© 1995 American Heart Association, Inc.
Articles |
Atherosclerotic Disease in Marked Hyperalphalipoproteinemia
Combined Reduction of Cholesteryl Ester Transfer Protein and Hepatic Triglyceride Lipase
From the Second Department of Internal Medicine, Osaka University Medical School, Suita, and the First Department of Internal Medicine, Hiroshima University School of Medicine, Minami-ku (Y.K., K. Hayashi), Japan.
Correspondence to Ken-ichi Hirano, MD, PhD, Section of Gastroenterology, Department of Medicine, University of Chicago, 5841 S Maryland Ave, Chicago, IL 60637.
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Abstract |
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Abstract Hyperalphalipoproteinemia (HALP) has been regarded as a beneficial state accompanied by a longevity syndrome. However, we reported the cases of markedly hyperalphalipoproteinemic subjects with juvenile corneal opacification. These patients had reduced postheparin hepatic triglyceride lipase (HTGL) activities, and one of them has recently been identified to be homozygous for a missense mutation in exon 15 (D442: G) in the cholesteryl ester transfer protein (CETP) gene. In the current study, to elucidate the clinical significance of and atherogenicity in marked HALP, we determined the incidence of atherosclerotic cardiovascular disease (ACD) in patients with marked HALP and characterized the lipoprotein abnormalities in those who had ACD, focusing especially on CETP and HTGL. The subjects were 201 patients (111 males and 90 females) with marked HALP (
2.58 mmol/L
[100 mg/dL]), 67% of whom were demonstrated to have the CETP gene
mutations in the intron 14 splice donor site or in exon 15. Their mean
age was 54±15 years. Plasma levels of total cholesterol,
HDL cholesterol, and triglyceride in all
subjects were 6.28±1.78, 3.15±0.90, and 1.08±0.53 mmol/L,
respectively. Ten of the male patients (9.0%) and two of the female
patients (2.2%) had apparent ACD such as myocardial infarction, angina
pectoris, and peripheral vascular diseases. Ten patients
with HALP who had ACD were identified to be heterozygotes for CETP
deficiency. To further clarify the characteristics of marked HALP in
patients with ACD, we compared the plasma lipids, lipoproteins, CETP,
and HTGL activities between heterozygotes for CETP deficiency who were
with and without ACD. There was no significant difference in plasma
lipids, lipoproteins, and CETP between the two groups, whereas HTGL
activities were significantly lower in the heterozygotes for CETP
deficiency with ACD than in the heterozygotes without ACD and in
control subjects. These results suggest that marked HALP may not always
be a beneficial state and that people who are heterozygotes for CETP
deficiency and who have low HTGL may be susceptible to ACD.
Key Words: atherosclerosis • cholesteryl ester transfer protein • hepatic triglyceride lipase • reverse cholesterol transport • hyperalphalipoproteinemia
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Introduction |
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Many epidemiological studies have shown that a mild or moderate increase in plasma HDL cholesterol is associated with a reduced incidence of CHD.1 2 3 Furthermore, in vitro and in vivo experiments demonstrated that HDL has an ability to remove cholesterol from lipid-laden macrophages and that the infusion of HDL induced a regression of atherosclerotic lesions in cholesterol-fed rabbits.4 Therefore, it is established that HDL particles have an antiatherogenic function.5
Although the detailed mechanism for the antiatherogenicity of HDL has not been fully clarified, RCT6 7 may be one of the protective systems against atherosclerosis. In this system, HDL plays a crucial role as a shuttle carrying cholesterol derived from peripheral tissues. In the first step of RCT, HDL removes cholesterol from atherosclerotic lesions. The cholesterol incorporated into HDL particles is esterified by the action of LCAT. Besides HDL and its apolipoproteins, plasma enzymes, and proteins such as LCAT, CETP, and lipases are thought to take part in this system.8 CETP in particular transfers cholesteryl ester from HDL to apo B–containing lipoproteins. These apo B–containing lipoproteins are finally taken up by the liver, a terminal of RCT, via the LDL receptor.
It is needless to say that a complete deficiency of plasma HDL, such as that in familial apo A-I deficiency, would impair the RCT system, causing premature CHD.9 10 On the other hand, the clinical significance of a marked elevation of HDL cholesterol has not been fully understood. Because plasma HDL cholesterol level is known to be influenced by various environmental11 12 and genetic factors,13 14 15 marked HALP is thought to be a heterogeneous syndrome. We have reported the cases of two patients with marked HALP who suffered from CHD and juvenile corneal opacification.16 These two subjects had reduced activities of HTGL.17 Recently, one of these patients was determined to be homozygous for the missense mutation of exon 15 (D442: G) in the CETP gene.18
To elucidate the clinical significance and atherogenicity of marked HALP, we determined the incidence of ACD in patients with this disorder. We also characterized lipoprotein abnormalities in patients who had both marked HALP and ACD, focusing especially on plasma enzymes, including CETP and lipases. We discussed their atherogenicity from the viewpoint that marked HALP may be a model for the impairment of RCT.
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Methods |
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Subjects
The subjects composed a consecutive series of 201 patients (111 males and 90 females) who were referred to our lipid research clinic with a diagnosis of marked HALP with HDL cholesterol levels of 2.58 mmol/L (100 mg/dL) or greater. The mean ages of the male and female subjects were 55±15 and 53±15 years (mean±SD), respectively. Forty female subjects (44.4%) were postmenopausal. None of the female subjects received contraceptives or hormone replacement therapy. Blood was obtained after an overnight fast. Thirty age- and sex-matched healthy and normolipidemic subjects without CETP gene mutations were the control subjects.
Information on coronary risk factors, including hypertension
(defined as a history of systolic blood pressure 150 mm Hg
and/or diastolic blood pressure 95 mm Hg), diabetes
(history of diabetes or treatment with oral hypoglycemic agents or
insulin), smoking (one or more cigarettes per day), and massive alcohol
consumption (defined as consumption of more than 80 g ethanol per day),
as well as on medications was noted by direct interview or from the
patients' medical charts.
ACD included disorders such as myocardial infarction, angina pectoris,
cerebral infarction, transient ischemic attack, and
peripheral vascular disease. In nine patients with marked
HALP, ACD was diagnosed on the basis of angiographic findings. For
patients in whom angiography could not be performed (patients 4, 5, and
12), we used the criteria for ACD as follows: angina pectoris was
diagnosed when a subject experienced recurrent chest discomfort that
was brief in duration (
15 minutes), worsened by exertion or emotion,
and relieved by rest or nitroglycerin. Myocardial
infarction was diagnosed on the basis of at least two of three standard
criteria (typical chest pain, QRS and ST-T changes on
electrocardiograms, and the transient elevation of
myocardial enzymes). Sudden death was defined as a witnessed death that
occurred within 1 hour after the onset of acute symptoms and without
any history in which violence or accident played a role in the fatal
outcome. Stroke was diagnosed on the basis of rapid onset of local and
persistent neurological deficit in the absence of any other disease
process that explained the symptoms. Transient ischemic attack
was diagnosed by any sudden focal neurological deficit that cleared
completely within 24 hours.
Isolation of Plasma Lipoproteins
VLDLs, IDLs, LDLs, HDL2s, and
HDL3s were isolated by sequential preparative
ultracentrifugation at densities of 1.006, 1.019,
1.063, 1.125, and 1.210 g/mL, respectively.19
Activity and Protein Mass of CETP
CETP activity was measured according to the method of Kato et
al.20 Discoidal bilayer particles containing
[14C]cholesteryl oleate were prepared, as described
previously. In brief, an ethanol solution containing 22.5 µmol egg
phosphatidylcholine, 7.5 µmol cholesterol, and 0.3 µmol
[14C]cholesteryl oleate (10 µCi, Amersham) was injected
into 20 mL phosphate buffer (pH 7.4) containing EDTA. After the
solution was mixed for 15 minutes at room temperature, 1.9 mL 200
mmol/L sodium cholate containing 9 mg purified apo A-I was added to the
mixture while it was stirred. The mixture was incubated for 30 minutes
and then dialyzed against 8 L PBS at 4°C to remove ethanol and
cholate. The solution of 14C-DBP thus obtained was diluted
to 25 mL with PBS. Plasma CETP activity was measured in terms of the
radioactivity of [14C]cholesteryl ester transferred from
discoidal bilayer particles to LDL as described previously. The
reaction mixture containing 100 µL 14C-DBP and 130 µg
LDL was incubated with 2 µL plasma for 30 minutes at 37°C in the
presence of 1.4 mmol/L DTNB, an inhibitor of LCAT. After
incubation, 30 µL 0.1% dextran sulfate and 30 µL 60 mmol/L
MgCl2 were added to the incubation mixture. The mixtures
were kept on ice for 20 minutes and centrifuged at 12 000 rpm
for 10 minutes. Supernatants were collected and the pellets (LDL) were
dissolved in 0.1 mol/L NaOH. Radioactivities in the supernatants and
pellets were counted by use of a Beckman liquid scintillation counter.
Percentage transfer of [14C]cholesteryl ester was
calculated. CETP activities in the patients were expressed as
percentage of the mean transfer of control subjects.
Protein mass of CETP was measured according to the method of Sato et al (personal communication) by use of enzyme-linked immunosorbent assay with monoclonal antibodies against CETP.
Activity and Protein Mass of LPL and HTGL in
Postheparin Plasma
Plasma samples were obtained 15 minutes after
intravenous injection of heparin (50 IU/kg body weight).
Activities of LPL and HTGL were measured nonradioisotopically by the
method described previously.21 In brief, a selective assay
of each lipase was performed by addition of SDS and NaCl to
inactivate HTGL and LPL, respectively. Triolein emulsion
with gum arabic was used as a substrate. For LPL assay, 100 µL
postheparin plasma was preincubated with 100 µL 100
mmol/L SDS for 60 minutes at 26°C. The reaction was then started by
addition of 10 µL SDS-treated postheparin plasma to 0.49
mL incubation mixture (0.1 mol/L NaCl, 0.2 mol/L Tris-HCl [pH 8.2],
5% BSA, 15 mmol/L triolein, and 100 to 140 µL serum
activator). After 60 minutes of incubation at 28°C, free
fatty acids released were extracted by a modification of the method of
Dole.22 Each aliquot of the extract was then evaporated
under a nitrogen stream. After emulsification of the residue with
Triton X-100, the NEFA kit (Nippon Shoji) reagent was added. After
color formation, the turbidity was removed by addition of chloroform,
the mixture was centrifuged at 5500g for 30 minutes,
and the absorbance at 550 nm was measured. For the HTGL assay, the
reaction was initiated by adding 5 µL postheparin plasma
to 0.495 µL incubation mixture (0.75 mol/L NaCl, 0.2 mol/L Tris-HCl,
5% BSA, and 15 mmol/L triolein, pH 8.8). The subsequent procedure was
the same as that for the LPL assay.
The protein masses of HTGL and LPL were measured by use of a sandwich enzyme immunoassay with monoclonal antibodies.23
Apo E Phenotyping
Apo E phenotyping was performed by isoelectric focusing of apo
VLDL. VLDL isolated by ultracentrifugation was
delipidated sequentially with acetone-ethanol (vol/vol=1/1) twice
and diethyl ether. VLDL apolipoproteins were resuspended in 0.01 mol/L
Tris-HCl/8 mol/L urea/0.001 mol/L dithiothreitol, pH 8.6. Isoelectric
focusing was performed according to the method of Bouthillier et
al.24 The separated apo E isoforms were detected by
protein staining (Coomassie brilliant blue G-250).25
Measurement of Lp(a)
Serum concentrations of Lp(a) were measured by an
enzyme-linked immunosorbent assay with a Tint Eliza Lp(a) kit
(Biopool).26 Sheep polyclonal antibodies against purified
human Lp(a) were immobilized on microtest plates as catch
antibodies and conjugated to HRP as tag antibodies. Serum samples were
diluted 2601-fold before the assay. Interassay and intra-assay
coefficients of variation were 7.3% and 4.0% at an Lp(a)
concentration of 10 mg/dL and 4.1% and 2.6% at an Lp(a) concentration
of 40 mg/dL. The assay allowed a highly reproducible determination of
Lp(a) with a satisfactory accuracy in the range of 1 to 60 mg/dL.
Detection of CETP Gene Mutations
In all subjects, we analyzed two mutations in the CETP
gene by the method using PCR, as we reported
previously.18 27 One was a G-to-A mutation at the 5'
splice donor site of intron 14,27 which is most commonly
observed in Japan. The other was a missense mutation, an A-to-G change
in exon 15 (442D: G).18 In brief, genomic DNA was prepared
from whole blood according to the method of Kunkel et
al.28 After PCR with specific primers, the fragments were
digested by Nde I for the detection of the intron 14
splicing defect and Msp I for identification of the missense
mutation.
Analytical Methods
Protein concentration was determined by the method of Lowry et
al.29 Total cholesterol and
triglyceride were measured enzymatically by use of
commercial kits (Determiner TC-5 and TGS-555, respectively; Kyowa
Medex). HDL cholesterol levels were measured by the
heparin-Ca2+ precipitation method.30
Serum concentrations of apolipoproteins A-I, A-II, B, C-II, C-III, and
E were measured by a single radial immunodiffusion
method.31
Statistical Analysis
All values were expressed as mean±SD. Statistical significance
was evaluated by use of Student's t test for comparison of
unpaired data. Multiple comparison was performed by the method of
Tukey.
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Results |
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Table 1
shows the clinical profiles, plasma lipids,
and apolipoproteins in subjects with marked HALP. Ten male subjects
(9.0%) and two female subjects (2.2%) also had apparent ACD. In the
subjects with marked HALP, total cholesterol, HDL
cholesterol, and apolipoproteins A-I, A-II, C-III, and E
were significantly increased in subjects of both sexes, compared with
those in control subjects. There was no significant difference in
plasma apo B levels between subjects with marked HALP and control
subjects.
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We and other Japanese laboratories reported that many Japanese subjects
with marked HALP had genetic mutations in the CETP
gene.27 32 33 Two common mutations were reported: an
intron 14 splicing defect27 and a missense mutation of
exon 15 (D442: G).18 To clarify the genetic basis for the
marked HALP, we screened for the two mutations in 121 subjects from
whom DNA could be obtained, using the PCR-RFLP methods we developed. As
shown in Table 2, 81 subjects (67%) were found to have
at least one of the two mutations. Six subjects had both mutations,
suggesting compound heterozygosity of each mutation. We were able to
perform a family study in one of these patients and confirmed that he
was a compound heterozygote of these two mutations (K. Hirano, MD, PhD,
et al, unpublished data, 1995).
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Of 201 subjects with marked HALP, we identified 12 who also had ACD.
Table 3 shows the clinical profiles of patients with
marked HALP and ACD. Their mean age was 61±8 years. Ten patients
suffered from CHD. The other two had peripheral vascular
disease. Fig 1 shows angiograms of the coronary
artery and abdominal aorta of patient 3, who suffered from angina
pectoris and intermittent claudication. He was diagnosed as having
double-vessel CHD and arteriosclerosis
obliterans, as shown in Fig 1. Two of the subjects with
both HALP and ACD (patients 8 and 9) died suddenly during our
follow-up period. Some patients had coronary risk factors
such as hypertension, smoking, and diabetes mellitus. Corneal arcus was
observed in all subjects with ACD. Ten subjects were found to have CETP
gene mutations with decreased CETP activities. We could measure HTGL
activities in postheparin plasma in seven subjects. They
had reduced activities of HTGL, as shown in Table 3. All subjects whose
data appear in Table 3 had the wild-type apo E phenotype
(apo E 3/3). Plasma concentrations of Lp(a) were within the normal
range (data not shown).
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To further clarify the characteristics of patients with marked HALP and
ACD, we compared the levels of plasma lipids, lipoproteins, and
apolipoproteins and the activities of CETP and lipases between male
heterozygous CETP-deficient patients with and without ACD. As shown in
Table 4, there was no significant difference in these
variables between male heterozygous CETP-deficient patients with
and without ACD. We next compared the activities of CETP, LPL, and HTGL
between the male subjects with and without ACD (Fig 2).
In the male subjects with ACD, HTGL activities were markedly and
significantly reduced compared with those in subjects without ACD
(P<.05) and male control subjects (P<.01). LPL
activities in the subjects with ACD were not significantly different
from those in the control subjects. In the subjects without ACD,
activities of LPL were higher than those in the control subjects.
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indicates heterozygotes with ACD;
,
heterozygotes without ACD; and 
, control subjects. Values are
expressed as mean±SD. FFA indicates free fatty acids.
Fig 3 demonstrates the distribution of CETP and HTGL
activities in the subjects whose postheparin plasma could
be obtained. In this figure, we separated the areas into four parts
(Areas 1 through 4) according to the cutoff values as follows: For CETP
activities, we selected a cutoff value of 70% of control, because this
value was the highest level of CETP activity in the genetically
identified CETP-deficient subjects investigated. For HTGL activities,
the cutoff value was 1 SD below the mean level in control subjects.
There was a close correlation between CETP activity and protein mass
(r=.786, P<.001) and between HTGL activity and
protein mass (r=.789, P<.001) (data not shown).
Most of the patients with ACD were in Area 1 with decreases in both
CETP and HTGL. We performed a multiple comparison by Tukey's method on
the incidence of ACD between these four areas. The incidence of ACD in
patients in Area 1 was significantly higher than those in the other
three areas (P<.05). There is no difference in risk factor
profile between the six male subjects with ACD in Area 1 and the four
male subjects without ACD in Area 1 (data not shown). These data
suggest that markedly hyperalphalipoproteinemic subjects with a
concomitant reduction of both CETP and HTGL may be susceptible to ACD.
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female patients without ACD. |
Discussion |
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The present study investigated for the first time the incidence of ACD in patients with marked HALP and the clinical characteristics of patients with marked HALP who have ACD. Most of these patients in our study had heterozygous CETP deficiency. In contrast to findings in previous reports,13 CETP-deficient patients had ACD. In male heterozygous CETP-deficient patients with ACD, HTGL activities were significantly lower than those in heterozygous CETP-deficient patients without ACD or in control subjects. These results suggest that marked HALP is not an antiatherogenic state and, especially, that a combined reduction of CETP and HTGL activities observed in patients with marked HALP may be closely associated with atherosclerosis.
What are the mechanisms for the atherogenicity in the patients with
HALP who were investigated in the current study? As shown in Table 3
,
most of the patients with ACD had some conventional risk factors for
atherosclerosis. It was also shown that the incidence
of ACD was lower in female subjects with marked HALP than in male
subjects with marked HALP (2.2% versus 9.0%). These observations
suggested that the known risk factors, such as sex (male), smoking,
hypertension, and sex hormone status, may play some role in the ACD
observed in patients with marked HALP as well as in patients with low
and normal HDL cholesterol levels. However, we speculate
that marked HALP may reflect an impairment of the RCT system. Fig 4 shows our proposed model for the processing of the RCT
system. Under normal conditions, as the first step of RCT, HDL removes
cholesterol from atherosclerotic lesions. The removed
cholesterol is esterified by the action of LCAT. HDL
becomes larger and richer in cholesteryl ester–containing
particles. In the next step, cholesteryl ester on HDL is transferred to
apo B–containing lipoproteins by CETP,34 subsequently
being cleared from the circulation as a result of hepatic uptake by
means of receptor-mediated and receptor-independent
pathways.35
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Since familial CETP deficiency was found in Japanese subjects with
marked HALP,36 37 this disorder has been known to be one
of the major causes of marked HALP. The lipoprotein abnormalities in
CETP-deficient patients homozygous for the intron 14 splicing defect
are characterized by the presence of small and polydisperse
LDLs,37 38 which were revealed to have a reduced affinity
for LDL receptors of normal human fibroblasts.39 Large and
cholesteryl ester–rich HDL particles40 obtained from
homozygotes could not prevent the accumulation of
cholesterol in macrophages induced by acetylated
LDLs.41 Recently we found a unique area in which about
27% of the general population has the intron 14 splicing defect. In
this area, the prevalence of both marked HALP and CETP gene mutation
was observed less frequently in elderly subjects (80 years old) than
in the younger generations (K. Hirano, MD, PhD, et al, unpublished
data, 1995). These observations indicate that the deficiency of CETP
caused qualitative and quantitative abnormalities in LDLs as well as in
HDLs, suggesting that these lipoprotein abnormalities observed in
CETP-deficient patients might accelerate
atherosclerosis. We reported that the decrease in HDL
cholesterol was closely correlated with the reduction in
Achilles' tendon thickness in patients with familial
hypercholesterolemia during treatment with
probucol,17 which was shown to raise plasma CETP activity.
Although there has been a controversy about whether or not CETP
deficiency is an antiatherogenic state, these observations indicate at
least that CETP deficiency is never a longevity syndrome.
Two lipolytic enzymes, LPL and HTGL, regulate serum HDL2 cholesterol levels in a reciprocal manner; high LPL activity increases HDL2 cholesterol levels, whereas high HTGL activity is responsible for the transformation of HDL2 into HDL3, consequently lowering plasma HDL2 cholesterol levels.42 43 Previous clinical studies showed that low levels of HTGL might be associated with CHD. Genetic deficiency of HTGL was reported to be associated with CHD.44 We speculate that the patients with low HTGL might have some genetic mutations in the HTGL and related genes. However, some difference in the lipoprotein profiles was noted between patients with genetic HTGL deficiency reported previously45 46 and our patients in the current study. The patients with low HTGL and low CETP activity in our study showed neither high plasma triglyceride levels nor accumulation of remnant lipoproteins. Although the mechanism for this difference is unknown, it could be partly explained by the impairment of the transfer of cholesterol from HDL to apo B–containing remnant lipoproteins due to the reduction in CETP activity. From these observations, we conclude that the accumulation of remnant lipoproteins cannot be attributed to the atherogenicity in the patients.
HTGL has been speculated to play an important role in the interaction between HDL particles and liver in addition to the one it plays in the hydrolysis of triglycerides in lipoproteins. Collet et al47 reported that HTGL-modified HDLs display an increased ability to deliver cholesteryl ester and apolipoproteins to cultured hepatocytes. As we reported previously, patients with HALP who have primary biliary cirrhosis, which is often associated with xanthomas, have reductions in both protein mass and activity of HTGL.48 Therefore, decreased activities of HTGL observed in the patients with HALP who have ACD may be attributed partly to the development of atherosclerosis.
It was very interesting that subjects with low CETP activity and without ACD had increased LPL activity compared with that in patients with ACD or with that in control subjects, although the mechanism for the increase has not been clarified. Earlier studies on HALP revealed an association between elevated LPL activity and high HDL cholesterol level.49 The mutation of the LPL gene was reported to be associated with reduced HDL cholesterol levels in premature atherosclerosis.50 Recently cell biology studies demonstrated that LPL is important in the interaction between lipoproteins and tissues51 such as macrophages, adipocytes, and smooth muscle cells, as well as in the hydrolysis of triglycerides. These studies suggested that LPL may have a dual (atherogenic and antiatherogenic) in vivo function in atherosclerosis. We think that further studies are necessary to understand the significance of the increased LPL activity observed in subjects with marked HALP.
We think that a concomitant reduction in CETP and HTGL may be involved
in the atherogenicity in the patients with ACD. We found that in vitro
addition of both exogenous purified CETP and HTGL to plasma from
homozygous CETP-deficient patients induced the appearance of very small
HDL particles. These very small HDL particles had a greater capacity to
remove cholesterol from lipid-laden
macrophages, whereas the native large and cholesteryl
ester–rich HDL particles from the CETP-deficient patients did not
have an antiatherogenic function.52 Furthermore, Newnham
and Barter53 reported that CETP and HTGL synergistically
play an important role in forming very small HDL particles. In the
current study, patients with a complete deficiency of plasma CETP,
whose activities of HTGL were higher than those in heterozygous
CETP-deficient patients, did not suffer from ACD. Because of these data
taken together, we speculate that a combined reduction in HTGL and CETP
may impair the RCT system more severely than a sole deficiency of CETP
or HTGL, as illustrated in Fig 4.
In conclusion, marked HALP is not always beneficial. We consider it essential to re-evaluate the clinical profiles and pathophysiology of marked HALP from the viewpoint that it manifests some impairments in RCT.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported by grants from the Japanese Ministry of Education (Nos 4404085 and 3557117), a Research Grant for the Adult Disease, the HMG-CoA Reductase Research Fund from Sankyo Co, and the Japan Foundation for Aging and Health. The authors thank Drs Naito (Nagoya University, Aichi, Japan), Hisashi Akioka, Kunitsugu Masuda, Toshimichi Inoue, and Norimichi Nakajima for referring the patients. We are grateful to Drs Makoto Kinoshita (Teikyo University School of Medicine, Tokyo, Japan) and Hiroyuki Arai (The University of Tokyo, Tokyo, Japan) for technical advice on the measurement of CETP activity. We thank Dr Sato (Eizai Co, Tsukuba, Japan) for measuring the protein mass of cholesteryl ester transfer protein. The skillful technical assistance of Mayumi Koyama and Masako Masuda is gratefully acknowledged.
Received April 20, 1995; accepted August 14, 1995.
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