Arteriosclerosis, Thrombosis, and Vascular Biology. 1997;17:1032-1038
(Arteriosclerosis, Thrombosis, and Vascular Biology. 1997;17:1032-1038.)
© 1997 American Heart Association, Inc.
Organ Loci of Catabolism of Short Truncations of ApoB
Xian-Feng Zhu;
Davide Noto;
Rick Seip;
Aviv Shaish;
;
Gustav Schonfeld
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
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Abstract Truncations of apolipoprotein (apo) B shorter than
3200 amino acids (3200/4536=apoB-70) do not possess the LDL
receptorrecognition domain and are not recognized by altered
cells with normally functioning LDL receptors. To ascertain
which organs remove such truncated apoBcontaining particles,
we isolated apoB-31, apoB-38.9, and apoB-43.7containing
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-DLTapoB-100containing
LDLs, and the decay of
125I- and
131I-TCAprecipitated
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 receptorrecognition
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
truncationcontaining 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 syndromes
1 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-100containing particles and apoB truncationcontaining
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-48containing 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-100containing lipoproteins
are detectable.
The metabolism of both the apoB-100 and apoB truncationcontaining 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 truncationcontaining 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 indexmatched 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 receptorrecognition 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 receptorrecognition 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 truncationcontaining particles and into which organs. We report on the decay rates from plasmas of rabbits of three short truncationcontaining 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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Methods
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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 antiapoB-100 Mab C1.4.
17 22
Isolation of ApoB-100, ApoB-31, ApoB-38.9, and ApoB-43.7Containing 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-100containing LDLs were isolated by ultracentrifugation at d=1.063 g/mL. Since the majority of apoB-31, apoB-38.9, and apoB-43.7containing lipoproteins float in the HDL density range,27 28 the HDL fractions from the apoB-31, apoB-38.9, and apoB-43.7containing 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-43.7Containing 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-100containing 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-38.9containing 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-100containing 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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Results
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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-31containing lipoproteins is documented
in Fig 1

. Similar data were obtained for the apoB-38.9
and apoB-43.7containing 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
truncationcontaining 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 truncationcontaining and apoB-100containing
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-100containing 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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Figure 1. Analysis of purified apoB-31containing lipoproteins by immunoblotting. The area between the LDL apoB-100 and the HDL bands in the preparative nondenaturing GGE was divided into four horizontal strips. The gel strips were excised, proteins were electroeluted, and aliquots were subjected to analytic electrophoresis in a 3% to 20% SDSpolyacrylamide gel. The resultant bands were electrotransferred to an immobilon-P membrane, and one part of the membrane was probed with the anti-apoB Mab C1.4 (A). The other part was probed with the antiapoA-I Mab A7D3 (B). A, Lanes 1 and 2 contain the plasma and the ultracentrifugally isolated LDL (d=1.019 to 1.063) and lane 3 the HDL (d=1.063 to 1.21) of the donor subject (apoB-100/apoB-31). Lanes 4 and 5 contain the purified apoB-31 in lipoproteins eluted from strips 1 and 2 of the preparative gel. Lanes 6 and 7 contain "contaminating" HDL from strips 3 and 4 of the preparative GGE, which does not react with the anti-apoB antibody. B, Lanes 4 and 5 contain apoB-31, which does not react with the antiapoA-I antibody, and lanes 6 and 7 contain the "contaminating" HDL that does react. An HDL lane is included as positive control.
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Figure 2. Plasma decay curves of I-DLT/apoB-100 LDL and I-DLTapoB truncation particles in NZW rabbits. Mean decays of labeled apoB-31, apoB-38.9, and apoB-43.7 particles are shown in three, five, and three rabbits, respectively. Results are mean±SE for each time point. The y axis is expressed as percentage of plasma radioactivity at 1 minute after injection.
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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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Figure 3. The distribution in rabbit plasma of I-DLTapoB-31 particles. Aliquots of plasma collected at 5 minutes and at 2, 8, and 24 hours were subjected to gel permeation chromatography. Dotted lines represent radioactivity due to I-DLTapoB-31 particles. Dashed lines represent plasma cholesterol profiles, with elution positions of rabbit VLDL, LDL, and HDL indicated.
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Figure 4. Distribution of apoB-100 and apoB-31 in the plasma of the apoB-100/apoB-31 heterozygote donor. The dashed line represents total cholesterol. Solid circles and triangles represent apoB-100 and apoB-31, respectively. The inset in the upper left quadrant shows a Western blot analysis of whole plasmas subjected to nondenaturing GGE (2% to 16%). Inset, lane 1: normal apoB-100/apoB-100; lane 2: apoB-100/apoB-43.7; lane 3: apoB-89/apoB-40; lane 4: apoB-100/apoB-38.9; lane 5: apoB-100/apoB-31; and lane 6: apoB-100/apoB-100. The membrane was probed with anti-apoB Mab C1.4.
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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 truncationcontaining 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 truncationcontaining lipoproteins (Table 5
).
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Table 3. Distributions of Human I-DLTApoB-100 and I-DLTApoB TruncationContaining Lipoproteins in Kidneys and Livers of NZW Rabbits
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Table 4. Organ Distributions of Human ApoB-100Containing LDLs Prepared by Ultracentrifugation or by Ultracentrifugation Plus Preparative Electrophoresis
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Figure 5. Organ distributions of apoB-38.9 and apoB-100containing particles. Both types of particles were isolated by combined ultracentrifugation and preparative electrophoresis. Results are expressed as dpm per organ divided by dpm recovered from the whole carcass x100. Solid bars represent a paired study, ie, dual labels 125I and 131I injected into one rabbit; open bars represent each label injected into a separate animal.
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Discussion
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Our aims were to assess the plasma kinetics of disappearance
of shorter apoB truncationcontaining 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 receptorrecognition 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-43.7containing 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 apoBcontaining 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 receptormediated 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 truncationcontaining particles (Tables 3
and 5
). ApoB-31containing 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 truncationcontaining particles appears not to have noticeably altered them with respect to size (compare Figs 3
and 4
). With respect to biological activity, apoB-100containing 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-38.9containing 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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Selected Abbreviations and Acronyms
|
|---|
| apo |
= |
apolipoprotein |
| DLT |
= |
dilactitol tyramine |
| dpm |
= |
disintegrations per minute |
| FCR |
= |
fractional catabolic rate |
| FHBL |
= |
familial hypobetalipoproteinemia |
| GGE |
= |
gradient gel electrophoresis |
| I-DLT |
= |
125I or 131I-DLT |
| Mab |
= |
monoclonal antibody |
| NZW |
= |
New Zealand White |
| TCA |
= |
trichloroacetic acid |
|
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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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