to their apoE content in normolipidemic women. |
Methods |
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For the complete Methods section, please refer to http://atvb.ahajournals.org.
Twelve healthy normolipidemic postmenopausal women were recruited. None was receiving medications that affect lipoprotein metabolism, including estrogen replacement therapy.14 After an overnight fast, subjects received a primed continuous intravenous infusion of [D3]L-leucine and a bolus infusion of [D5]L-phenylalanine. Blood specimens were obtained at 20, 40, 60, and 90 minutes and hourly, from 2 to 12 hours, and plasma was separated. The monoclonal anti-apoE antibody, 1D7 (obtained from Dr Yves Marcel, Ottawa Heart Institute, Ottawa, Canada), was selected to separate plasma. 1D7 binds to the LDL receptor–binding epitope of apoE15 and would therefore bind lipoproteins that had apoE in a metabolically active conformation. It is known that epitopes of apoE that are critical to binding to cell surface receptors or to heparin are variably expressed on VLDL.3,16–18 We used this monoclonal antibody because we were concerned that if the LDL receptor binding region was not exposed on a substantial amount of apoE in VLDL and IDL, we might not be able to detect an effect of apoE because the effect of metabolically active apoE would be diluted by nonmetabolically active apoE. In additional experiments, the fraction of plasma that was not retained by 1D7 was separated by immunoaffinity chromatography with affinity-purified goat polyclonal anti-apoE (Genzyme Corp) as previously described.6 Light and dense VLDL and IDL were prepared from the bound (E+) and unbound (E-) fractions of plasma by ultracentrifugation. LDL was also isolated, but the masses and tracer enrichments of apoE-containing LDL were very low or highly variable in several subjects, and for this reason, LDL kinetics was not studied. ApoB was prepared by precipitation, and apoB tracer/tracee ratio and pool size were determined by quantitative gas chromatography/mass spectrometry. Kinetic model development used SAAM II (SAAM II Institute) to simultaneously solve the tracer/tracee data for primed continuous and bolus infusions, producing a single set of rate constants. The model was initially established by using the average data of the 12 subjects, and then the data for each subject were modeled individually.
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Results |
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Subjects
The mean age of the subjects was 57 (range 49 to 68) years, and body mass index was 25 (range 18 to 33) kg/m2. Mean total cholesterol was 184 (range 139 to 221) mg/dL, total triglyceride level was 97 (64 to 126) mg/dL, VLDL cholesterol was 12 (6 to 25) mg/dL, LDL cholesterol was 104 (62 to 140) mg/dL, HDL cholesterol was 60 (45 to 83) mg/dL, apoB was 96 (59 to 127) mg/dL, apoE was 6 (5 to 9) mg/dL, and apoC-III was 13 (10 to 16) mg/dL. There were 4 subjects with apoE genotype E2E3, 2 subjects with E2E4, 4 subjects with E3E3, and 2 subjects with E3E4. Characteristics of each subject are shown in online Table I (which can be accessed at http://atvb.ahajournals.org).
Model Structure
Tracer appeared first for light VLDL, followed by dense VLDL and then IDL for the E- as well as the E+ particles (Figure 1), suggesting that some light particles were converted to dense particles. Tracer appeared at similar times for E- and E+ particles within light VLDL, dense VLDL, and IDL (Figure 1), implying that within a density class, E- and E+ particles are predominantly not precursors or products of each other. Within each density class, the rates at which the bolus tracer enrichment decreased were faster for the E- particles than for the E+ particles. Similarly, the enrichment rates of the primed continuous tracer infusion were more rapid for the E- particles than for the E+ particles. This suggested a higher fractional catabolic rate (FCR) for E- particles than for E+ particles. These preliminary kinetic findings were tested and refined to produce a quantitative kinetic description of VLDL and IDL metabolism (Table 1, Figure 2). The rate constants for the major pathways in the final model generally had low fractional standard deviations, demonstrating a high degree of resolution of the model-derived parameters (Table 1). Pool sizes, rate constants, and fluxes for the individual subjects appear in online Table II (which can be accessed at http://atvb.ahajournals.org).
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P<0.05.
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Plasma Amino Acid System and Liver
Three pools were required to fit the later portions of the plasma phenylalanine and leucine tracer curves (Figure 1). An intrahepatic delay element with 8 subcompartments was required to account for the 24-minute delay in appearance of tracer in plasma apoB and the sharp increase in slope for tracer enrichment into light VLDL that followed, as was found previously.14 The flux of apoB from the liver was distributed to all VLDL and IDL subfractions (Figure 2A). Total apoB synthesis was 40 (range 17 to 152) mg/kg per day. A single hepatic precursor pool for E- and E+ particles produced excellent fits of the data.
Light VLDL
It was necessary to divide each light VLDL fraction, E- and E+, into a fast and slow compartment to obtain an optimal fit of the later slow components of the leucine or phenylalanine tracer enrichments (Figure 1, top panels). A significantly greater proportion of light VLDL E- than E+ particles was cleared from plasma (57% versus 18%, respectively; P<0.01), whereas a greater proportion of E+ particles underwent lipolysis to dense VLDL (82% for E+ and 43% for E-, P<0.01; Figure 2A). A significantly greater percentage of fast light VLDL E+ than E- was converted to a slow pool (11% versus 2%, respectively; P<0.05), and the slow pool constituted 44% of the mass of light VLDL E+ and 21% of the mass of light VLDL E- (P<0.01, Table 1). However, the relatively large standard deviations, 87% for the rate constant for lipolysis of light VLDL E- to dense VLDL E- and 60% for the rate constant for conversion of light VLDL E+ from a fast to a slow pool, are potential limitations of the results that apportion the FCR for light VLDL into rate constants for component pathways. The E+ particles in light VLDL had a slower FCR than did the E- particles (9 versus 32 pools per day, respectively; P<0.01; Table 1), with low standard deviations. The sum of the rate constants for the delipidation pathways was similar for E+ and E- light VLDL particles (16 versus 18 pools per day), with low standard deviations. Conversion pathways for light VLDL E+ to dense VLDL E- or IDL E- consistently were assigned zero values during computer iteration. The conversion pathway of light VLDL E- to light VLDL E+ was assigned a zero value as well, consistent with electron microscopic and compositional studies showing that light VLDL E+ is larger and more triglyceride rich than is light VLDL E-.6
Dense VLDL
Dense VLDL E+ received most of its flux (62%) directly from light VLDL E- as a result of lipolysis and acquisition of apoE (Figure 2B). This precursor-product relationship is consistent with a classic interpretation of the bolus tracer curves shown in Figure 1 (replotted in online Figure I, which can be accessed at http://atvb.ahajournals.org, to illustrate this relationship). As with light VLDL E+, formation of dense VLDL E+ from dense VLDL E- was not favored in modeling experiments or by size or compositional analysis.6 A greater proportion of dense VLDL E+ than E- particles (85% versus 45%, respectively; P<0.01) was removed directly from plasma, whereas a lesser proportion of dense VLDL E+ than E- underwent lipolysis to IDL (Figure 2A). Modeling experiments consistently found that apoE loss from dense VLDL E+ to produce dense VLDL E- was grossly incompatible with the tracer enrichments. Moreover, initial assigned rate constants for conversion of dense VLDL E+ to IDL E- always reverted to zero during the iteration procedure. Thus, conversion of dense VLDL E+ to dense VLDL E- or IDL E- is not required to fit the data.
We conducted an in vitro experiment to further evaluate the finding from modeling that VLDL E+ is not converted to VLDL E-. Plasma from a normolipidemic person was separated by the anti-apoE column to produce lipoproteins with apoE. The apoE-rich lipoproteins were then mixed with plasma from the same subject from which VLDL had been removed by ultracentrifugation and were incubated for 4 hours at 37°C. The plasma was then separated by anti-apoE columns, and the VLDL E+ and E- were prepared by ultracentrifugation. No VLDL E- was detected.
The mean FCR for dense VLDL E+ was slower than that for E- (8 versus 11 pools per day, respectively; P=0.09; Table 1). The lower overall FCR for dense VLDL E+ than for E- was accounted for by a lower rate constant for lipolysis of dense VLDL to IDL for E+ than E- particles (1 versus 7 pools per day, respectively; P<0.05). In contrast, the rate constant for clearance from plasma was higher for dense VLDL E+ than E- (7 versus 5 pools per day, respectively; P=0.06).
Intermediate Density Lipoprotein
IDL E+ was produced by several means, 50% from the liver directly, 38% from lipolysis of dense VLDL E+, and 12% from lipolysis and acquisition of apoE by dense VLDL E- (Figure 2B). Formation of IDL E+ from IDL E- was given a zero value by the SAAM II program. The mean FCR was lower for IDL E+ than for E- (4 versus 8 pools per day, respectively; P=0.06).
Lipoprotein Kinetics After Separation by ApoE Polyclonal Antibody
Evaluation by Western blotting with a polyclonal anti-apoE antibody of the plasma fraction that did not bind to the anti-apoE monoclonal antibody 1D7 showed the presence of apoE in VLDL and IDL. The apoE/apoB ratio was 4-fold higher in the VLDL E+ particles that bound to the monoclonal antibody compared with those that did not (8 versus 2 mol/mol, Table 2). In 4 subjects, the plasma fraction that did not bind to 1D7 was further separated by polyclonal anti-apoE affinity resin into fractions designated as polyE+ and polyE-. ApoE was not found in the polyE- fraction by silver-stained PAGE or Western blot. The anti-apoE polyclonal antibody extracted additional VLDL and IDL particles from the plasma fraction that was not retained by 1D7. Approximately half of the VLDL and IDL that contained apoE had 1D7 binding activity. The primed continuous tracer enrichment curves for light VLDL, dense VLDL, and IDL polyE+ were similar to those prepared by the monoclonal anti-apoE in terms of the relationship between E- and E+ fractions of the same density (compare Figures 1 and 3). There were several differences evident. The tracer enrichment curves for the VLDL prepared by polyclonal anti-apoE indicate more independence of light and dense VLDL, with little evidence of lipolytic conversion either for light VLDL E- or E+ (Figure 1, which was replotted to show this relationship in online Figures II and III, which can be accessed at http://atvb.ahajournals.org). The tracer enrichment curves for the polyclonal anti-apoE also show less evidence for formation of dense VLDL E+ from light VLDL E-. A greater proportion of E+ particles that bound to the polyclonal but not to the monoclonal antibody were secreted directly by the liver (42% versus 22%, respectively, for dense VLDL; 81% versus 28%, respectively, for IDL) rather than arising from acquisition of apoE by E- particles. Thus, it appears that less apoE on VLDL and IDL directly secreted by the liver has the LDL receptor binding epitope available compared with apoE that is transferred to VLDL and IDL in the circulation. Finally, the tracer/tracee curves for dense VLDL separated by the polyclonal anti-apoE did not show the broad peak found for dense VLDL E-, prepared by the monoclonal antibody, suggesting that the polyclonal antibody produces more homogeneous VLDL fractions because of its capturing the complete group of apoE-containing particles.
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ApoE Alleles
The percentage of light VLDL E+ mass that resided in the slow pool was greater for the 6 subjects who had an e2 allele than for the 6 who did not (26±10% versus 11±5%, respectively; P=0.01). Other than that, the kinetic characteristics for VLDL E+ and IDL E+ were not significantly different between the e2 and non-e2 groups.
ApoC-III/ApoB Ratio
The VLDL samples that were retained by the monoclonal antibody (E+) were enriched in apoC-III compared with unretained VLDL (E-), as shown in Table 2.
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Discussion |
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We found that much of the VLDL and IDL particles with apoE arose from hepatic production. Intrahepatic mechanisms could include association of newly synthesized apoE with nascent apoB lipoproteins19 and recycling of apoE from endocytosed VLDL.20 ApoE is also present in the extracellular matrix of hepatocytes and can detach on lipidation, such as during contact with newly secreted VLDL.21 We found that dense VLDL E+ and IDL E+ are also produced in plasma from light or dense VLDL E-, receiving apoE during lipolysis, such as from HDL.22,23 Lipolysis exposes a heparin binding site on apoB to which apoE can bind.24 Another source of the apoE on VLDL could be from VLDL E+ transferring to nascent VLDL E-, although not so extensively as to produce a donor VLDL particle that no longer binds to the anti-apoE column.
The FCR for light VLDL E+ was lower than the FCR for light VLDL E-, contrary to expectation. This result is consistent with that of a previous study in hypertriglyceridemic patients in which the decay in plasma of radioiodinated VLDL occurred more slowly in the apoE-rich than in the apoE-poor fraction in 5 of 7 patients and occurred similarly in 2 of them.25 This may be caused by a high apoC-III content. We previously reported that apoE and apoC-III coexist on VLDL and IDL and that few particles have apoE only.6 ApoC-III reduces the binding of apoE-rich VLDL to LDL receptors,26 the LDL receptor–related protein,8 and proteoglycan11,27 and inhibits VLDL uptake by the liver,28 antagonizing the accelerating effect of apoE on particle clearance. In contrast to the results for light VLDL, we found that the clearance rate for dense VLDL E+ was greater than that for the E- particles and that the apoC-III content of dense VLDL E+ particles was reduced from the content of their light VLDL E+ precursors. Reduced apoC-III content of dense VLDL E+ may have allowed apoE to interact with its hepatic receptors. Similarly, a low apoC-III content of light VLDL E- may have been responsible for its high clearance rate, presumably by means of apoB-100. Dense VLDL E+ compared with E- had a reduced lipolysis rate constant. This may also have been caused by the action of apoC-III27,29 or of apoE itself.30,31
We note that the present study is not strictly an evaluation of the effect of apoE on VLDL or IDL metabolism, because it did not experimentally alter the content of apoE or its functional state on otherwise identical lipoprotein particles, and the results by no means discount a role for apoE to increase the clearance of lipoproteins from plasma. The subjects all had normal plasma apoE concentrations, and the number of apoE molecules per VLDL particle averaged 5 to 7, similar to previous reports in normolipidemic persons.1,6 Because the apoE-containing VLDL and IDL had binding activity to a receptor blocking antibody, 1D7, it would be expected that these particles would be able to use their apoE molecules for receptor-mediated clearance in vivo. The FCRs for VLDL E+ (9 pools per day for the light subfraction and 8 pools per day for the dense subfraction), although lower than those for VLDL E-, are not abnormal. They are higher than the FCR for total VLDL in E2E2 normolipidemic persons (6 pools per day for light VLDL and 2 pools per day for dense VLDL)32 and much higher than VLDL in apoE deficiency (1 pool per day).33 The subjects also did not have evidence of cholesterol-rich VLDL or type III hyperlipidemia, as found in those with apoE deficiency or E2E2.13 Thus, it is likely that apoE on these particles is performing its established function to facilitate the clearance of VLDL and IDL. In fact, the clearance rate from plasma was higher for dense VLDL that had apoE than for dense VLDL that did not have apoE, although this difference was not found for light VLDL.
Our findings of reduced FCR for VLDL and IDL particles that are enriched in apoE and apoC-III help explain epidemiological results on associations between apoB-containing lipoproteins that have apoE and apoC-III and coronary heart disease.7,34 A long residence time in plasma for these particles is probably atherogenic, because it may result in uptake by low-affinity high-capacity pathways by cells involved in atherosclerosis.
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Acknowledgments |
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This study was supported by grants from the National Institutes of Health, Bethesda, Md, National Heart, Lung, and Blood Institute (R01-HL-34980 and R01-HL-56210); the Office for Women’s Research; and General Clinical Research Center grant NCRR GCRC M01-RR-02635 to Brigham and Women’s Hospital, Boston, Mass. The authors wish to acknowledge the insights and ideas contributed to this project by Robert Phair, PhD, BioInformatics Services, Rockville, Md, and to express appreciation for his critical reading of this manuscript.
Received December 6, 2000; accepted May 17, 2001.
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S.-J. Lee, H. Campos, L. A. Moye, and F. M. Sacks LDL Containing Apolipoprotein CIII Is an Independent Risk Factor for Coronary Events in Diabetic Patients Arterioscler Thromb Vasc Biol, May 1, 2003; 23(5): 853 - 858. [Abstract] [Full Text] [PDF]
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 H. N. Ginsberg New Perspectives on Atherogenesis: Role of Abnormal Triglyceride-Rich Lipoprotein Metabolism Circulation, October 15, 2002; 106(16): 2137 - 2142. [Full Text] [PDF]
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K. K. Berneis and R. M. Krauss Metabolic origins and clinical significance of LDL heterogeneity J. Lipid Res., September 1, 2002; 43(9): 1363 - 1379. [Abstract] [Full Text] [PDF]
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