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Articles |
1
Department of Laboratory Medicine and
2
Central Laboratory for Ultrastructure Research, Hamamatsu University School of Medicine, 3600 Handa-cho, Hamamatsu City 431-3192, Japan.
3
Materials Technology Research Laboratories and
4
Diagnostics Research Laboratories, Daiichi Pure
Chemicals Co., Ibaraki 301-0852, Japan.
aAuthor for correspondence. Fax 81-53-435-2794; e-mail akikondo{at}hama-med.ac.jp.
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Methods: We measured LDL particle size, using gradient gel electrophoresis, and malondialdehyde-modified LDL (MDA-LDL), using an ELISA, and investigated the association between triglyceride (TG) concentrations, LDL size, and MDA-LDL.
Results: TG concentrations correlated negatively with the
predominant LDL size (r = -0.650) and HDL-C
concentration (r = -0.556). The relationship
between TG concentration and LDL size, evaluated by measuring MDA-LDL,
distinguished subgroups derived from four subfractions of TG
concentrations and four distribution ranges of LDL size. These
experiments indicated that there is a threshold for oxidation
susceptibility at an LDL size of 25.5 nm and a TG concentration of 1500
mg/L. To investigate the relationship between LDL size, MDA-LDL
concentration, and other lipids (TGs, HDL-C, apolipoprotein B, and
total cholesterol), we evaluated them in control subjects and patients
with diabetes mellitus or hypertriglyceridemia. When the size range for
normal LDL was postulated to be 25.5 
(LDL diameter) < 26.5
nm, the MDA-LDL concentration was significantly higher in the subgroups
of patients with LDL in the size range 24.5 < 25.5 nm
compared with patients with normal LDL. This result also suggests that
the threshold is at a LDL size of 25.5 nm.
Conclusion: The threshold for oxidation susceptibility coincided with the point of LDL size separation between the LDL subclass patterns A and B as an atherosclerotic risk.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Austin et al. (3) have shown that LDL subclass pattern B, which is characterized by a preponderance of small dense LDL particles, is associated with an increased risk of myocardial infarction and that it is correlated with increased concentrations of IDL-cholesterol, VLDL-cholesterol, and triglycerides (TGs), and low concentrations of HDL-cholesterol (HDL-C). Because hypertriglyceridemia is concomitant with increasing small dense LDL, hypertriglyceridemic matter is replaced by small dense LDLs. Indeed, it is known that the TG concentration is inversely associated with LDL size. Researchers have reported that when different subpopulations of small dense LDLs are isolated from the same donor, the smallest LDL fraction shows the poorest LDL-receptor binding (4). Furthermore, small LDL is considerably more susceptible than normal-sized LDL to oxidation in the presence of copper ions (5)(6). We previously reported that malondialdehyde-modified LDL (MDA-LDL) is distributed to small dense LDL fractions by density gradient ultracentrifugation (7). These findings evoked interest in the relationship between small dense LDL and oxidation. In this study, we measured LDL size by gradient gel electrophoresis and MDA-LDL concentrations by ELISA and thereby evaluated the association between LDL size and MDA-LDL.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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subjects
Study subjects included 91 patients and 42 healthy controls. Among
the patients, 49 had diabetes mellitus (DM) and 42 had
hypertriglyceridemia without DM. Control subjects and patients with DM
or hypertriglyceridemia were matched for age and sex. All DM patients
(21 women and 29 men; age range, 30–72 years) were randomly selected
from diabetic patients who had glycosylated hemoglobin (HbA1c) values
6% at the onset of study participation. DM was diagnosed according
to the criteria of the World Health Organization (8). All
patients with hypertriglyceridemia (17 women and 25 men; age range,
29–71 years) were selected from patients who had a serum TG
concentration >1500 mg/L and a serum HDL-C <600 mg/L. Among the 49
diabetic subjects, 12 were receiving lipid-lowering drugs and 1 was
receiving vitamin E supplementation. Of the 42 hypertriglyceridemic
patients, 3 were receiving lipid-lowering medication, 1 was receiving
vitamin C supplementation, and 1 was receiving vitamin E
supplementation. Control subjects (17 women and 25 men; age range,
31–72 years) were selected from healthy volunteers who had serum total
cholesterol (TC) concentrations 2200 mg/L and serum TG concentrations
1500 mg/L.
analytical methods for lipids and other analytes
Serum TC, TG, and HDL-C concentrations were determined
enzymatically (Kyowa Medex Co., Ltd.). Serum concentrations of apo B
and apo A-I were measured with a commercial immunoturbidimetric assay
(Daiichi). These assays as well as the following electrophoresis were
carried out within 1 week after blood was drawn, and serum samples were
stored at 4 °C. HbA1c in whole blood was measured by HPLC. The
reference interval for HbA1c was 4.0–5.8%.
quantification of mda-ldl by elisa
The ELISA method used was based on the same principles as the
method used in the previous report by Kotani et al. (7).
Briefly, serum samples were diluted 2400-fold in a dilution buffer
containing 25 mmol/L HEPES, 3.5 mmol/L sodium dodecyl sulfate, 2 g/L
bovine serum albumin (cat. no. A-7030; Sigma), and 1 g/L
NaN3 (pH 7.8). The diluted sample was
preincubated for 1 h at 37 °C and returned to room temperature.
Duplicate 100-µL portions of the diluted sample were then added to
the wells of plates that were coated with monoclonal antibody against
MDA-LDL (ML25; 0.8 µg/well). The reaction was allowed to stand for
1 h at room temperature, and the plates were then washed.
ß-Galactosidase-conjugated monoclonal antibody against apo B (AB16;
100 µL) was then added, and the mixture was incubated for 30 min at
room temperature. Excess enzyme-labeled antibody was removed by
washing, and 100 µL of 10 mmol/L
o-nitrophenyl-ß-galactopyranoside as a substrate was
pipetted into the wells. After 2 h, the reaction was stopped by
adding 100 µL of 0.2 mol/L sodium carbonate (pH 12). Absorbance in
the individual wells was determined at 415 nm with an MPR-4A microplate
reader. The intra- and interassay CVs were 6.5% and 9.0%,
respectively. Serum samples were used within 4 days after serum was
separated by centrifugation and stored at 4 °C.
Primary standard was used with preparative MDA-LDL, in which 15% of the total amino groups were modified. We tentatively defined 1 unit/L MDA-LDL as the absorbance obtained with the primary standard at a concentration of 1 mg/L. A calibration curve was prepared by diluting a reference serum as a secondary standard from 300- to 9600-fold with a dilution buffer and calculating the amount of MDA-LDL in the samples. Reference sera were prepared from pooled sera from healthy volunteers, and 100 g/L sucrose, 37.5 mmol/L NaCl, and 0.25 mmol/L disodium EDTA were added to each serum pool. The sera were then divided into aliquots and stored at -80 °C. For each assay, aliquots of reference sera were thawed and used.
procedure for nondenaturing gradient gel electrophoresis
The diameter of the LDL in the major LDL peak was estimated by
nondenaturing polyacrylamide gradient gel electrophoresis using a
modified version of the technique described by Krauss and Burke
(9). Briefly, 5 µL of serum from each subject was diluted
twofold with 400 g/L sucrose and electrophoresed for 24 h at
10 °C on 2–15% polyacrylamide gradient gels with a buffer
containing 90 mmol/L Tris, 80 mmol/L boric acid, and 3 mmol/L disodium
EDTA (pH 8.3). The gels were stained with oil red O. The lane
containing the calibrators was stained with Coomassie Blue R250, and a
calibration curve was constructed based on the migration distances of
five markers with known diameters: ferritin (12.2 nm), thyroglobulin
(17.0 nm), thyroglobulin dimer (23.6 nm; Pharmacia), and protein-coated
gold particles (21.1 and 29.2 nm; our preparations). A control serum
was run as a reference on each gel. The locations of individual bands
were compared with the control serum when each was scanned. The
predominant LDL size in each sample lane was calculated from the
equation given below after the migration distance of the major LDL peak
was measured.
Each gel lane was scanned with a densitometer interfaced with a PC computer. Control serum was drawn from one healthy volunteer and combined with 100 g/L sucrose, 37.5 mmol/L NaCl, and 0.25 mmol/L disodium EDTA. This was divided into aliquots and stored at -80 °C.
preparation for protein-coated gold particles
When used as a size marker in electrophoresis, a latex particle is
not clearly visible. We therefore prepared novel markers using
protein-coated gold particles. Briefly, one vial of carbonic anhydrase
(50 mg) was diluted to 5 mL in buffer containing 89 mmol/L Tris, 89
mmol/L boric acid, and 2.5 mmol/L disodium EDTA (pH 8.3). We added 200
µL of this carbonic anhydrase solution and 400 µL each of both
colloidal gold particles (diameters, 10 and 15 nm, respectively) to a
microcentrifuge tube. For all solutions, 1 mL was then vortex-mixed
thoroughly and incubated for 1 h at room temperature. The reaction
mixture was centrifuged at 12 000g for 1 h at
10 °C. After the supernatant was removed, the bottom fraction was
adjusted to a final solution by mixing with an equal volume of 500 g/L
sucrose containing 2.7 mmol/L disodium EDTA. The final solution was
stored at 10 °C for up to 1 month.
determination of diameter of protein-coated gold particles by
shadowing
The final solution of protein-coated gold particles was diluted
10-fold in 25 mmol/L phosphate buffer containing 150 mmol/L NaCl (pH
7.2). The diluted sample was placed on a Formvar/carbon-coated grid and
immobilized for 0.5 min. Excess fluid was removed with filter paper.
The specimen was exposed to platinum shadowing at a 30° angle and
irradiated for several minutes using a JEOL JEE-5E vacuum evaporator.
The specimen was then immediately placed in a microscope specimen
chamber and observed with a JEM-1220 electron microscope at 80 kV.
On the electron micrograph, we measured particle sizes from the shadow
cast by platinum shadowing (10). The shadow width was always
constant and equal to the particle diameter (Fig. 1
). Mean particle sizes were calculated from a sample of 30–100
particles; the mean diameter of the small particles was 21.1 nm, and
the mean of the large particles was 29.2 nm.
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application of both protein-coated gold particles to
electrophoresis
The two protein-coated gold particles were used as size markers in
the gradient gel electrophoresis. Fig. 2
-1 shows that electrophoresis produced clear bands of both
particles (lane 2). Using the method of Williams et al. (11)
with some modifications, we could calculate the equation for converting
molecular diameter (nm) to migration distance
(Rf). The equation was derived from
the migration distances of both protein-coated gold particles
(diameters, 21.1 and 29.2 nm, respectively) and from the migration
distances of the thyroglobulin dimer (23.6 nm), thyroglobulin (17.0
nm), and apoferritin (12.2 nm). The Rf
of each particle measured relative to apoferritin was plotted against
particle diameter (nm; Fig. 2
-2). As a result, LDL diameters were
calculated from the following equation:
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where e is the natural logarithm, and x is the particle diameter (nm).
isolation of ldl and its subspecies
LDL and its subspecies were isolated by sequential
ultracentrifugation from human serum. Sequential ultracentrifugation
was performed in a Beckman Model Optima TL ultracentrifuge with a TLA
100.2 fixed-angle rotor and Beckman polycarbonate 1.5-mL centrifuge
tubes. Fresh serum was mixed with one-half volume of KBr solution
(d = 1.045 kg/L), which adjusted the density of the
mixture to d = 1.019 kg/L. The preparative serum (600
µL) was placed in a tube, and 500 µL of KBr solution
(d = 1.019 kg/L) was layered on top. After
centrifugation at 436 000g for 2 h at 15 °C, the
top layer (500 µL; d <1.019 kg/L) was collected by
aspiration. The bottom fraction was adjusted to d =
1.063 kg/L by mixing with one-half volume of KBr solution
(d = 1.151 kg/L). Subsequently, 500 µL of KBr
solution (d = 1.063 kg/L) was layered onto this
preparative fraction (600 µL). Centrifugation was performed again at
436 000g for 4 h at 15 °C. LDL (500 µL of the
1.019 < d < 1.063 kg/L fraction) was recovered
from the top of the tube. If the bottom fraction (d >1.019
kg/L) was divided according to LDL subspecies, that fraction was
adjusted to d = 1.040 kg/L by adding one-half volume of
KBr solution (d = 1.082 kg/L). Thereafter, the
preparative fraction (600 µL) was placed in a tube, 500 µL of KBr
solution (d = 1.040 kg/L) was layered on top, and the
material was then recentrifuged at the conditions described above. The
supernatant (500 µL; 1.019 < d < 1.040 kg/L)
was stored as the "normal LDL" fraction. The infranate was mixed
with one-half volume of KBr solution (d = 1.109 kg/L),
which adjusted the density of the mixture to d = 1.063
kg/L. Finally, small dense LDL was separated by centrifugation at
436 000g for 4 h at 15 °C. The top layer (500 µL;
1.040 < d < 1.063 kg/L) was recovered as the
small dense LDL fraction (12). All salt solutions contained
1 mmol/L EDTA.
When the cholesterol concentration in the d <1.019 kg/L and 1.019 < d < 1.063 kg/L fractions was defined as the amount of HDL-C subtracted from the TC amount in serum, recovery of cholesterol content in the d <1.063 fractions was 93.1–97.1%. The interassay CVs were <2.5% as determined by measurement of cholesterol in the LDL fraction. Electrophoresis of the LDL fraction in sodium dodecyl sulfate-polyacrylamide gels stained with Coomassie blue R250 revealed contamination of apo A-I in that fraction that was estimated densitometrically as <1.0% of the total protein moiety. Other lipoproteins in the LDL fraction could not be detected by agarose gel electrophoresis.
determination of 2-thiobarbituric acid-reactive substances in
isolated ldl
The MDA concentrations in isolated LDL fractions were determined
by measuring 2-thiobarbituric acid-reactive substances (TBARS) with a
commercially available method (Wako Pure Chemical Industries, Ltd.).
Each LDL fraction (100 µL) isolated by ultracentrifugation was mixed
with 4 mL of distilled water and 1 mL of TBA reagent containing
2-thiobarbituric acid. After vortex-mixing, the samples were incubated
in boiling water for 1 h. The complex formed with 2-thiobarbituric
acid was extracted with 5 mL of butanol and quantified fluorometrically
(excitation, 515 nm; emission, 553 nm). TBARS were expressed as MDA
equivalents. The MDA calibrator was prepared from
1,1,3,3-tetraethoxypropane. Addition of the KBr and EDTA solutions used
in the LDL purification procedure produced no interference in the
assay.
statistical analysis
Data are shown as the mean ± SD. Comparisons of mean values
between control subjects and patients with DM or hypertriglyceridemia
and between subgroups divided on the basis of LDL size or further
subgroups divided by TG concentration were performed with one-way ANOVA
followed by the Scheffé test. However, comparison of variables
between the subgroups except for subgroups containing only one subject
was assessed by the Student t-test. Spearman rank
correlation coefficients were computed to identify correlations that
were significantly associated with variations between lipid values.
Significance was set at P <0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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. For subjects with DM or hypertriglyceridemia, HDL-C and apo
A-I concentrations were lower (P <0.001) than those in
control subjects. The predominant LDL size in hypertriglyceridemic
patients was significantly lower (P <0.001) than that in
control subjects. No significant difference in LDL size existed between
control and diabetic subjects. TG, MDA-LDL, and apo B concentrations
were significantly higher in subjects with DM or hypertriglyceridemia
than in control subjects [P <0.001 except for the
difference in TG concentrations between diabetic patients and control
subjects (P <0.01)].
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correlations between lipids
The correlation coefficients for comparisons between lipid values
for three distinct groups (controls, DM patients, and
hypertriglyceridemic patients) combined are shown in Table 2
. LDL particle size was inversely correlated with TG and MDA-LDL
concentrations and positively correlated with the HDL-C concentration.
HDL-C concentration was weakly correlated with other lipid values.
MDA-LDL was correlated with TG concentration and LDL size. Overall,
TGs, LDL size, and MDA-LDL were closely correlated.
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relationships among tg concentration, ldl size, and mda-ldl
On the basis of distribution of the total LDL particles, we
divided particles into four LDL size groups with diameters () <24.5
nm, 24.5 < 25.5 nm, 25.5 < 26.5 nm,
and 26.5 nm. The distribution of TGs was separated into four
intervals: 0 < TGs 1500 mg/L, 1500 < TGs
3000 mg/L, 3000 < TGs 4500 mg/L, and TGs >4500 mg/L.
Fig. 3
shows a diagram of the subgroup combinations for ranges of LDL
size and TG concentration. Mean values of MDA-LDL in each subgroup were
calculated. The bottom panel in Fig. 3
shows the number of subjects in
each subgroup and the statistical analysis for mean comparisons of
MDA-LDL for the normal subgroup (LDL size 25.5 < 26.5
nm; 0 < TGs 1500 mg/L) and the other subgroups. Only in
subgroups with LDL size range 25.5 nm and TG concentrations
>1500 mg/L was there significantly higher MDA-LDL than in the normal
group. This suggests that there are borderlines (dividing lines between
high and low susceptibility) at a LDL size of 25.5 nm and a TG
concentration of 1500 mg/L for susceptibility to LDL oxidation.
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The top panel in Fig. 3
shows mean MDA-LDL values in each subgroup and
indicates that even subjects with a TG concentration within the
reference interval possess small dense LDLs, with MDA-LDL
concentrations inversely related to LDL size. At TG concentrations
3000 mg/L, there was virtually no large LDL ( 25.5 nm).
distribution of mda-ldl in control subjects and patients
We compared MDA-LDL concentrations in each distribution range of
LDL size between control subjects and patients with DM and with
hypertriglyceridemia (Fig. 4
). There were statistically more (P <0.05) diabetic
patients than control subjects with LDL size ranges of <24.5 nm
and 25.5 < 26.5 nm. In the LDL size distribution of
25.5 < 26.5 nm, patients with hypertriglyceridemia
had significantly higher (P <0.01) MDA-LDL concentrations
than control subjects; in the <24.5 nm size range, patients with
hypertriglyceridemia had significantly lower MDA-LDL concentrations
(P <0.05) than diabetic patients. In the other LDL size
ranges, MDA-LDL concentrations in both patient groups were somewhat
higher than those in control subjects, but the differences did not
reach statistical significance.
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comparisons between lipids in each ldl size range
Assuming a LDL size range of 25.5 < 26.5 nm in
control subjects as a normal LDL, we compared TC, HDL-C, TG, MDA-LDL,
and apo B concentrations in individual subjects on the basis of normal
LDL and other LDL size ranges. Table 3
shows the comparisons between lipid values and LDL size in
control subjects. None of the lipid values for control subjects in the
LDL size ranges <25.5 nm or 26.5 nm differed significantly
from those in the subgroup with normal LDL. For DM patients, the
concentrations of MDA-LDL and apo B for patients in the LDL size ranges
<25.5 nm were significantly higher than the concentrations in control
subjects with normal LDL. TC and TG concentrations were significantly
higher only in DM patients with LDL size range <24.5 nm. For
patients with hypertriglyceridemia, the TG concentrations in patients
in the three LDL size ranges <26.5 nm were significantly higher than
those in control subjects with normal LDL. Conversely, the
concentration of HDL-C in patients in the same LDL size-range subgroups
was significantly lower than that in control subjects with normal LDL.
MDA-LDL and apo B concentrations were significantly higher in patients
in the LDL size ranges 24.5 < 25.5 nm and <24.5
nm, and 25.5 < 26.5 nm and 24.5 <
25.5 nm, respectively.
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measurements of tbars in fractions of normal and small dense ldl
When MDA-LDL concentrations in 20 randomly selected subjects were
compared with the corresponding TBARS concentrations in LDL isolated by
ultracentrifugation, we found no correlation between variables
(r = 0.076; data not shown). However, MDA-LDL in
isolated LDL correlated with the MDA-LDL in serum (r =
0.638; P <0.01). Furthermore, we compared TBARS in
fractions of normal (1.019 < d < 1.040 kg/L) and
small dense LDL (1.040 < d < 1.063 kg/L; Table 4
). In all four randomly selected cases, TBARS were localized in
the fractions of small dense LDL. Cholesterol and apo B were also
present at higher concentrations in normal LDL than in small dense LDL.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Austin and Krauss (18) categorized LDL particles into two
types, the A and B patterns. Pattern A is defined as a normal LDL
pattern with a major peak at a LDL size 25.5 nm. Pattern B is defined
as predominant small dense LDLs <25.5 nm in diameter and is associated
with an increased risk of CHD. Several mechanisms have been proposed to
explain the association of small dense LDL with increased risk of CHD.
One hypothesis is that small dense LDLs are responsible for oxidation,
increasing atherogenic risk (5)(6)(7). When the MDA-LDL
concentration was evaluated as an index of LDL oxidation
(19), it was higher in subjects with DM or
hypertriglyceridemia than in control subjects. This finding supports
previous evidence of progressive oxidation in patients with such
disorders (20)(21)(22).
We assessed the relationship between LDL size and TG concentration by
measuring MDA-LDL concentrations in corresponding subgroups (Fig. 3
).
Using statistical analysis for comparison of the mean MDA-LDL in the
normal LDL size group (LDL size, 25.5 < 26.5 nm;
0 < TG 1500 mg/L) and each subgroup, we observed that
25.5 nm (for LDL particle size) and 1500 mg/L (for TG concentration)
were the cutoff values marking susceptibility of LDL to oxidation. This
finding supports a LDL particle diameter of 25.5 nm as the dividing
point between LDL subclass patterns A and B. In addition, even when
concentrations of TG were 1500 mg/L, it was apparent not only that
small dense LDLs were present in some subgroups but also that
concentrations of MDA-LDL increased in these subgroups with decreasing
LDL size. Overall, subgroups of subjects with a LDL diameter <25.5 nm
and with increased TGs showed more significantly increased
concentrations of MDA-LDL.
When we examined the relationship between LDL size and the
concentration of MDA-LDL in control subjects and patients with DM or
hypertriglyceridemia, we found that LDL particle diameters and MDA-LDL
concentrations were inversely related in all groups (Fig. 4
). MDA-LDL
concentrations differed between controls and patients regardless of LDL
size range. Furthermore, in the same groups, we evaluated the
relationship between lipid markers and LDL size. When we postulated the
particle size range of 25.5 < 26.5 nm in control
subjects to be normal, only MDA-LDL in both patient groups was
significantly increased when the LDL size was just below normal
compared with normal LDL (Table 3
). It is understood that both small
dense LDL and large buoyant LDL have reduced clearance from circulation
because of their lower affinities for the LDL receptor (23).
Therefore, our postulate has merit for defining normal LDL as LDL
particles with a size range 25.5 < 26.5 nm. This also
suggests that the separation point for susceptibility to LDL oxidation
is at 25.5 nm. TG concentrations in subjects with hypertriglyceridemia
increased as LDL size decreased from 26.5 nm. The relationship between
TG concentration and LDL size distribution diminishes to a certain
extent at higher TG concentrations.
We also examined whether MDA-LDL in serum detected by our assay was directly comparable with TBARS in isolated LDL particles. Subsequently, although the former was associated with MDA-LDL in LDL, we found no correlation between MDA-LDL in serum and TBARS in LDL. Whereas the MDA value obtained as a TBARS concentration is provided from the reaction between free MDA and 2-thiobarbituric acid, the ELISA detects LDL modified by MDA but not free MDA. Thus, there is a possibility that the reactants detected by each method differ. This may be the reason that the MDA-LDL concentration in serum was not correlated with the TBARS concentration in isolated LDL. However, TBARS are generally used as a marker of lipid oxidation (24). It was important to compare TBARS concentrations between fractions of normal (1.019 < d <1.040 kg/L) and small dense LDL (1.040 < d < 1.063 kg/L). TBARS localized in the fraction of small dense LDL, supporting our finding that a LDL particle size of 25.5 nm is the cutoff for susceptibility of LDL to oxidation.
In conclusion, we evaluated the relationship between TG concentration and LDL size, using an ELISA to measure MDA-LDL concentrations, and deduced that decreased LDL particle size with an increased TG concentration leads to an increased concentration of small dense LDLs with oxidative modification, thereby increasing atherogenic risk. The threshold of susceptibility to oxidative modification appears to be at a LDL particle diameter of 25.5 nm. This coincides with the point of distinction between LDL subclass patterns A and B proposed by Austin and Krauss (18).
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Acknowledgments |
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Footnotes |
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References |
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