© 2001 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Point Mutation (-69 G
A) in the Promoter Region of Cholesteryl Ester Transfer Protein Gene in Japanese Hyperalphalipoproteinemic Subjects
From the Research Department, R&D Center, BML, Saitama (M.N., T.K., M.I., Y.S., H.H., T.E.); the Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University, Osaka (S.Y., K.H., T.M., N.S.); and Nakajima Clinic, Akita (N.N.), Japan.
Correspondence to Shizuya Yamashita, MD, PhD, Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan. E-mail shizu{at}imed2.med.osaka-u.ac.jp
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Abstract—Cholesteryl ester transfer protein (CETP) transfers cholesteryl ester (CE) from HDL to apolipoprotein (apo) B–containing lipoproteins and plays a crucial role in reverse cholesterol transport, which is a major protective system against atherosclerosis. Genetic CETP deficiency is the most common cause of a marked hyperalphalipoproteinemia (HALP) in the Japanese, and various mutations have been identified in the coding region as well as in the exon/intron boundaries in the CETP gene. In the present study, we identified a novel mutation in the promoter region of the CETP gene. This mutation was a G-to-A substitution at the -69 nucleotide of the promoter region (-69 G
A), corresponding to the second
nucleotide of the PEA3/ETS binding site
(CGGAA) located upstream of the
putative TATA box. Four (2.0%) of 196 unrelated subjects with a marked
HALP (HDL cholesterol 
2.59 mmol/L=100 mg/dL) were
revealed to be heterozygous for the -69 GA mutation, and the
allelic frequency of the mutant was 0.0102 in the subjects with a
marked HALP. The subjects with the -69 GA mutation had low plasma
CETP levels. Reporter gene assay showed that this mutation markedly
reduced the transcriptional activities in HepG2 cells (8% of wild
type). These results suggested that this mutation would be dominant
negative. In conclusion, a novel -69 GA mutation in the CETP gene
causes the decreased transcriptional activity leading to
HALP.
Key Words: cholesteryl ester transfer protein deficiency • hyperalphalipoproteinemia • mutation • promoter • PEA3/ETS binding site
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Cholesteryl ester transfer protein (CETP) is a plasma glycoprotein that catalyzes the transfer of cholesteryl ester (CE) from HDL to apolipoprotein (apo) B–containing lipoproteins and is one of the major determinants of plasma HDL cholesterol levels.1 2 3 Genetic CETP deficiency is the most common cause of hyperalphalipoproteinemia (HALP) in the Japanese.4 5 6 7 8 9 10 It has been demonstrated that a G-to-A substitution at the 5' splice donor site of intron 14 (Int14 +1 G
A) and a missense mutation of
exon 15 (D442G) in the CETP gene are common mutations associated with
HALP. These 2 mutations are relatively frequent in the Japanese
population.5 7 8 10
Patients with CETP deficiency have moderate
hypercholesterolemia and markedly increased
levels of HDL cholesterol. The lipoprotein abnormalities in
CETP deficiency are also characterized by the presence of polydisperse
LDL enriched with triglycerides and large, CE-rich HDL
particles.11 12 13 14
These results indicated that CETP is involved in the regulation of
plasma lipoproteins by modulating both the quantity and quality of each
lipoprotein particle.
In addition, CETP plays an important role in reverse
cholesterol transport from peripheral tissues
to the
liver.15 16
Recently, CETP deficiency has been thought to be a proatherogenic state
because of the crucial role of CETP in reverse cholesterol
transport despite high HDL cholesterol levels. The study of
the Omagari area in Japan, where the Int14 +1 GA mutation is
extremely frequent, indicated that a marked HALP caused by CETP gene
mutation may not represent a longevity
syndrome.17 The Honolulu
Heart Program demonstrated that the prevalence of coronary
heart disease in men with CETP gene mutation was
increased.18 Therefore,
genetic CETP deficiency appears to be an independent risk factor for
coronary heart disease. In the present study, we screened
CETP gene mutations in 196 marked HALP subjects and identified a novel
one in the promoter region of the CETP gene. Furthermore, we
investigated the effects of this novel mutation on lipoprotein
metabolism and its prevalence in the Japanese HALP
subjects.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Study Subjects
Four hundred sixty-six unrelated Japanese subjects (163 men and 303 women) with HALP (HDL cholesterol
2.07 mmol/L=80 mg/dL) were referred to the lipid clinic in
Osaka University Hospital and Nakajima Clinic in Omagari City,
Akita Prefecture. Among these subjects, 196 had a marked HALP (HDL
cholesterol 2.59 mmol/L=100 mg/dL). Subjects with
primary biliary cirrhosis, nephrotic syndrome, and thyroid dysfunction
and massive alcohol drinkers (80 g/d) were excluded from this study.
Ninety healthy normolipidemic subjects (53 men and 37 women) were
examined as control subjects.
Lipoprotein Preparation
LDL
(1.006<d<1.063 g/mL) was
isolated from human plasma by sequential
ultracentrifugation in a Beckman Ti 50.2 rotor with
solid KBr to adjust the density at 1.063
g/dL.19 LDL was extensively
dialyzed against PBS (pH 7.4) containing 1 mmol/L EDTA and 0.02%
NaN3 and stored at 4°C.
Measurement of CETP Activity
The plasma CETP activity was determined according to
the method described by Kato et
al,20 with minor
modifications. In brief, 80 µL of diluted (1:40) plasma sample was
added to 70 µL of reaction mixture containing LDL (65 µg protein)
and reconstituted HDL consisting of 36 µg apoA-I and 0.94 nmol
[1-14C]cholesteryl oleate and incubated at
37°C for 30 minutes. LDL was then precipitated with 30 µL of 0.05%
dextran sulfate and 30 mmol/L MgCl2, and
the radioactivity in the precipitates was measured by a scintillation
counter (Beckman LS5000TD). CETP activity was expressed as the
percentage of pooled normal plasma compared with control levels, in
which CETP activity was 360±69 nmol ·
h-1 · mL-1.
The intra-assay and interassay (n=8) coefficients of variation were
2.7% and 6.0%, respectively.
Measurement of CETP Mass
The plasma CETP mass was measured by a sandwich ELISA
using 2 monoclonal antibodies (mAbs) specific to human CETP, JHC1 and
JHC2, as described.21 In
brief, 100 µL of mAb JHC1 (20 µg/mL) in PBS was coated on a plate
(Nunc Immunoplate II MaxiSorp) by incubation at
4°C overnight. The wells were then blocked with 200 µL of PBS
containing 1% BSA (Sigma Chemical Co) for 2 hours at room temperature.
After the plate had been washed with PBS containing 0.1% Tween 20, 100
µL of standard solution or diluted 1:400 plasma samples was added and
incubated for 2 hours at room temperature. After washing, 100 µL of
biotinylated mAb JHC2 (0.1 µg/mL) was added to each well and
incubated for 1 hour at room temperature. After washing, 100 µL of
horseradish peroxidase–conjugated streptavidin (1 µg/mL) (Vector
Laboratories, Inc) was added and incubated for 30 minutes, followed by
incubation with 100 µL of substrate solution containing 0.25 mg/mL
o-phenylenediamine
and 0.6% H2O2. After 30
minutes, the reaction was stopped by the addition of 100 µL of 2N
H2SO4. Absorbance at 492
nm was measured by a plate reader (Labsystems). A pooled culture medium
from Raji cells expressing recombinant human CETP was used as a
secondary standard and purified human CETP as a primary standard. The
assay range of the ELISA method was from 0.025 to 1.5 ng CETP/well. The
assay was performed in duplicate for each sample. The intra-assay and
interassay (n=8) coefficients of variation were 2.7% and 7.8%,
respectively. No interfering effect on ELISA assay was observed with
hemoglobin (10 g/L), bilirubin (0.2 g/L), or
triacylglycerol (4.25 g/L). There was a strong
positive correlation between plasma CETP mass and CETP activity
(r=0.940,
P<0.001).
Polymerase Chain Reaction
Genomic DNA was isolated from whole blood with a
QIAamp Blood Kit (Qiagen). The promoter region and each exon of the
CETP gene were individually amplified by polymerase chain reaction
(PCR). In general, PCR was carried out on 
0.1 µg of genomic
DNA in a buffer containing 10 mmol/L Tris (pH 8.3), 50 mmol/L
KCl, 0.2 mmol/L each dNTP, 1.5 mmol/L
MgCl2, 0.2 nmol/L of each primer, and 0.5 U
Taq polymerase (Perkin-Elmer
Cetus). PCR conditions were denaturation at 95°C for 5 minutes,
followed by 35 cycles of denaturation at 95°C for 30 seconds,
annealing at 56°C to 65°C for 30 seconds, and extension at 70°C
for 1 minute, with final extension at 72°C for 10 minutes. The
abundance and quality of DNA fragments were analyzed by
electrophoresis on 3% agarose gels, followed by ethidium bromide
staining and inspection under UV light.
Mutation Screening Using PCR–Restriction
Fragment Length Polymorphism Analysis
The 6 known mutations were analyzed by
PCR–restriction fragment length polymorphism (RFLP). The PCR
amplification was performed with pairs of primers:
5'-CAGGGGCTCATTGTGGTGCT-3' (sense), 5'-GACCACAGGGAGTCAGCCAG-3'
(antisense) for G181X22 ;
5'-GGACTTTACTCCACCCACC-3' (sense),
5'-GGATTGGGGTA-CGTGAGTAAAC-3' (antisense) for
Q309X23 and Int10 +2
TG24 ;
5'-CTTCTGTGCTCCAGGGAGGACTCA-3' (sense),
5'-CAGTTTC-CCCTCCAGCCCACACAT-3'
(mismatch primer, antisense) for Int14 +1
GA4 5 6
and Int14 +3 T ins7 ; and
5'-CAGCAAAGGCGTGA-GCCTGGTC-3'
(mismatch primer, sense), 5'-CCCAGGAATCCT-GTCTGGGCC-3'
(antisense) for
D442G.9 10 The
amplified PCR products were digested with the restriction enzymes
MaeIII for G181X,
DdeI for Q309X,
MaeIII for Int10 +2 TG,
NdeI for Int14 +1 GA,
HpaI for Int14 +3 T ins, and
SalI for D442G at 37°C for 3
hours. After digestion, the reaction mixture was electrophoresed on a
10% polyacrylamide gel. After staining with ethidium bromide,
DNA fragments were visualized on a standard UV transilluminator. The
novel -69 GA mutation was also analyzed by PCR-RFLP. A
substitution of G to A at nucleotide -69 in the promoter
region of the CETP gene caused the disappearance of a restriction site
for HapII. A 371-bp fragment
was amplified with a pair of primers:
5'-AAAATGGTGCAGATG-GTGGAGGG-3' (sense) and
5'-GATGCTACTGATACTTA-CACAACCAG-3' (antisense). By
digestion with HapII, PCR
products yielded a fragment of 371 bp in the wild allele and
fragments of 232 bp and 139 bp in the mutated
allele.
Direct Sequencing of PCR Products
PCR products were purified with the QIAquick Gel
Extraction Kit (Qiagen). Gel-purified products were sequenced by an
ABI Prism 377 DNA sequencer (Applied Biosystems) using a BigDye
Terminator Cycle Sequencing Kit (Perkin-Elmer
Cetus).
Construction of the Promoter-Luciferase
Fusion Plasmid
For evaluating the transcriptional activity in
the promoter region of the CETP gene, we constructed a plasmid
consisting of 164-bp and 570-bp promoter sequences of the CETP gene.
Each promoter region was obtained by PCR using the primers
5'-CAGCACTTGGTCATCTG-GTCAC-3' (sense) and
5'-GTAAGTGGCTCGAGCCGTTCA-GCCTGGA-3' (antisense) for
the 164-bp fragment and 5'-AGTTGGGGTACCCTTGTTGAATGTCTGGCTCTGAACTC-3'
(sense) for the 570-bp fragment. The PCR products were digested
with KpnI and
XhoI and then ligated to
PicaGene basic vector 2 (Wako Pure Chemicals Industries Ltd),
constructing plasmids pCETP -570 (-69 G) luc or pCETP -570 (-69
A) luc and pCETP -164 (-69 G) luc or pCETP -164 (-69 A) luc,
respectively.
Cell Culture and Transient Transfection
Analysis
HepG2 cells were obtained from the American Type
Culture Collection. Cells were cultured in Dulbecco’s MEM (Gibco BRL)
supplemented with 10% FCS (JRH Bioscience), 100 U/mL penicillin, and
100 µg/mL streptomycin in 5% CO2 at 37°C.
One day before the transfection procedure, HepG2 cells
(2x105 cells/well) were plated onto 6-well
plates (Iwaki Glass). After 24 hours of incubation, 1.0 µg of each
plasmid was transfected into the cells by use of the Fugene 6 Transfect
Reagent (Boehringer Mannheim) along with 0.5 µg of the
pSV-ßgal plasmid (Promega) to calibrate the transfection efficiency.
The cells were harvested 24 hours after transfection with 250 µL of
lysis buffer LCB (Wako Pure Chemicals Industries Ltd). Luciferase and
ß-galactosidase activities in the lysate were then determined with a
Picagene Luminescence Kit (Wako Pure Chemicals Industries Ltd) and an
Aurora GAL-XE kit (ICN), respectively, according
to the manufacturer’s instruction. The luciferase activity was
normalized with the ß-galactosidase activity for the transcriptional
activities of the vector. The transfection experiment was carried out
in triplicate and repeated 3 times for each experiment. Luciferase
activity for the control vector was
0.37x106 relative luciferase units
(RLU).
Analytical Methods
Total cholesterol,
triglyceride, and HDL cholesterol in plasma
were measured with an automated analyzer (Hitachi 7450) and
commercial kits (Daiichi Pure Chemical Industries Co Ltd). LDL
cholesterol concentration was calculated according to the
equation of Friedewald et
al.25 Plasma concentrations
of apos A-I, A-II, B, C-II, C-III, and E were measured by the
immunoturbidimetry method (Daiichi Pure Chemical Co
Ltd).
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
In the present study, we analyzed plasma CETP mass and activity in 196 unrelated Japanese subjects with a marked HALP (HDL cholesterol
2.59 mmol/L=100 mg/dL), in
which plasma levels of total cholesterol, HDL
cholesterol, and triglyceride averaged
6.31±1.16 (mean±SD), 3.21±0.65, and 0.88±0.49 mmol/L,
respectively
(Table 1
). Plasma CETP mass and activity in 196
marked HALP subjects were 1.6±1.1 µg/mL and 68±43%, respectively.
Subsequently, the 6 known mutations in the CETP gene, G181X, Q309X,
Int10 +2 TG, Int14 +1 GA, Int14 +3 T ins, and D442G, were
screened by PCR-RFLP analysis. We detected 1 homozygote with
G181X, 31 with Int14 +1 GA, and 6 with D442G. There were also 1
heterozygote with G181X, 27 with Int14 +1 GA, and 32 with D442G. Two
compound heterozygotes with Int14 +1 GA and G181X, and with Int14 +1
GA and Int14 +3 T ins, and 15 with Int14 +1 GA and D442G were
also identified. No subjects with Q309X and Int10 +2 TG were
identified in this study. Among 196 marked HALP subjects, 118 subjects
(60%) had 1 of these known mutations
(Figure 1).
|
|
In 8 of 78 marked HALP subjects without known mutations,
plasma CETP levels were <60% of controls (CETP mass <1.4 µg/mL),
suggesting the presence of other unknown mutation(s) in the CETP gene
(Figure 1
). Subsequently, 17 exons and the promoter region of
the CETP gene were analyzed by direct sequencing. Thus, a novel
mutation has been identified in the promoter region of the CETP gene in
a subject with low plasma CETP mass (0.9 µg/mL) and activity (43% of
control levels). This mutation was a G-to-A nucleotide
substitution at the -69 nucleotide in the promoter region
(-69 GA) (the number indicates the location from the transcription
start point, +1)
(Figure 2). The nucleotide substitution was
revealed at the second nucleotide of the ETS binding site
(CGGAA), which has been
described as the PEA3
motif,26 located upstream of
the putative TATA box. The proband was a 22-year-old woman, and her
plasma total cholesterol and triglyceride
levels were 5.53 and 0.66 mmol/L, respectively. Her HDL
cholesterol concentration was moderately elevated
(2.92 mmol/L).
|
Furthermore, we screened the -69 GA mutation with
PCR-RFLP analysis in 466 unrelated HALP (HDL
cholesterol 2.07 mmol/L=80 mg/dL) subjects,
including 196 marked HALP subjects, and found 6 subjects with this
mutation
(Table 1). Of 6 HALP subjects with this mutation, 1 was a
compound heterozygote with -69 GA and G181X and 2 with -69 GA
and D442G. The allelic frequencies of the -69 GA mutation were
calculated to be 0.0102 and 0.0037 in the marked HALP and HALP
subjects, respectively
(Table 1). The CETP mass level in 5 subjects with the novel
mutation ranged from 0.4 to 1.6 µg/mL, suggesting that their plasma
CETP levels were similar to those with the heterozygous Int14 +1 GA
mutation
(Table 2). Furthermore, a compound heterozygote with -69
GA and G181X had markedly elevated plasma HDL
cholesterol (3.65 mmol/L) and significantly decreased
CETP activity (13%), a lipid profile similar to that observed in
subjects with a homozygous Int14 +1 GA mutation
(Table 2).
|
To know the mechanism by which the mutation causes a
reduction of CETP mass and activities, we performed transfection
experiments for the transcriptional activity at the PEA3/ETS binding
site of the CETP gene. The major site of CETP mRNA expression is
liver.27 It has been shown
that isolated human hepatocytes express CETP mRNA and that
the human hepatocyte–derived cell line HepG2 secretes
CETP.28 29
Therefore, we performed transfection experiments for transcriptional
activity using HepG2 cells. The 164-bp and 570-bp promoter regions of
the CETP gene were cloned into luciferase reporter gene vector and
transfected into HepG2 cells to measure transcriptional activities
(Figure 3). The luciferase activity in the mutant, pCETP
-164 (-69 A) luc or pCETP -570 (-69 A) luc, was markedly
decreased compared with that in the wild-type sequence, pCETP -164
(-69 G) luc or pCETP -570 (-69 G) luc
(11.32x106 versus
1.22x106 RLU, and
4.33x106 versus
0.38x106 RLU, respectively), indicating a
markedly reduced transcriptional activity in the mutation of the
PEA3/ETS binding site.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
In the present study, we have identified a novel G-to-A mutation in subjects with a marked HALP, which was located in the promoter region of the CETP gene. This is the first mutation identified in the promoter region of the CETP gene. The novel mutation is a G-to-A substitution at the -69 nucleotide in the promoter region (-69 G
A), which is located in the consensus ETS
binding site designated as the PEA3
motif.26 The allelic
frequency of the -69 GA mutation was lower than the other common
mutations in the CETP gene; however, this mutation was identified in 6
unrelated subjects with HALP, whose lipid profiles and plasma CETP
levels were similar to those with the known CETP deficiency.
Furthermore, the luciferase promoter assay clearly demonstrated that
the mutated promoter almost lost its activity in HepG2 cells. These
results strongly suggested that the mutation in the PEA3/ETS binding
site of the CETP gene would cause the reduction of CETP mass, leading
to HALP.
To date, 22 ETS transcriptional factors have been identified
in mammalians, which bind to the ETS binding
site.30 All of these ETS
transcriptional factors have DNA binding regions, so-called ETS
domains. These transcriptional factors were classified into 9 groups
based on the similarity of the ETS domain, ie, PEA3, ETS, ERG, ERF,
ELG, ELK, ELF, YAN, and SPI. The ETS domain contains the structure of
branched helix-loop-helix and binds to the ETS binding site: consensus
sequence, 5'-(C/A)GGA(A/T)-3'. Although the PEA3/ETS binding site is
believed to be quite important for promoter activity, spontaneous
mutations at some PEA3/ETS binding site(s) appeared to be very rare. To
our best knowledge, there was only 1 example that the PEA3/ETS binding
site was mutated in the human disorder, reported by Nichols et
al.31 They found a G-to-A
mutation at the second nucleotide of the PEA3/ETS binding
site located at the promoter region of the acetylcholine receptor E
subunit gene in a white patient with congenital myasthenic syndrome. In
the CETP gene, 2 putative PEA3/ETS binding sites have been identified
within 100-bp promoter
regions.26 32 The
mutation found was located just upstream of the putative TATA box. The
importance of the particular PEA3/ETS binding site may be supported by
the site-directed mutagenesis study performed by Gaudet and
Ginsburg.33 They extensively
mutated the same PEA3/ETS binding site and examined transcriptional
activity, showing that the mutated PEA3/ETS binding site
(CGGAACGTAT)
reduced the transcriptional activity to 40% of the wild type and
lacked the specific binding of nuclear extracts in both HepG2 cells and
Caco-2 cells. In the promoter region of the CETP gene, there are also
several binding sites for transcriptional factors, such as the LXR
element, retinoic acid receptor element, orphan nuclear hormone
receptor response element, and Sp1
site.26 32 33 34
It would be interesting to know the functional interaction between the
PEA3/ETS transcriptional factor(s) and other transcriptional factors in
the promoter region of the CETP gene.
Although HALP was thought to be heterogeneous, the present study confirmed the previous reports that CETP deficiency contributed to 60% of HALP in Japan.24 We have shown that a marked HALP caused by CETP gene mutation is the impairment of reverse cholesterol transport. In addition, knockout mice of scavenger receptor class B type I with high levels of plasma HDL cholesterol caused accelerated atherosclerosis in the apoE-negative background.35 These data indicated that HALP is not always beneficial, but rather may be atherogenic. Therefore, elucidation of the molecular basis and pathophysiology in HALP other than CETP deficiency is the important issue for the future.
|
Acknowledgments |
|---|
We thank Tomoichiro Oka and Mitsuaki Ishihara for useful discussion. The skillful technical assistance of Satomi Ishihara is gratefully acknowledged.
Received January 22, 2001; accepted March 8, 2001.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Tall A. Plasma lipid transfer protein. Annu Rev Biochem. 1995;64:235–257.[Medline] [Order article via Infotrieve]
2. Yamashita S, Sakai N, Hirano K, Arai T, Ishigami M, Maruyama T, Matsuzawa Y. Molecular genetics of plasma cholesteryl ester transfer protein. Curr Opin Lipidol. 1997;8:101–110.[Medline] [Order article via Infotrieve]
3. Yamashita S, Hui DY, Wetterau JR, Sprecher DL, Harmony JA, Sakai N, Matsuzawa Y, Tarui S. Characterization of plasma lipoproteins in patients heterozygous for human plasma cholesteryl ester transfer protein (CETP) deficiency: plasma CETP regulates high-density lipoprotein concentration and composition. Metabolism. 1991;40:756–763.[Medline] [Order article via Infotrieve]
4. Brown ML, Inazu A, Hesler CB, Agellon LB, Mann C, Whitlock ME, Marcel YL, Milne RW, Koizumi J, Mabuchi H, Takeda R, Tall AR. Molecular basis of lipid transfer protein deficiency in a family with increased high-density lipoproteins. Nature. 1989;342:448–451.[Medline] [Order article via Infotrieve]
5. Inazu A, Brown ML, Hesler CB, Agellon LB, Koizumi J, Takata K, Maruhama Y, Mabuchi H, Tall AR. Increased high-density lipoprotein levels caused by a common cholesteryl-ester transfer protein gene mutation. N Engl J Med. 1990;323:1234–1238.[Abstract]
6. Yamashita S, Hui DY, Sprecher DL, Matsuzawa Y, Sakai N, Tarui S, Kaplan D, Wetterau JR, Harmony JA. Total deficiency of plasma cholesteryl ester transfer protein in subjects homozygous and heterozygous for the intron 14 splicing defect. Biochem Biophys Res Commun. 1990;170:1346–1351.[Medline] [Order article via Infotrieve]
7. Inazu A, Jiang XC, Haraki T, Yagi K, Kamon N, Koizumi J, Mabuchi H, Takeda R, Takata K, Moriyama Y, Doi M, Tall AR. Genetic cholesteryl ester transfer protein deficiency caused by two prevalent mutations as a major determinant of increased levels of high density lipoprotein cholesterol. J Clin Invest. 1994;94:1872–1882.
8. Hirano K, Yamashita S, Funahashi T, Sakai N, Menju M, Ishigami M, Hiraoka H, Kameda-Takemura K, Tokunaga K, Hoshino T, Kumasaka K, Matsuzawa Y. Frequency of intron 14 splicing defect of cholesteryl ester transfer protein gene in the Japanese general population: relation between the mutation and hyperalphalipoproteinemia. Atherosclerosis. 1993;100:85–90.[Medline] [Order article via Infotrieve]
9. Takahashi K, Jiang XC, Sakai N, Yamashita S, Hirano K, Bujo H, Yamazaki H, Kusunoki J, Miura T, Kussie P, Matsuzawa Y, Saito Y, Tall AR. A missense mutation in the cholesteryl ester transfer protein gene with possible dominant effects on plasma high density lipoproteins. J Clin Invest. 1993;92:2060–2064.
10. Sakai N, Yamashita S, Hirano K, Menju M, Arai T, Kobayashi K, Ishigami M, Yoshida Y, Hoshino T, Nakajima N, Kameda-Takemura K, Matsuzawa Y. Frequency of exon 15 missense mutation (442D:G) in cholesteryl ester transfer protein gene in hyperalphalipoproteinemic Japanese subjects. Atherosclerosis. 1995;114:139–145.[Medline] [Order article via Infotrieve]
11. Yamashita S, Matsuzawa Y, Okazaki M, Kako H, Yasugi T, Akioka H, Hirano K, Tarui S. Small polydisperse low density lipoproteins in familial hyperalphalipoproteinemia with complete deficiency of cholesteryl ester transfer activity. Atherosclerosis. 1988;70:7–12.[Medline] [Order article via Infotrieve]
12.
Sakai N,
Matsuzawa Y, Hirano K, Yamashita S, Nozaki S, Ueyama Y, Kubo M, Tarui
S. Detection of two species of low density lipoprotein particles in
cholesteryl ester transfer protein deficiency.
Arterioscler Thromb. 1991;11:71–79.
13. Sakai N, Yamashita S, Hirano K, Ishigami M, Arai T, Kobayashi K, Funahashi T, Matsuzawa Y. Decreased affinity of low density lipoprotein (LDL) particles for LDL receptors in patients with cholesteryl ester transfer protein deficiency. Eur J Clin Invest. 1995;25:332–339.[Medline] [Order article via Infotrieve]
14.
Ishigami M,
Yamashita S, Sakai N, Arai T, Hirano K, Hiraoka H, Kameda-Takemura K,
Matsuzawa Y. Large and cholesteryl ester-rich high-density lipoproteins
in cholesteryl ester transfer protein (CETP) deficiency can not protect
macrophages from cholesterol accumulation induced
by acetylated low-density lipoproteins.
J Biochem. 1994;116:257–262.
15.
Reichl D, Miller
NE. Pathophysiology of reverse cholesterol transport:
insights from inherited disorders of lipoprotein
metabolism.
Arteriosclerosis. 1989;9:785–797.
16. Bruce C, Chouinard RA, Tall AR. Plasma lipid transfer protein, high-density lipoproteins, and reverse cholesterol transport. Annu Rev Nutr. 1998;18:297–330.[Medline] [Order article via Infotrieve]
17.
Hirano K,
Yamashita S, Nakajima N, Arai T, Maruyama T, Yoshida Y, Ishigami M,
Sakai N, Kameda-Takemura K, Matsuzawa Y. Genetic cholesteryl ester
transfer protein deficiency is extremely frequent in the Omagari area
of Japan. Arterioscler Thromb Vasc
Biol. 1997;17:1053–1059.
18. Zhong S, Sharp DS, Grove JS, Bruce C, Yano K, Curb JD, Tall AR. Increased coronary heart disease in Japanese-American men with mutation in the cholesteryl ester transfer protein gene despite increased HDL levels. J Clin Invest. 1996;97:2917–2923.[Medline] [Order article via Infotrieve]
19. Havel RJ, Eder HA, Bragdom JH. The determination and chemical composition of ultracentrifugally separated lipoproteins in human serum. J Clin Invest. 1955;34:1345–1353.
20.
Kato H, Nakanishi
T, Arai H, Nishida H, Nishida T. Purification,
microheterogeneity, and stability of human lipid
transfer protein. J Biol
Chem. 1989;264:4082–4087.
21. Sawada S, Sugano M, Makino N, Okamoto H, Tsuchida K. Secretion of preß HDL increases with the suppression of cholesteryl ester transfer protein in HepG2 cells. Atherosclerosis. 1999;146:291–298.[Medline] [Order article via Infotrieve]
22. Arai T, Yamashita S, Sakai N, Hirano K, Okada S, Ishigami M, Maruyama T, Yamane M, Kobayashi H, Nozaki S, Funahashi T, Kameda-Takemura K, Nakajima N, Matsuzawa Y. A novel nonsense mutation (G181X) in the human cholesteryl ester transfer protein gene in Japanese hyperalphalipoproteinemic subjects. J Lipid Res. 1996;37:2145–2154.[Abstract]
23. Gotoda T, Kinoshita M, Shimano H, Harada K, Shimada M, Ohsuga J, Teramoto T, Yazaki Y, Yamada N. Cholesteryl ester transfer protein deficiency caused by a nonsense mutation detected in the patient’s macrophage mRNA. Biochem Biophys Res Commun. 1993;194:519–524.[Medline] [Order article via Infotrieve]
24. Sakai N, Santamarina-Fojo S, Yamashita S, Matsuzawa Y, Brewer HB. Exon 10 skipping caused by intron 10 splicing donor site mutation in cholesteryl ester transfer protein gene results in abnormal downstream splice site selection. J Lipid Res. 1996;37:2065–2073.[Abstract]
25. Friedewald TW, Levy RI, Fredrickson DS. Estimation of the concentration of the low density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem. 1972;18:499–502.[Abstract]
26.
Oliveira HCF,
Chouinard RA, Agellon LB, Bruce C, Ma L, Walsh A, Breslow JL, Tall AR.
Human cholesteryl ester transfer protein gene proximal promoter
contains dietary cholesterol positive responsive elements
and mediates expression in small intestine and periphery while
predominant liver and spleen expression is controlled by 5'-distal
sequences. J Biol Chem. 1996;271:31831–31838.
27. Drayna D, Jarnagin AS, McLean J, Henzel W, Kohr W, Fielding CJ, Lawn R. Cloning and sequencing of the human cholesteryl ester transfer protein cDNA. Nature. 1987;327:632–634.[Medline] [Order article via Infotrieve]
28.
Swenson TL,
Simmons JS, Hesler CB, Bisgaier C, Tall AR. Cholesteryl ester transfer
protein is secreted by HepG2 cells and contains asparagine-linked
carbohydrate and sialic acid. J Biol
Chem. 1987;262:16271–16274.
29.
Faust RA, Albers
JJ. Synthesis and secretion of plasma cholesteryl ester transfer
protein by human hepatocarcinoma cell line, HepG2.
Arteriosclerosis. 1987;7:267–275.
30. Graves BJ, Peterson JM. Specificity within the ets family of transcription factors. In: Vande Woude GF, Klein G, eds. Advances in Cancer Research. Vol 75. San Diego, Calif: Academic Press; 1998:1–55.
31. Ohno K, Anlar B, Engel AG. Congenital myasthenic syndrome caused by a mutation in the Ets-binding site of the promoter region of the acetylcholine receptor epsilon subunit gene. Neuromuscul Disord. 1999;9:131–135.[Medline] [Order article via Infotrieve]
32. Tall A, Luo Y. Sterol upregulation of human CETP expression in vitro and in transgenic mice by an LXR element. J Clin Invest. 2000;105:513–520.[Medline] [Order article via Infotrieve]
33.
Gaudet F,
Ginsburg GS. Transcriptional regulation of the cholesteryl ester
transfer protein gene by the orphan nuclear hormone receptor
apolipoprotein AI regulatory protein-1.
J Biol Chem. 1995;270:29916–29922.
34. Jeoung NH, Jang WG, Nam JII, Pak YK, Park YB. Identification of retinoic acid receptor element in human cholesteryl ester transfer protein gene. Biochem Biophys Res Commun. 1999;258:411–415.[Medline] [Order article via Infotrieve]
35.
Trigatti B,
Rayburn H, Vinals M, Braun A, Miettinen H, Penman M, Hertz M, Schrenzel
M, Amigo L, Rigotti A, Krieger M. Influence of the high density
lipoprotein receptor SR-BI on reproductive and
cardiovascular pathophysiology.
Proc Natl Acad Sci
U S A. 1999;96:9322–9327.
This article has been cited by other articles:
 |
|
 |
|
  S. M. Boekholdt and J. F. Thompson Natural genetic variation as a tool in understanding the role of CETP in lipid levels and disease J. Lipid Res., July 1, 2003; 44(6): 1080 - 1093. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Oka, S. Yamashita, T. Kujiraoka, M. Ito, M. Nagano, Y. Sagehashi, T. Egashira, M. N. Nanjee, K.-i. Hirano, N. E. Miller, et al. Distribution of human plasma PLTP mass and activity in hypo- and hyperalphalipoproteinemia J. Lipid Res., August 1, 2002; 43(8): 1236 - 1243. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Nagano, S. Yamashita, K.-i. Hirano, M. Ito, T. Maruyama, M. Ishihara, Y. Sagehashi, T. Oka, T. Kujiraoka, H. Hattori, et al. Two novel missense mutations in the CETP gene in Japanese hyperalphalipoproteinemic subjects: high-throughput assay by Invader (R) assay J. Lipid Res., July 1, 2002; 43(7): 1011 - 1018. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||