HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) All Versions of this Article: M300198-JLR200v1 45/3/448    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Asztalos, B. F. Articles by Mabuchi, H. Search for Related Content PubMed PubMed Citation Articles by Asztalos, B. F. Articles by Mabuchi, H. Social Bookmarking                      What's this?

Journal of Lipid Research, Vol. 45, 448-455, March 2004
Copyright © 2004 by American Society for Biochemistry and Molecular Biology

Apolipoprotein composition of HDL in cholesteryl ester transfer protein deficiency

Bela F. Asztalos^1,*, Katalin V. Horvath^*, Kouji Kajinami^*, Chorthip Nartsupha^*, Caitlin E. Cox^*, Marcelo Batista^*, Ernst J. Schaefer^*, Akihiro Inazu and Hiroshi Mabuchi

^* Lipid Metabolism Laboratory, Jean Mayer United States Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, Boston, MA
Molecular Genetics of Cardiovascular Disorders, Division of Cardiovascular Medicine, Kanazawa University, Kanazawa, Japan

Published, JLR Papers in Press, December 1, 2003. DOI 10.1194/jlr.M300198-JLR200

¹ To whom correspondence should be addressed. e-mail: bela.asztalos{at}tufts.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

 
Our purpose was to compare HDL subpopulations, as determined by nondenaturing two-dimensional gel electrophoresis followed by immunoblotting for apolipoprotein A-I (apoA-I), apoA-II, apoA-IV, apoCs, and apoE in heterozygous, compound heterozygous, and homozygous subjects for cholesteryl ester transfer protein (CETP) deficiency and controls. Heterozygotes, compound heterozygotes, and homozygotes had CETP masses that were 30, 63, and more than 90% lower and HDL-cholesterol values that were 64, 168, and 203% higher than those in controls, respectively. Heterozygotes had 50% lower preß-1 and more than 2-fold higher levels of -1 and pre-1 particles than controls. Three of the five heterozygotes' -1 particles also contained apoA-II, which was not seen in controls. Compound heterozygotes and homozygotes had very large particles not observed in controls and heterozygotes. These particles contained apoA-I, apoA-II, apoCs, and apoE. However, these subjects did not have decreased preß-1 levels.

Our data indicate that CETP deficiency results in the formation of very large HDL particles containing all of the major HDL apolipoproteins except for apoA-IV. We hypothesize that the HDL subpopulation profile of heterozygous CETP-deficient patients, especially those with high levels of -1 containing apoA-I but no apoA-II, represent an improved anti-atherogenic state, although this might not be the case for compound heterozygotes and homozygotes with very large, undifferentiated HDL particles.

Supplementary key words lipoproteins • high density lipoprotein subpopulations • reverse cholesterol transport

	INTRODUCTION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

 
Cholesteryl ester transfer protein (CETP) is a 74 kDa hydrophobic glycoprotein bound mainly to HDL. CETP catalyzes the equilibrium of nonpolar lipids [triglyceride (TG) and cholesteryl ester (CE)] between plasma lipoprotein particles (1, 2). The major role of CETP is a net transfer of CE from HDL to TG-rich lipoprotein (TRL) and of LDL and TG from TRL to LDL and HDL. CETP mRNA is expressed in several tissues, but the majority of circulating CETP originates from the liver (3).

CETP plays a key role in HDL metabolism (4). It regulates total plasma HDL-cholesterol (HDL-C) level and also facilitates the remodeling of HDL particles (5). A high CETP concentration correlates with a low HDL-C level, a strong risk factor for coronary artery disease (6). On the other hand, Asian subjects with CETP deficiency have markedly increased HDL-C (3- to 6-fold) and apoA-I concentrations (7–9). CETP deficiency-induced increase in HDL-C level is mainly found in the large HDL2 subclass. Moreover, the average HDL size of CETP-deficient subjects is significantly increased and enriched in cholesterol (10). These large HDL particles have been reported to be less effective in promoting cholesterol efflux from lipid-loaded macrophages than HDL particles of control subjects (11).

Several mutations of the CETP gene have been identified as causes of CETP deficiency and increased HDL-C levels. These include a G-to-A substitution within intron 14 at the donor splice site (Int14A), a mutation that is present in up to 2% of the total Japanese population and in as many as 27% of people in the Omagari area of Japan, as well as a missense mutation in exon 15 (D422G) present in up to 7% of the Japanese population (12–16). Inazu et al. (9) reported that heterozygous CETP deficiency caused by the Int14A mutation was potentially anti-atherogenic and might be associated with an increased life span. Hirano et al. (16) found no correlation between CETP deficiency and longevity. They published a U-shaped correlation curve between HDL-C and the incidence of ischemic electrocardiogram changes indicating that both low and high HDL-C levels can be atherogenic. Hirano et al. (17) and Kakko et al. (18) speculated that alcohol intake might modify the atherogenicity of some CETP polymorphisms, because it decreases CETP levels. Recently, Barter et al. (19) summarized these finding in a review article.

In the present study, we investigated the size and apolipoprotein composition of HDL, separated by two-dimensional nondenaturing gel electrophoresis (2dE), from the plasma of 9 homozygous, 4 compound heterozygous, and 5 heterozygous subjects with CETP deficiency and compared them with those of 50 age- and gender-matched controls.

	METHODS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

 
Study population
Plasma samples were obtained from subjects with genetic CETP deficiency and compared with those of healthy controls. We studied nine subjects (three males and six females) homozygous for the mutation involving intron 14 (Int14A), resulting in the null phenotype, four compound heterozygotes (two males and two females) with the same Int14A plus one missense mutation of D442G in exon 15, resulting in a defective phenotype with a potentially dominant-negative effect, and five heterozygotes (three males and two females), two with the Int14A and three with the D442G mutation. The control group was composed of 25 healthy male and 25 healthy female subjects of similar age. Table 1 contains data about age, gender, and biochemical parameters of the subjects studied. None of the subjects were on medication known to alter lipid levels. All participants of the study gave written informed consent. The study protocol was approved by Kanazawa University.

Lipid, apolipoprotein, and CETP measurements
Total cholesterol, HDL-C, and TG were measured by automated enzymatic assays using a Hitachi 911 analyzer and kits from Roche Diagnostics (Indianapolis, IN). LDL-C was calculated by the Friedewald formula. Phospholipids and free cholesterol (FC) were measured by automated enzymatic assays using kits from Wako Diagnostics (Richmond, VA). CE was calculated by subtracting FC from total cholesterol. ApoA-I and apoA-II were assayed immunoturbidimetrically using Wako kits. Lipoprotein A-I (LpA-I) was measured by rocket electrophoresis, using cross-electrophoresis kits from Sebia (Norcross, GA). LpA-I:A-II was calculated by subtracting LpA-I from plasma total apoA-I. CETP mass was measured by ELISA kits from Wako. ApoA-IV, apoC-I, apoC-II, apoC-III, and apoE were determined by dot-blot analyses, and their concentrations were expressed as percentile of controls. Between-run coefficients of variation for all assays were less than 10%.

HDL subpopulation analysis
Two-dimensional nondenaturing agarose-polyacrylamide gel electrophoresis and image analysis to determine the apoA-I-containing HDL subpopulations were carried out on plasma previously stored at -80°C as described (20, 21). Briefly, in the first dimension, HDL particles were separated on an agarose gel according to charge. This separation identified three fractions, referred to as preß, , and pre particles, on the basis of mobility relative to albumin. Low-endosmosity 0.7% agarose was cast into 3 mm thick vertical glass cassettes and electrophoresed in a Pharmacia GE 2/4 recirculating apparatus. Four microliters of plasma per sample channel was electrophoresed at constant voltage (250 V) and temperature (10°C) in Tris-tricine buffer until the endogenous albumin, stained with bromophenol blue, moved 3.5 cm from the origin. Individual strips were cut out and transferred to the top of nondenaturing concave-gradient (3–35%) polyacrylamide gels, and particles were further separated according to size. Electrophoresis was performed to completion in Tris-borate buffer at constant voltage (250 V) and temperature (10°C) for 24 h. Gels were electrotransferred to nitrocellulose membranes at constant voltage (30 V) and temperature (10°C) for 24 h in Tris-glycine buffer.

Before immunoblotting, membranes were fixed with 0.03% glutaraldehyde and the free protein binding capacity was blocked by incubating membranes in PBS containing 0.05% Tween (PBST) and 5% nonfat dry milk. ApoA-I was immunolocalized by incubation with PBST containing 5% milk and monospecific goat anti-human apoA-I antibody for 7 h followed by incubation with ¹²⁵I-labeled secondary antibody [Fa(b)² fragment of rabbit anti-goat IgG] overnight. ApoA-II was immunolocalized with fluorochrome (Cy-5)-labeled first antibody [F(ab')₂ fragment of goat anti-human apoA-II] added to the incubation medium together with the secondary antibody for apoA-I. Separate membranes were immunoprobed for apoA-IV, apoC-I, apoC-II, apoC-III, and apoE as described above with primary antibodies specific for these apolipoproteins and ¹²⁵I-labeled secondary antibody. Signals were quantitatively determined by image analysis using a FluoroImager in X-ray mode for the ¹²⁵I label and in red-fluorescent mode for the Cy5 label.

The subpopulations were determined both as percentage distribution and concentration relative to apoA-I. Preß-1 and preß-2 particles did not overlap with any other HDL particles, so they were easily delineated. Designation of the -mobility HDL subpopulations was based on the integration of -migrating HDL. We delineated each peak area shown on the integration curve for the -mobility particles. Pre-mobility particles had similar sizes as their -mobility counterparts and were clearly separated from each other. Finally, all apoA-I-containing HDL subpopulations were encircled (we pooled the two preß-1 particles into one subpopulation and also the three preß-2 particles into one subpopulation), and signals were measured in each area and used to calculate the percentage distribution of the apoA-I-containing HDL subpopulations. Data were expressed as pixels linearly correlated with the disintegrations per minute of the ¹²⁵I bound to the antigen-antibody complex (22). The apoA-I concentrations of the subpopulations were calculated by multiplying percentiles of subfractions by plasma total apoA-I concentrations. We had a coefficient of variation of less than 10% for all of the -mobility subpopulations and less than 15% for the rest of the particles.

Statistical analysis
ANOVA was used to test the hypothesis of no difference between data obtained from control and affected subjects. P < 0.05 was considered significant. For analysis, nonnormally distributed data were logarithmically transformed.

	RESULTS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

 
Table 1 shows the plasma biochemical parameters of the four groups: homozygotes (HOs), compound heterozygotes (CHs), heterozygotes (HEs), and controls. Subjects with either mutation had significantly lower levels of CETP mass: HOs, <0.1 µg/ml; CHs, 0.46 µg/ml; and HEs, 0.87 µg/ml, compared with controls (1.24 µg/ml). The nine HOs had increased total cholesterol levels (44%) but normal free-to-esterified cholesterol ratios. They had slightly decreased LDL-C (-14%) and TG (-13%) levels, whereas their mean HDL-C level was 3-fold higher than the mean control value. HOs had 75% higher apoA-I and 13% higher apoA-II concentrations than controls. The differences between CHs and controls were very similar to the differences described for HOs and controls. Compared with controls, HEs had 35% and 27% lower LDL-C and TG, respectively, and 64% higher HDL-C, with no notable differences for apoA-I and apoA-II. In all affected groups, the LpA-I fraction was increased to approximately the same extent as that of LpA-I:A-II.

The apoA-I-containing HDL subpopulations are expressed both as percentage distribution and as absolute concentrations (mg/dl) in Tables 2 and 3. We detected two extra, large -mobility particles in HO and CH subjects with mean sizes of 12.9 nm (-L) and 16.6 nm (-VL) (Fig. 1) . Adjacent to the -L and -VL particles, there were pre-mobility particles with similar sizes. These very large and pre particles were not present in any of the control or HE subjects. In HOs, the percentiles of the -L, pre-L, -VL and pre-VL were 24.7, 4.6, 18.9, and 1.4%, respectively. The normal-sized -1 was 17% lower, whereas the normal-sized pre-1 was 23% higher, than these percentiles in controls. The percentiles of -2, -3, and the adjacent pre-2 and pre-3 were 72, 75, 69, and 73% lower, respectively, in HOs than in controls. Moreover, a new, small particle, similar in size to preß-1 HDL but with faster mobility, was detected in HO subjects. We designated this particle as fast preß-1 (preß-1F). Among the CHs, only one subject had -VL particles, but all of them had -L particles and their major HDL particle was the regular-sized -1. HEs had no HDL fraction that was not present in controls. They had more than 2-fold higher percentiles of -1 and pre-1 than did controls. The percentiles of -2, -3, and the adjacent pre-2 and pre-3 particles, and the smallest particle, preß-1, were markedly lower by 15, 43, 29, 35, and 43%, respectively, in HEs compared with controls.

View larger version (34K): [in this window] [in a new window]   Fig. 1. The apolipoprotein A-I (apoA-I)-containing HDL subpopulations of a male control subject (A), a male heterozygous (B), a male compound heterozygous (C), and a male homozygous (D) cholesteryl ester transfer protein (CETP)-deficient subject. Bands representing Pharmacia high molecular weight standards can be seen at left. Asterisks represent the positions of endogenous albumin marking the -mobility front. Notice the eight regular apoA-I-containing HDL subpopulations (preß-1, preß-2, -1, -2, -3, pre-1, pre-2, and pre-3) in panel A and the extra subpopulations [fast preß-1 (preß-1F), very large (VL) and pre, and large (L) and pre] in homozygotes in panel D. Note that the figure allows for the quantitative comparison of the apoA-I-containing HDL subpopulations within each subject and for qualitative comparison among the representative subjects.

We also compared plasma total apoA-II, apoA-IV, apoC-I, apoC-II, apoC-III, and apoE concentrations and their distribution and mass within the HDL subpopulations, as determined by immunoblotting for these apolipoproteins, among the four groups. Compared with controls, apoA-II was slightly increased in CH (18%) and HO (13%) subjects and was similar in HEs. ApoA-II was present in the -2 and -3 subpopulations of controls, whereas, in affected subjects, apoA-II was present in all -mobility HDL subpopulations (Table 4, Fig. 2) . In HOs, apoA-II was also present in the preß-1F particle. In affected subjects, the apoA-I/A-II ratio increased in all LpA-I:A-II subpopulations compared with controls as a result of a disproportionate increase of total apoA-I to total apoA-II and of a disproportionate displacement of these proteins into the larger sized particles (Table 5).

View larger version (59K): [in this window] [in a new window]   Fig. 2. ApoA-II-containing HDL subpopulations of a control subject (A) and a homozygous CETP-deficient subject (B). The homozygous subject has apoA-II in the preß-1F and in the three largest -mobility particles.

Plasma apoC-I concentration was higher by 13% in HE, 23% in CH, and 34% in HO subjects compared with controls. In control subjects, apoC-I was present in the three -mobility HDL particles, with large individual variability in the percentage distributions. In HE and CH subjects, apoC-I was present predominantly in the -1 subpopulation, whereas in HOs, 95% of apoC-I was in the three large -mobility particles (-1, -L, and -VL).

ApoC-II concentration in plasma was lower by 23% and 10% in HE and CH subjects, respectively, whereas it was 18% higher in HO subjects than in controls. The distribution of apoC-II in controls and affected subjects was very similar to that of apoC-I in these subjects.

Plasma apoC-III concentration was 13% lower in HEs and was similar in CHs compared with controls. Despite a 50% higher apoC-III level in three of the HO subjects, the mean concentration of apoC-III in the nine HOs was only 11% higher than that in controls. In control subjects, apoC-III was present in the -2 and -3 particles and in a small preß-mobility particle. ApoC-III distribution in HE and control subjects was similar; however, in HOs and CHs, the majority of apoC-III was in the three largest -mobility particles, unlike in controls. In the HO and CH groups, some apoC-III was also detected in a small -mobility particle (similar in size to the preß-mobility apoC-III in controls).

ApoE concentration was increased by 16, 38, and 43% in HE, CH, and HO subjects, respectively, compared with the control group. ApoE did not comigrate with apoA-I in control subjects, although it comigrated with apoA-I in the three largest -mobility particles (-1, -L, and -VL) of all affected subjects but most markedly in HOs (Fig. 3) .

View larger version (75K): [in this window] [in a new window]   Fig. 3. ApoE-containing HDL particles of a control subject (A) and a homozygous CETP-deficient subject (B). The ovals indicate the positions of the apoA-I-containing HDL particles of the same subjects after concomitant immunoprobing of the membranes for apoA-I. The asterisks mark the positions of the endogenous albumin.

	DISCUSSION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

It has also been reported that statin treatment not only modestly increases HDL-C but also causes a significant increase in large HDL particles (24, 25), attributable, at least in part, to decreased CETP activity (26). Pharmaceutical companies have had great interest in developing small molecules to increase HDL-C and decrease coronary heart disease (CHD) risk. For this reason, a number of companies have developed CETP inhibitors. One of these agents has been reported to decrease diet-induced atherosclerosis in animals and to significantly increase HDL-C in these animals as well as in humans (27, 28).

The 2dE method followed by immunoblotting and image analysis allows for the precise delineation of specific HDL subspecies and provides metabolic information as it separates intermediates (lipid-poor, discoidal, and spheroidal fractions) representing the main stages of HDL synthesis. Using this methodology, we have reported the presence of 12 apoA-I-containing HDL subspecies in human plasma (20). The largest -mobility HDL particle, -1, resembles HDL-2 separated by ultracentrifugation (29). In control subjects, only -2 and -3 HDL particles contain apoA-II, the rest are apoA-I-only particles (21). In patients with defective cellular cholesterol efflux with mutations in the ATP-binding cassette transporter A1 gene (Tangier disease), HOs not only have a marked decrease in HDL but they only have preß-1 HDL, whereas HEs have markedly reduced -1 and -2 HDL particles (30). Homozygous Tangier patients have an 3-fold increased risk for CHD, whereas for HEs, this risk is increased 1.5-fold.

We have documented that patients with CHD have marked decreases in -1 and pre-1 HDL and that statins can increase both -1 and pre-1 HDL levels significantly (24, 25, 29). More recently, we have reported that simvastatin-niacin treatment in the HDL Atherosclerosis Treatment Study markedly increased both -1 and pre-1 HDL and that subjects with the greatest increases in -1 had no progression of coronary artery stenosis, in contrast to other subjects (31). Based on these data, we believe that the large LpA-I -1 is an anti-atherogenic HDL particle.

In the present study, we document the presence of novel apoA-I-containing particles in patients with CETP deficiency. We confirm previous observations that subjects with heterozygous CETP deficiency have increased HDL-C level and size. In these subjects, a 30% decrease in CETP mass resulted in a marked alteration in the HDL particle distribution. Most notably, there was an increase in the large -1 and pre-1 particles and a decrease in the small preß-1 particle. The unique finding was that three of the five HEs had apoA-II in -1 HDL, which was an LpA-I particle in controls.

As expected, the magnitude of the HDL alterations observed in HEs was significantly amplified in CHs and HOs, with 63% lower and no detectable CETP masses, respectively. These subjects not only had marked increases in -1 HDL but also the appearance of larger than normal - and pre-mobility HDL particles not observed in controls and HEs. The -mobility particles contained apoA-II besides apoA-I but, possibly even more significantly, contained other apolipoproteins, specifically apoE, apoC-III, apoC-II, and apoC-I in order of decreasing abundance. It has to be noted that comigration of different apolipoproteins generally does not mean that these proteins are in the same particle. However, comigration of different apolipoproteins in a two-dimensional system significantly increases the probability of their being in the same particle.

Our data are in agreement with earlier observations that subjects homozygous for CETP deficiency have HDL particles containing apoA-I, apoA-II, and apoE and also with reports that apoE resides mainly in the large HDL particles (8, 32, 33). It has been reported that HDL particles enriched in apoA-II and apoE have a decreased capacity for efflux of cholesterol from macrophages (11) and that the plasma residence time of apoE is 10 times longer if apoE is present in LpE:A-II:A-I particles (34).

It is difficult to speculate about the interaction of these undifferentiated large particles with the HDL-modifying enzymes and CETP, in light of the fact that all three C apolipoproteins are present in these particles. ApoC-I and apoC-III inhibit lipoprotein lipase (LPL) activity, whereas apoC-II activates LPL activity. Both apoC-II and apoC-III reduce hepatic lipase (HL) activity, whereas apoC-I has no effect on it. On the other hand, apoC-I activates LCAT, whereas the other two apoCs inhibit LCAT. ApoC-I reduces and apoC-III increases CE transfer by CETP. Recently, Jong, Hofker, and Havakes (35) summarized the influence of apoCs on these factors. It would be interesting to know how these large lipid-rich particles (-1, -L, and -VL) influence the distribution of apoC-III between the HDL and TRL fractions, because non-HDL apoC-III is a CHD risk factor. The precise role of these particles in promoting cholesterol efflux remains to be determined.

In contrast to HEs, CHs and HOs had significantly increased concentrations of preß-1 particles. We assume that the observed increase in preß-1 level was not attributable to lower LCAT activity because the plasma FC/CE ratios of CETP-deficient subjects were not different from those of controls. The increased preß-1 level was not the result of higher HL activity either, because HL produces small -mobility particles besides preß-1, but those particles were significantly lower in CETP-deficient subjects. We postulate that the higher than normal preß-1 levels in HO subjects were the result of increased phospholipid transfer protein (PLTP) activity, based on reports that PLTP produces preß-1 and large HDL-2-like particles (36).

Our data strongly indicate that CETP plays a significant role in modulating HDL metabolism affecting HDL-C level and the distribution, size, and apolipoprotein composition of HDL particles. Our studies suggest that CETP deficiency not only causes the appearance of very large HDL particles but also causes the apoA-I in these particles to associate initially with apoA-II and then with all of the other HDL apolipoproteins except apoA-IV. Consequently, CETP is essential for the formation of heterogeneous HDL not only in size but also in apolipoprotein composition.

In agreement with others, we postulate that HDL particles with altered apolipoprotein composition in HOs and CHs may not be as efficient as regular HDL particles in promoting reverse cholesterol transport. We believe that the LpA-I:A-II HDL particles have lesser capability to promote scavenger receptor class B type I-mediated cholesterol uptake in the liver than LpA-I HDL. This issue was recently reviewed by Fidge (37) and debated by deBeer et al. (38).

On the other hand, we assume that the significantly increased apoA-I but not apoA-II in -1 HDL particles in HEs, along with the significantly decreased -3 and preß-1 levels, mark an effective reverse cholesterol transport. In addition, HE subjects have very low LDL-C levels, probably attributable to decreased lipid exchange between LDL and HDL, resulting in small CE-poor but TG-rich LDL particles. In complete CETP deficiency in humans, the cholesteryl esters of VLDL and its catabolic product, LDL, originate predominantly from intracellular ACAT (39).

Considering this information, we assume that the HDL subpopulation profile of heterozygous CETP-deficient patients, especially those with high LpA-I -1 levels, represents an improved anti-atherogenic state, although this might not be the case for CHs and HOs with very large, undifferentiated HDL particles.

	ACKNOWLEDGMENTS

 
This research was supported by a Grant from the National Institutes of Health/National Heart, Lung, and Blood Institute (HL-64738).

Manuscript received May 13, 2003 and in revised form November 10, 2003.

	REFERENCES

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

1. Tall, A. 1995. Plasma lipid transfer proteins. Annu. Rev. Biochem. 64: 235–257.[CrossRef][Medline]

2. Lagrost, L. 1994. Regulation of cholesteryl ester transfer protein (CETP) activity: review of in vitro and in vivo studies. Biochim. Biophys. Acta. 1215: 209–236.[Medline]

3. Quinet, E., A. Tall, R. Ramakrishnan, and L. Rudel. 1991. Plasma lipid transfer protein as a determinant of the atherogenicity of monkey plasma lipoproteins. J. Clin. Invest. 87: 1559–1566.

4. Fielding, C. J., and P. E. Fielding. 1995. Molecular physiology of reverse cholesterol transport. J. Lipid Res. 36: 211–228.[Abstract]

5. Ohta, T., R. Nakamura, K. Takata, Y. Saito, S. Yamashita, S. Horiuchi, and I. Matsuda. 1995. Structural and functional differences of subspecies of apoA-I-containing lipoprotein in patients with plasma cholesteryl ester transfer protein deficiency. J. Lipid Res. 36: 696–704.[Abstract]

6. NIH Consensus Development Panel on Triglyceride, High-Density Lipoprotein, and Coronary Heart Disease. 1993. Triglyceride, high-density lipoprotein, and coronary heart disease. J. Am. Med. Assoc. 269: 505–510.[CrossRef][Medline]

7. Kurasawa, T., S. Yokoyama, Y. Miyake, T. Yamaura, and A. Yamamoto. 1985. Deficiency of serum cholesteryl ester transfer between high and low density lipoproteins in human serum and a case with decreased transfer rate in association with hyperalphalipoproteinemia. J. Biochem. 98: 1499–1508.[Abstract/Free Full Text]

8. Koizumi, J., H. Mabuchi, A. Yoshimura, I. Michishita, M. Takeda, H. Itoh, Y. Sakai, T. Sakai, K. Ueda, and R. Takeda. 1985. Deficiency of serum cholesteryl-ester transfer activity in patients with familial hyperalphalipoproteinemia. Atherosclerosis. 58: 175–186.[CrossRef][Medline]

9. Inazu, A., M. L. Brown, C. B. Hesler, L. B. Agellon, J. Koizumi, K. Takata, Y. Maruhama, H. Mabuchi, and A. R. Tall. 1990. Increased high-density lipoprotein levels caused by a common cholesteryl-ester transfer protein gene mutation. N. Engl. J. Med. 323: 1234–1238.[Abstract]

10. Arai, T., T. Tsukada, T. Murase, and K. Matsumoto. 2000. Particle size analysis of high density lipoproteins in patients with genetic cholesteryl ester transfer protein deficiency. Clin. Chim. Acta. 301: 103–117.[CrossRef][Medline]

11. Ishigami, M., S. Yamashita, N. Sakai, T. Arai, K. Hirano, H. Hiraoka, K. Kameda-Takemura, and Y. Matsuzama. 1994. 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. 116: 257–262.[Abstract/Free Full Text]

12. Inazu, A., X. C. Jiang, T. Haraki, K. Yagi, N. Kamon, J. Koizumi, H. Mabuchi, R. Takeda, K. Takata, Y. Moriyama, M. Doi, and A. Tall. 1994. 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. 94: 1872–1882.

13. Inazu, A., J. Koizumi, T. Haraki, K. Yagi, T. Wakasugi, T. Takegoshi, H. Mabuchi, and R. Takeda. 1993. Rapid detection and prevalence of cholesteryl ester transfer protein deficiency caused by an intron 14 splicing defect in hyperalpha-lipoproteinemia. Hum. Genet. 91: 13–16.[Medline]

14. Hirano, K., S. Yamashita, T. Funahashi, N. Sakai, M. Menju, M. Ishigami, H. Hiraoka, K. Kameda-Takemura, K. Tokugana, and T. Hoshino. 1993. Frequency of intron 14 splicing defect of cholesteryl ester transfer protein gene in the Japanese general population: relation between the mutation and hyperalphalipoproteinemia. Atherosclerosis. 100: 85–90.[CrossRef][Medline]

15. Sakai, N., S. Yamashita, K. Hirano, M. Menju, T. Arai, K. Kobayashi, M. Ishigami, Y. Yoshida, T. Hoshino, and N. Nakajima. 1995. Frequency of exon 15 missense mutation (442D:G) in cholesteryl ester transfer protein gene in hyperalphalipoproteinemic Japanese subjects. Atherosclerosis. 114: 139–145.[CrossRef][Medline]

16. Hirano, K., S. Yamashita, N. Nakajima, T. Arai, T. Maruyama, Y. Yoshida, M. Ishigami, N. Sakai, K. Kameda-Takemura, and Y. Matsuzawa. 1997. Genetic cholesteryl ester transfer protein deficiency is extremely frequent in the Omagari area of Japan. Arterioscler. Thromb. Vasc. Biol. 17: 1053–1059.[Abstract/Free Full Text]

17. Hirano, K., Y. Matsuzawa, N. Sakai, H. Hiraoka, S. Nozaki, T. Funahashi, S. Yamashita, M. Kubo, and S. Tarui. 1992. Polydisperse low-density lipoproteins in hyperalphalipoproteinemic chronic alcohol drinkers in association with marked reduction of cholesteryl ester transfer protein activity. Metabolism. 41: 1313–1318.[CrossRef][Medline]

18. Kakko, S., M. Tamminen, M. Paivansalo, H. Kauma, A. O. Rantala, M. Lilja, A. Reunanen, Y. A. Kesaniemi, and M. J. Savolainen. 2000. Cholesteryl ester transfer protein gene polymorphisms are associated with carotid atherosclerosis in men. Eur. J. Clin. Invest. 30: 18–25.[CrossRef][Medline]

19. Barter, P. J., B. H. Brewer, J. M. Chapman, C. H. Hennekens, D. J. Rader, and A. R. Tall. 2002. Cholesteryl ester transfer protein. A novel target for raising HDL and inhibiting atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 23: 160–167.

20. Asztalos, B. F., C. H. Sloop, L. Wong, and P. S. Roheim. 1993. Two-dimensional electrophoresis of plasma lipoproteins: recognition of new apoA-I-containing subpopulations. Biochim. Biophys. Acta. 1169: 291–300.[Medline]

21. Asztalos, B. F., M. Lefevre, T. A. Foster, R. Tulley, M. Windhauser, L. Wong, and P. S. Roheim. 1997. Normolipidemic subjects with low HDL cholesterol levels have altered HDL subpopulations. Arterioscler. Thromb. Vasc. Biol. 17: 1885–1893.[Abstract/Free Full Text]

22. Johnson, R. F., S. C. Pickett, and B. L. Barker. 1990. Autoradiography using storage phosphor technology. Electrophoresis. 11: 355–360.[CrossRef][Medline]

23. Yamashita, S., D. L. Sprecher, N. Sakai, Y. Matsuzawa, S. Tarui, and D. Y. Huy. 1990. Accumulation of apolipoprotein E-rich high density lipoproteins in hyperalphalipoproteinemic human subjects with deficiency of cholesteryl ester transfer protein. J. Clin. Invest. 86: 688–695.

24. Asztalos, B. F., K. V. Horvath, J. R. McNamara, P. S. Roheim, J. J. Rubinstein, and E. J. Schaefer. 2002. Effects of atorvastatin on the HDL subpopulation profile of coronary heart disease patients. J. Lipid Res. 43: 1701–1707.[Abstract/Free Full Text]

25. Asztalos, B. F., K. V. Horvath, J. R. McNamara, P. S. Roheim, J. J. Rubinstein, and E. J. Schaefer. 2002. Comparing the effects of five different statins on the HDL subpopulation profiles of coronary heart disease patients. Atherosclerosis. 164: 361–369.[CrossRef][Medline]

26. Guerin, M., T. S. Lassel, W. Le Goff, M. Farnier, and M. J. Chapman. 2000. Action of atorvastatin in combined hyperlipidemia: preferential reduction of cholesteryl ester transfer from HDL to VLDL1 particles. Arterioscler. Thromb. Vasc. Biol. 20: 189–197.[Abstract/Free Full Text]

27. Okamoto, H., F. Yonemori, K. Wakitani, T. Minowa, K. Maeda, and H. Shinkai. 2000. A cholesteryl ester transfer protein inhibitor attenuates atherosclerosis in rabbits. Nature. 406: 203–207.[CrossRef][Medline]

28. de Grooth, G. J., J. A. Kuivenhoven, A. F. H. Stalenhoef, J. De Graaf, A. H. Zwinderman, J. L. Posma, A. van Tol, and J. J. P. Kastelein. 2002. Efficacy and safety of novel cholesteryl ester transfer protein inhibitor, JTT-705, in humans. A randomized phase II dose-response study. Circulation. 105: 2159–2165.[Abstract/Free Full Text]

29. Asztalos, B. F., P. S. Roheim, R. L. Milani, M. Lefevre, J. R. McNamara, K. V. Horvath, and E. J. Schaefer. 2000. Distribution of apoA-I-containing HDL subpopulations in patients with coronary heart disease. Arterioscler. Thromb. Vasc. Biol. 20: 2670–2676.[Abstract/Free Full Text]

30. Asztalos, B. F., M. E. Brousseau, J. R. McNamara, K. V. Horvath, P. S. Roheim, and E. J. Schaefer. 2001. Subpopulations of high density lipoproteins in homozygous and heterozygous Tangier disease. Atherosclerosis. 156: 217–225.[CrossRef][Medline]

31. Asztalos, B. F., M. Batista, K. V. Horvath, C. E. Cox, G. E. Dallal, J. S. Morse, G. B. Brown, and E. J. Schaefer. 2003. Change in -1 HDL concentration predicts progression in coronary artery stenosis. Arterioscler. Thromb. Vasc. Biol. 23: 847–852.[Abstract/Free Full Text]

32. Duverger, N., D. Rader, K. Ikewaki, M. Nishiwaki, T. Sakamoto, T. Ishikawa, M. Nagano, H. Nakamura, and H. B. Brewer. 1995. Characterization of high-density apolipoprotein particles A-I and A-I:A-II isolated from humans with cholesteryl ester transfer protein deficiency. Eur. J. Biochem. 227: 123–129.[Medline]

33. Chiba, H., H. Akita, K. Tsuchihashi, S. P. Hui, Y. Takahasi, H. Fuda, H. Suzuki, H. Shibuya, M. Tsuji, and K. Kobayashi. 1997. Quantitative and compositional changes in high density lipoprotein subclasses in patients with various genotypes of cholesteryl ester transfer protein deficiency. J. Lipid Res. 38: 1204–1216.[Abstract]

34. Hannuksela, M. L., M. E. Brousseau, S. M. Meyn, H. Nahiz, G. Bader, R. D. Shamburek, P. Alaupovic, and H. B. Brewer. 2002. In vivo metabolism of apolipoprotein E with the HDL subpopulations LpE, LpE:A-I, LpE:A-II, and LpE:A-I:A-II. Atherosclerosis. 165: 205–220.[CrossRef][Medline]

35. Jong, M. C., M. H. Hofker, and L. M. Havakes. 1999. Role of apoCs in lipoprotein metabolism. Functional differences between apoC1, apoC2, and apoC3. Arterioscler. Thromb. Vasc. Biol. 19: 472–484.[Free Full Text]

36. Settasatian, N., N. Duong, L. Curtiss, C. Ehnholm, M. Jauhiainen, J. Huuskonen, and K. A. Rye. 2001. The mechanism of the remodeling of high density lipoproteins by phospholipid transfer protein. J. Biol. Chem. 276: 26898–26905.[Abstract/Free Full Text]

37. Fidge, N. H. 1999. High density lipoprotein receptors, binding proteins, and ligand. J. Lipid Res. 40: 187–201.[Abstract/Free Full Text]

38. deBeer, M. C., D. M. Durbin, L. Cai, N. Mirocha, A. Jonas, N. R. Webb, F. C. deBeer, and D. R. van der Westhuyzen. 2001. Apolipoprotein A-II modulates the binding and selective lipid uptake of reconstituted high density lipoprotein by scavenger receptor B1. J. Biol. Chem. 276: 15832–15839.[Abstract/Free Full Text]

39. Bisgaier, C. L., M. V. Siebenkas, M. L. Brown, A. Inazu, J. Koizumi, H. Mabuchi, and A. R. Tall. 1991. Familial cholesteryl ester transfer protein deficiency is associated with triglyceride-rich low density lipoproteins containing cholesteryl esters of probable intracellular origin. J. Lipid Res. 32: 21–33.[Abstract]

CiteULike

Complore

Connotea

Del.icio.us

Digg

Reddit

Technorati

This article has been cited by other articles:

				R. D. Santos, E. J. Schaefer, B. F. Asztalos, E. Polisecki, J. Wang, R. A. Hegele, L. R. C. Martinez, M. H. Miname, C. E. Rochitte, P. L. Da Luz, et al. Characterization of high density lipoprotein particles in familial apolipoprotein A-I deficiency J. Lipid Res., February 1, 2008; 49(2): 349 - 357. [Abstract] [Full Text] [PDF]

				R. P F Dullaart, A. K Groen, G. M Dallinga-Thie, R. de Vries, W. J Sluiter, and A. van Tol Fibroblast cholesterol efflux to plasma from metabolic syndrome subjects is not defective despite low high-density lipoprotein cholesterol Eur. J. Endocrinol., January 1, 2008; 158(1): 53 - 60. [Abstract] [Full Text] [PDF]

				N. Settasatian, P. J. Barter, and K.-A. Rye Remodeling of apolipoprotein E-containing spherical reconstituted high density lipoproteins by phospholipid transfer protein J. Lipid Res., January 1, 2008; 49(1): 115 - 126. [Abstract] [Full Text] [PDF]

				M. Guerin, W. Le Goff, E. Duchene, Z. Julia, T. Nguyen, T. Thuren, C. L. Shear, and M. J. Chapman Inhibition of CETP by Torcetrapib Attenuates the Atherogenicity of Postprandial TG-Rich Lipoproteins in Type IIB Hyperlipidemia Arterioscler. Thromb. Vasc. Biol., January 1, 2008; 28(1): 148 - 154. [Abstract] [Full Text] [PDF]

				M. Moerland, H. Samyn, T. van Gent, M. Jauhiainen, J. Metso, R. van Haperen, F. Grosveld, A. van Tol, and R. de Crom Atherogenic, enlarged, and dysfunctional HDL in human PLTP/apoA-I double transgenic mice J. Lipid Res., December 1, 2007; 48(12): 2622 - 2631. [Abstract] [Full Text] [PDF]

				B. F. Asztalos, E. J. Schaefer, K. V. Horvath, S. Yamashita, M. Miller, G. Franceschini, and L. Calabresi Role of LCAT in HDL remodeling: investigation of LCAT deficiency states J. Lipid Res., March 1, 2007; 48(3): 592 - 599. [Abstract] [Full Text] [PDF]

				W. A. van der Steeg, G. K. Hovingh, A. H. E. M. Klerkx, B. A. Hutten, I. C. Nootenboom, J. H. M. Levels, A. van Tol, G. M. Dallinga-Thie, A. H. Zwinderman, J. J. P. Kastelein, et al. Cholesteryl ester transfer protein and hyperalphalipoproteinemia in Caucasians J. Lipid Res., March 1, 2007; 48(3): 674 - 682. [Abstract] [Full Text] [PDF]

				A. Kontush and M. J. Chapman Functionally Defective High-Density Lipoprotein: A New Therapeutic Target at the Crossroads of Dyslipidemia, Inflammation, and Atherosclerosis Pharmacol. Rev., September 1, 2006; 58(3): 342 - 374. [Abstract] [Full Text] [PDF]

				K.-A. Rye, R. Bright, M. Psaltis, and P. J. Barter Regulation of reconstituted high density lipoprotein structure and remodeling by apolipoprotein E J. Lipid Res., May 1, 2006; 47(5): 1025 - 1036. [Abstract] [Full Text] [PDF]

				A. H.E.M. Klerkx, K. E. Harchaoui, W. A. van der Steeg, S. M. Boekholdt, E. S.G. Stroes, J. J.P. Kastelein, and J. A. Kuivenhoven Cholesteryl Ester Transfer Protein (CETP) Inhibition Beyond Raising High-Density Lipoprotein Cholesterol Levels: Pathways by Which Modulation of CETP Activity May Alter Atherogenesis Arterioscler. Thromb. Vasc. Biol., April 1, 2006; 26(4): 706 - 715. [Abstract] [Full Text] [PDF]

				B. F. Asztalos, D. Collins, L. A. Cupples, S. Demissie, K. V. Horvath, H. E. Bloomfield, S. J. Robins, and E. J. Schaefer Value of High-Density Lipoprotein (HDL) Subpopulations in Predicting Recurrent Cardiovascular Events in the Veterans Affairs HDL Intervention Trial Arterioscler. Thromb. Vasc. Biol., October 1, 2005; 25(10): 2185 - 2191. [Abstract] [Full Text] [PDF]

				M. E. Brousseau, M. R. Diffenderfer, J. S. Millar, C. Nartsupha, B. F. Asztalos, F. K. Welty, M. L. Wolfe, M. Rudling, I. Bjorkhem, B. Angelin, et al. Effects of Cholesteryl Ester Transfer Protein Inhibition on High-Density Lipoprotein Subspecies, Apolipoprotein A-I Metabolism, and Fecal Sterol Excretion Arterioscler. Thromb. Vasc. Biol., May 1, 2005; 25(5): 1057 - 1064. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) All Versions of this Article: M300198-JLR200v1 45/3/448    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles