© 1997 American Heart Association, Inc.
Articles |
Organ Loci of Catabolism of Short Truncations of ApoB
From the Division of Atherosclerosis, Nutrition, and Lipid Research, Washington University School of Medicine, St Louis, Mo (X.F.Z., A.S., G.S.); Cattedra Di Patologia Speciale Medica, E Matodiolgia Clinica, Istituto di Patologia Medica II, Universita di Palermo, Italy (D.N.); and the Human Performance Lab, University of Nebraska, Kearney (R.S.).
Correspondence to Xien-Feng Zhu, Division of Atherosclerosis, Nutrition, and Lipid Research, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO 63110.
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Abstract Truncations of apolipoprotein (apo) B shorter than 3200 amino acids (3200/4536=apoB-70) do not possess the LDL receptor–recognition domain and are not recognized by altered cells with normally functioning LDL receptors. To ascertain which organs remove such truncated apoB–containing particles, we isolated apoB-31–, apoB-38.9–, and apoB-43.7–containing particles from plasmas of familial hypobetalipoproteinemia heterozygous humans by a combination of sequential ultracentrifugation and preparative electrophoresis. Particles with labeled 125I- or 131I-dilactitol tyramine (I-DLT), were injected into New Zealand White rabbits, along with I-DLT–apoB-100–containing LDLs, and the decay of 125I- and 131I-TCA–precipitated counts was followed over 24 hours. At the end of 24 hours, rabbits were anesthetized and their bodies perfused. Organs were removed and homogenized, and TCA-precipitable counts determined. Fractional catabolic rates of apoB truncation particles were two to five times greater than those of apoB-100 LDLs. ApoB truncations accumulated in adrenals at one fifth the rates of apoB-100 LDL, compatible with the functional absences of LDL receptor–recognition domains in truncated apoBs. The major organ of uptake for apoB-100-LDLs was the liver, whereas truncation particles were readily removed by the kidney (kidney: liver uptake ratios were 0.10 to 0.30 for apoB-100 LDLs and 1.03 to 3.77 for truncations). Spleens accumulated little of either apoB-100 or truncation particles, suggesting particles were not "damaged" or aggregated. Thus, the absence of >56% of the carboxyl end of apoB-100 increases the plasma clearance and redirects the organ uptake of the apoB truncation–containing lipoproteins from liver to kidney.
Key Words: lipoproteins • apoB • apoB truncations • dilactitol tyramine
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Introduction |
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The low-cholesterol syndromes1 consist of abetalipoproteinemia, associated with deficiencies of microsomal triglyceride transfer protein,2 3 4 5 chylomicron retention disease of unknown etiology,6 7 and FHBL, most often defined as <5th percentile LDL cholesterol, which in most kindreds segregates as an autosomal dominant phenotype. In a subset of kindreds, the FHBL phenotype is linked to the apoB gene on chromosome 2. In some of those kindreds, various mutations of the apoB gene specify the formation of a number of COOH-terminal truncated forms of apoB that cosegregate with the FHBL phenotype.8 9 10 11 The plasmas of such apoB-100/apoB-truncation FHBL heterozygotes contain two populations of apoB-containing lipoproteins: apoB-100–containing particles and apoB truncation–containing particles. In general, longer truncations (eg, apoB-89 and apoB-75) are distributed among VLDL, IDL, and LDL density particles, and the short truncations (eg, apoB-31 and apoB-38.9) among small, dense LDL and HDL. ApoB-48–containing chylomicrons and chylomicron remnants may also be present in selected individuals.12 In another subset of FHBL kindreds in which the linkage of the hypobeta phenotype to the apoB gene is present, no products of truncation-specifying mutations are detectable in plasma and the molecular defect(s) responsible for the FHBL phenotype are unknown.13 In still other kindreds, the FHBL phenotype appears not to be linked with the apoB gene at all.14 15 In both of the latter cases, only apoB-100–containing lipoproteins are detectable.
The metabolism of both the apoB-100– and apoB truncation–containing lipoproteins has been studied,16 17 18 19 20 most recently using stable isotopically labeled amino acids as endogenous labels. Because both the apoB-100– and apoB truncation–containing lipoproteins become labeled, it is possible to use apoB-100 as internal control for the apoB truncations. Truncations are produced at lower rates than their apoB-100 counterparts. Indeed, there is a direct correlation between the size of a truncation and its rate of production relative to its counterpart apoB-100.21 The FCRs of apoB-89 and apoB-75 truncations are also increased relative to apoB-100.17 20 In addition, the production rates of apoB-100 in heterozygotes on average are 30% of those of apoB-100 in sex-, age-, race-, and body mass index–matched normolipidemic control subjects.16
Relatively little is known about the lipid-transporting functions and tissue loci of catabolism of truncated apoBs. ApoB-100 contains a recognition domain for the LDL receptor between amino acids 3100 and 3500, and the interaction of the apoB-100 domain with the LDL receptor mediates the removal of some VLDL, most IDL, and virtually all LDL particles from plasma.22 23 Particles containing apoB truncations long enough to retain the LDL receptor–recognition domain, eg, apoB-89 LDL and apoB-75 LDL, are readily recognized by LDL receptors (indeed, with even higher affinity than apoB-100 LDL) and are removed primarily by liver at higher rates than their counterpart apoB-100 LDLs.17 20 24 By contrast, shorter truncations, eg, apoB-31, apoB-37, apoB-38.9, apoB-40, and apoB-67, do not contain the LDL receptor–recognition domain, and apoB-37 and apoB-67 and presumably the others as well do not interact with LDL receptors.25 26 It is not clear which, if any, receptors mediate the removal of these shorter truncation–containing particles and into which organs. We report on the decay rates from plasmas of rabbits of three short truncation–containing lipoproteins, apoB-31, apoB-38.9, and apoB-43.7, and on their organ loci of uptakes. The truncation-containing lipoproteins are cleared more rapidly than their apoB-100 counterparts, and while apoB-100 LDLs accumulate predominantly in liver, the truncation particles are readily taken up by kidneys.
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Blood Collection
Fasted blood (58 mL) was obtained from previously identified FHBL heterozygous subjects with the following apoB genotypes: apoB100/31, apoB100/38.9, and apoB100/43.7 (Table 1
). The blood was drawn into tubes containing EDTA (1 mg/mL) and plasma separated by centrifugation. The following antioxidants and proteolytic inhibitors were added to minimize oxidation of lipoproteins and the cleavage of apoB: aprotinin (100 kallikrein inhibiting units per milliliter, Sigma Chemical Company), EDTA (1 mmol/L), and BHT (300 µmol/L, Eastman Kodak Company). To assess distributions of apoB-100 and apoB-31 among lipoproteins, gel permeation chromatography of whole plasma was performed followed by SDS-gel electrophoreses and immunoblotting of elution fractions with an anti–apoB-100 Mab C1.4.17 22
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Isolation of ApoB-100–, ApoB-31–, ApoB-38.9–, and ApoB-43.7–Containing Fractions by Sequential Ultracentrifugation
Under reduced light, plasma density was raised to d=1.019 g/mL by adding potassium bromide (Sigma), and ultracentrifugation was performed at 45 000 rpm, for 18 hours, at 10°C (Model L8M-70 ultracentrifuge, 55.2TI rotor, Beckman). VLDL and IDL were removed by tube slicing. ApoB-100–containing LDLs were isolated by ultracentrifugation at d=1.063 g/mL. Since the majority of apoB-31–, apoB-38.9–, and apoB-43.7–containing lipoproteins float in the HDL density range,27 28 the HDL fractions from the apoB-31–, apoB-38.9–, and apoB-43.7–containing plasmas were separated by ultracentrifugation at 1.21 g/mL, (45 000 rpm, 24 hours, at 10°C). The HDL fractions were then concentrated by ultrafiltration (Amicon Centrion-30 and Centrion-100).
Isolation of ApoB-31–, ApoB-38.9–, and ApoB-43.7–Containing Particles From HDL Fractions
HDL fractions were prestained with Sudan black dye (Fisher Scientific, prepared as previously described29 ). Preparative scale 2% to 16% nondenaturing electrophoretic gradient gels were prepared30 and prerun for 2 to 3 hours at 220 V at 10°C. Then 40 µL of the prestained HDL fractions was loaded into two small lateral gel wells as position markers during the electrophoresis. Concentrated unstained HDL fractions (5 mL) were loaded into a big preparative well in the middle of the gel. Electrophoresis was continued for 12 to 16 hours at 220 V and 10°C in the dark (SE600 series, Hoefer Scientific Instruments). When the electrophoresis was finished, the HDL area on the gel was identified by the stained bands in the two lateral lanes. The wide gel area above the HDL fraction area (which was known to contain the apoB truncation particles from preliminary experiments) was divided and cut into 4 to 6 gel bands. The gel pieces cut from GGE were placed into an electroeluter (model 422, Bio-Rad) and eluted in the GGE running buffer overnight at 8 to 10 mA at 10°C in the dark. The electroeluted samples were dialyzed for 8 hours against two changes of 2 liters each of equilibration buffer (0.9% NaCl and 0.01% EDTA; pH 7.4). Samples were then concentrated with Amicon Centrion-30. Isolated particles were derivatized with I-DLT as described.31
To ascertain whether preparative electrophoresis per se could have affected the plasma kinetics or altered the organ distribution of lipoproteins, apoB-100–containing LDL from a single normal donor was isolated by ultracentrifugation alone and also by ultracentrifugation followed by electrophoresis. In addition, on a separate occasion, the apoB-38.9 donor provided plasma from which both the apoB-100– and apoB-38.9–containing particles were isolated under identical conditions of electrophoresis (after preparative ultracentrifugation at appropriate densities).
Protein concentrations were determined by the modification of Markwell et al32 of the Lowry procedure, using BSA as standard. Purities of the apoB truncation particles were assessed by Western blot analysis. The samples were delipidated in Menzel buffer and electrophoresed in 3% to 20% gradient SDS polyacrylamide gels.16 Protein bands were electrotransferred to immobilon-P (P-15552) membranes (Millipore).16 Immobilon-P membranes were incubated with 5% (wt/vol) nonfat dry milk in PBS (0.01 mol/L; pH 7.4) followed by incubation with 125I-labeled anti-apoB Mab C1.4 (750 000 cpm/mL) or Mab A7D3 (anti-apoA-I). Mab C1.4 is directed against amino acid residues 97 to 401 near the amino terminal of apoB,22 and Mab A7D3 recognizes apoA-I (unpublished observation). Membranes were washed with 0.1% (wt/vol) Triton X-100 and 0.1% (wt/vol) Tween 80 in PBS, dried, and exposed to Kodak XAR-5 film at -70°C for autoradiography.
Plasma Clearance Kinetics and Organ Distributions of Labeled Particles in Rabbits
Labeled truncated apoB-containing lipoproteins and labeled apoB-100–containing LDLs (in 1 mL of sterilized 0.9% NaCl solution) were injected simultaneously into the marginal ear veins of NZW rabbits (female, 3 lb).24 Blood was drawn into EDTA-containing tubes at 1, 5, 10, 20, 40, 60, 120, 240, 480, 720, and 1440 minutes. More than 95% of whole plasma radioactivities were TCA precipitable. Radioactive counts were corrected for spillover (for 125I), radionuclide decay (for 131I), and for counting efficiency. FCRs were calculated by using radioactivities of TCA-precipitable fractions and the two-compartment SAAM model.33 To ascertain whether the injected particles remained intact as particles during the 24 hours after injection, plasmas collected at selected time points were subjected to gel filtration chromatography on two Superose 6 columns connected in series on the fast protein liquid chromatography system (Pharmacia), and fractions were counted in a gamma counter.
To obtain the organ distributions of radioactivities, 24 hours after injection the NZW rabbits were anesthetized with sodium pentobarbital and their bodies perfused through the left ventricle with sterilized 0.09% NaCl containing heparin (5 U/mL) until the lungs, heart, liver, and kidneys looked pale. The hematocrit of the perfused solution was usually <1%. Samples obtained from the following organs were weighed: skin, adipose tissue, skeletal muscle, bone marrow, esophagus, trachea, lung, stomach, aorta, heart, liver, spleen, pancreas, small intestine, adrenals, kidneys, bladder, and ovary. Whole organs (heart, stomach, liver, spleen, adrenal, and kidney) were weighed directly. Masses of dispersed organs (adipose, skeletal muscle, digestive tube) were estimated from their percentages of the total body mass.34 Tissue pieces were homogenized (Polytron, Brinkmann Instruments) in distilled water (3x volume), incubated for 1 hour at 4°C with TCA (10%, wt/vol), and centrifuged at 2600 rpm for 1 hour at 10°C. Supernatants were removed and precipitates counted. Accumulation of radioiodinated lipoproteins in tissues was expressed on two bases: as dpm per gram tissue (whole organ) x100, divided by either dpm injected or dpm recovered from the whole animal.
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The characteristics of the lipoprotein donors and the references wherein the specific characteristics of the different FHBL truncation mutations are described are given in Table 1
. The purity of the isolated apoB-31–containing lipoproteins is documented in Fig 1. Similar data were obtained for the apoB-38.9– and apoB-43.7–containing lipoproteins (data not shown). Each preparation contained only the appropriate apoB truncations and neither apoB-100 nor apoA-I. Lipoproteins labeled with 131I- or 125I-DLT were injected into the ear veins of rabbits. In most cases, paired injections were administered to the same rabbit, one containing the apoB-100 LDL and the other the apoB truncation–containing lipoproteins. Fig 2 shows the decay curves for the three truncations under study. Each truncation-containing particle disappeared from plasma more rapidly than control apoB-100 LDLs, and calculated FCRs were 2.1 to 4.9 times increased (Table 2). The results were comparable whether the two labels were injected into the same rabbit or two different rabbits. To ascertain whether apoB truncation–containing and apoB-100–containing lipoproteins isolated by two different procedures could safely be used for the purposes of this study, we needed to be certain that preparative electrophoresis after preparative sequential ultracentrifugation did not affect the plasma decay of LDL compared with LDL isolated by ultracentrifugation alone. We also wished to assess any effects of antioxidants added during isolations and any effect of 125I versus 131I labels. To minimize any variations, we used LDL isolated from a single normolipidemic donor. FCRs are relatively close to each other and did not consistently depend on the method of isolation, the label used, or the presence of BHT (data not shown). Finally, and most importantly, to avoid any artifactual differences in FCRs or organ distributions due to methods of isolation, we isolated both the truncation- and apoB-100–containing particles from the plasma of the apoB-38.9 donor by combined ultracentrifugation and electrophoresis. The differences in FCRs persisted (Table 2).
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The intactness of the injected particles was maintained during the metabolic study. Aliquots of rabbit plasma collected at various time points from a rabbit injected with labeled LDL/apoB-31 were analyzed by gel permeation chromatography (Fig 3). The labeled apoB-31 lipoproteins eluted between LDL and HDL and displayed some heterogeneity of size. Heterogeneity of apoB-31 particle size was seen also on gel filtration chromatography of whole plasma (Fig 4) and on GGE of whole plasma (Fig 4, inset), suggesting that the heterogeneity was not an artifact of isolation. Since the starting material for isolation of apoB-31 particles was material that floated with HDL, only density gradient ultracentrifugation fractions 31 and beyond (Fig 4) were used as starting material for electrophoretic isolations. These particles eluting with small LDL- and HDL-sized particles are the same ones seen in Fig 3. Although particles remained intact in plasma, their size distributions changed over time, with a preponderance of smaller particles remaining at 24 hours (Fig 3).
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Calculated lipoprotein distributions for liver and kidney are shown in Table 3 and for many more organs in Table 4. ApoB-100 LDL localized primarily to liver, with kidney:liver ratios of 0.1 to 0.3. By contrast, large proportions of apoB truncation–containing lipoproteins localized to kidney, with kidney:liver ratios ranging from 1.2 to 3.8. Here too, the method of isolation of lipoproteins did not matter (Table 3 and Fig 5). Of note, apoB-100 LDLs were much more avidly accumulated by the adrenals than were the apoB truncation–containing lipoproteins (Table 5).
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Discussion |
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Our aims were to assess the plasma kinetics of disappearance of shorter apoB truncation–containing particles relative to apoB-100 LDLs isolated from the same heterozygous subjects and, even more important, to find the major organ loci of catabolism of truncation particles. We chose the shorter truncations because they do not possess the LDL receptor–recognition domain and therefore, in contrast with the long truncations apoB-89 and apoB-75, which we have studied previously,17 20 24 their clearance from plasma would not be expected to be mediated by LDL receptors.26 27 We chose to perform the study in rabbits because human apoB-100 particles are metabolized by rabbit tissues as would be predicted from available knowledge of the metabolism of apoB-containing lipoproteins.35 Indeed, apoB-100 LDL, as expected, was removed primarily by liver, with high uptake by adrenals.35
Each truncation-containing particle was removed faster from plasma and had a higher FCR than its normal apoB-100 counterpart (Fig 2 and Table 3). These data are compatible with the increased FCRs displayed by various apoB truncations studied in apoB truncation/ apoB-100 heterozygous humans in vivo. In each human heterozygote there are two populations of lipoproteins, and the apoB-89–,20 apoB-75–,17 apoB-54.8–, apoB-52– (unpublished data), and apoB-43.7–containing particles36 have higher FCRs than the FCRs of the apoB-100 lipoproteins in the same subjects. This suggests that the rabbit may be metabolizing truncated apoB–containing lipoproteins similarly to humans. There is an unexplained discrepancy between the low FCR of apoB-31 particles in vivo in humans21 and the rapid FCR in rabbits (Fig 2). The particles stayed intact in plasma during the 24-hour time of the experiments (Fig 3), ie, we were tracing lipoproteins. The fact that the apoB-100 particles accumulated in the adrenals at about 4 to 50 times the rate of the truncation particles is compatible with the LDL receptor–mediated removal of the former but not the latter (Table 5). Whereas the liver was the major organ of removal of apoB-100 particles, confirming our previous work,24 35 the kidney was the major organ of removal of the apoB-38.9 and apoB-43.7 truncation–containing particles (Tables 3 and 5). ApoB-31–containing particles were removed approximately equally by kidney and liver. Perhaps the length of the truncation may affect its organ distribution. It is unlikely that the change in organ sites of catabolism was due to nonspecific "damage" to or aggregation of the truncation-containing particles, because removal of lipoproteins by spleen was low (Table 5).
The method of isolation of apoB truncation–containing particles appears not to have noticeably altered them with respect to size (compare Figs 3 and 4). With respect to biological activity, apoB-100–containing LDLs isolated by ultracentrifugation plus electrophoresis behaved similarly to LDLs isolated only by ultracentrifugation, as judged by similar FCRs and organ distributions. The presence or absence of antioxidants in the isolation buffers appears not to have had a significant effect. Furthermore, when the experiment was repeated using the lipoproteins of donor apoB-38.9, with both apoB-100– and apoB-38.9–containing lipoproteins isolated by ultracentrifugation plus electrophoresis, the FCRs (Table 2) and organ distributions (Fig 5) were similar to those in the rest of the experiments. The removal of proteins by kidneys is not unprecedented. For example, about 30% of apoA-I is removed by kidney in normal subjects. That proportion increases in subjects with low levels of HDL.37 Thus, the apoB truncations with absent LDL receptor domains appeared to be more rapidly removed and to accumulate in kidney. It remains to be determined which cell type in kidney is responsible or which, if any, receptors mediate the clearance of these short apoB truncation-bearing particles.
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Acknowledgments |
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This work was supported by NIH grant R0-1-HL-42460. We are grateful to Diana Tessereau, RN, for her good relations with our study subjects and for obtaining the blood samples, to Tom Kitchens and Tish Kettler for expert technical help, and to Mary Lou Rheinheimer for preparing the manuscript.
Received December 28, 1995; accepted August 8, 1996.
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References |
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G. Schonfeld Familial hypobetalipoproteinemia: a review J. Lipid Res., May 1, 2003; 44(5): 878 - 883. [Abstract] [Full Text] [PDF]
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Z. Chen, R. L. Fitzgerald, J. E. Saffitz, C. F. Semenkovich, and G. Schonfeld Amino Terminal 38.9% of Apolipoprotein B-100 Is Sufficient to Support Cholesterol-Rich Lipoprotein Production and Atherosclerosis Arterioscler Thromb Vasc Biol, April 1, 2003; 23(4): 668 - 674. [Abstract] [Full Text] [PDF]
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 Z. Chen, R. L Fitzgerald, and G. Schonfeld Hypobetalipoproteinemic Mice with a Targeted Apolipoprotein (Apo) B-27.6-specifying Mutation. IN VIVO EVIDENCE FOR AN IMPORTANT ROLE OF AMINO ACIDS 1254-1744 OF ApoB IN LIPID TRANSPORT AND METABOLISM OF THE ApoB-CONTAINING LIPOPROTEIN J. Biol. Chem., April 12, 2002; 277(16): 14135 - 14145. [Abstract] [Full Text] [PDF]
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J. Wu, J. Kim, Q. Li, P.-Y. Kwok, T. G. Cole, B. Cefalu, M. Averna, and G. Schonfeld Known mutations of apoB account for only a small minority of hypobetalipoproteinemia J. Lipid Res., May 1, 1999; 40(5): 955 - 959. [Abstract] [Full Text]
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Z. Chen, R. L. Fitzgerald, M. R. Averna, and G. Schonfeld A Targeted Apolipoprotein B-38.9-producing Mutation Causes Fatty Livers in Mice Due to the Reduced Ability of Apolipoprotein B-38.9 to Transport Triglycerides J. Biol. Chem., October 13, 2000; 275(42): 32807 - 32815. [Abstract] [Full Text] [PDF]
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