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Arteriosclerosis, Thrombosis, and Vascular Biology. 1996;16:441-449

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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1996;16:441-449.)
© 1996 American Heart Association, Inc.

Articles

Increased Cholesteryl Ester Transfer Activity in Plasma From Analbuminemic Patients

Sylvie Braschi; Laurent Lagrost; Emmanuel Florentin; Claude Martin; Anne Athias; Philippe Gambert; Michel Krempf; Christian Lallemant; Bernard Jacotot

From the Service de Médecine V and INSERM U391, Hôpital Henri Mondor (S.B., C.M., B.J.), Créteil; the Laboratoire de Biochimie des Lipoprotéines, INSERM CJF 93-10, Faculté de Médecine (L.L., E.F., A.A., P.G., C.L.), Dijon; and the Service d'Endocrinologie, Hôtel Dieu (M.K.), Nantes, France.

Correspondence to Laurent Lagrost, Laboratoire de Biochimie Médicale, Hôpital du Bocage, 21034 Dijon, France.


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Abstract Hypercholesterolemia associated with analbuminemia, an inherited disease manifesting low plasma albumin concentration, is characterized by enhanced LDL cholesterol levels and reduced HDL cholesterol levels. In addition, compared with normal counterparts, the esterified cholesterol:triglyceride ratio tends to be higher in analbuminemic apoB-containing lipoproteins and lower in analbuminemic HDL. The aim of the present study was to investigate the mechanism that may account for the association of a hypoalbuminemic state with alterations in the concentration and composition of plasma lipoprotein fractions. To this end, endogenous cholesterol esterification activity, phospholipid transfer activity, and cholesteryl ester transfer activity were measured in total plasma from three analbuminemic patients and five control subjects. Whereas endogenous cholesterol esterification and phospholipid transfer rates were not significantly affected in analbuminemia, the transfer of radiolabeled cholesteryl esters from HDL toward apoB-containing lipoproteins was constantly higher in analbuminemic plasmas than in normal control plasma (473.6±107.3%·h-1·mL-1 versus 227.5±84.0%·h-1·mL-1, respectively; P=.036). The rise in cholesteryl ester transfer protein (CETP) activity in analbuminemic plasma was due to a significant increase in the transfer of radiolabeled cholesteryl esters toward LDL but not toward the triglyceride-rich lipoproteins. The CETP mass was higher in analbuminemic patients than in control subjects, but the difference did not reach the significance level (5.18±0.82 mg/L versus 3.13±1.19 mg/L, respectively; P=.07). Since abnormally elevated nonesterified fatty acid (NEFA) levels were shown to be associated with analbuminemic lipoproteins, mostly LDL, the direct role of lipoprotein-bound NEFA in enhancing CETP activity was suspected. In support of this view, supplementation of total plasmas with fatty acid–poor albumin was shown to reduce CETP activity to a significantly greater extent in analbuminemic plasmas than in normal control plasma. It is concluded that hyperlipidemia associated with the hypoalbuminemic state can relate, at least in part, to the combined effect of CETP and NEFA in promoting the transfer of cholesteryl esters from the antiatherogenic HDL toward the proatherogenic apoB-containing lipoproteins.


Key Words: lipoprotein • cholesteryl ester transfer protein • hypoalbuminemia • triglyceride • cholesteryl ester


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Analbuminemia, or better called congenital hypoalbuminemia, is a rare, inherited disease characterized by an abnormally low plasma albumin concentration.1 2 3 4 5 6 7 8 9 10 11 12 13 In spite of the relatively small number of patients identified so far,1 2 3 4 5 6 7 8 9 10 11 12 13 inherited analbuminemia has been shown to be associated with several well-defined clinical symptoms, among them mild edema, low blood pressure, increased concentration of several plasma proteins, and hypercholesterolemia.6 7 9 10 11 13 14 15 The latter point is of particular interest and might account for the premature cardiovascular events that have been reported in several cases.3 5 6 13 Consequently, inherited analbuminemia may constitute an interesting model to elucidate the biochemical process that may account for the reported positive relationship between hypoalbuminemia and coronary artery disease.16 17 18

Whereas NEFAs are normally mostly bound to albumin, abnormally low albumin concentrations, such as those reported in analbuminemia15 and nephrotic syndrome,19 have been shown to be associated with the redistribution of NEFA toward the plasma lipoprotein fraction.19 These observations demonstrated clearly that in vivo lipoprotein particles can stand for alternative carriers of plasma NEFA.15 19 Moulin and coworkers20 reported increased CETP mass concentrations in dyslipidemic patients with nephrotic syndrome. In vitro studies achieved in the absence of albumin demonstrated that NEFA, when located at the surface of lipoproteins, can stimulate the ability of CETP to promote the redistribution of cholesteryl esters from HDL toward VLDL and LDL, together with the reciprocal transfer of triglycerides from VLDL+LDL toward HDL.21 22 Considered together, previously published data suggest, therefore, that the stimulation of plasma CETP by the lipoprotein-bound NEFA might account for the rise in LDL:HDL cholesterol ratio observed under pathological conditions that is associated with abnormally low plasma albumin levels.15 20

The latter hypothesis was investigated in the present study by measuring the CETP mass concentration and the isotopic exchange of cholesteryl esters between HDL and apoB-containing lipoproteins in three analbuminemic patients and five normolipidemic control subjects.


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Case 1
ZA, a 32-year-old woman, was first hospitalized in 1981 for a severe myopathy revealing a vitamin-sensitive osteomalacia.23 Laboratory examination at that time showed a combined hyperlipidemia together with a hypoalbuminemia without proteinuria. Study of the family revealed a consanguineous union of the parents.7 Analbuminemia was detected in plasma from two of ZA's brothers, the older one suffering slight generalized edema and the other being asymptomatic (Fig 1aDown). To date, ZA still exhibits a strong dyslipidemia (plasma total cholesterol level >400 mg/dL; plasma triglyceride levels >200 mg/dL), with no beneficial effects derived from a low-fat diet and hypolipidemic drug treatment. At the present time, the physical examination of ZA is normal, with blood pressure of 120/70 mm Hg and normal weight (BMI, 24.5 kg/m2). The only associated clinical abnormality is a bilateral corneal arcus, with no symptom of cardiovascular disease.



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  		Figure 1. Pedigrees of the three analbuminemic patients. a, Pedigree of ZA; b, pedigree of BR and RR. Adapted from Irunberry et al7 and Reynaud et al.13

Cases 2 and 3
BR and RR, two sisters, aged 25 and 32 years, respectively, were also investigated for a severe and persistent dyslipidemia associated with inherited hypoalbuminemia. BR was first admitted in the hospital in 1987 for a transient oligoarthritis, which remained unexplained, and edema of the legs. RR was hospitalized in 1990 and 1992 for superficial thrombophlebitis. Review of family history revealed a consanguineous union of the parents and maternal grandparents (Fig 1bUp). One of the maternal aunts had a myocardial infarction at 54 years old.13 Laboratory examination immediately after the infarction revealed hypercholesterolemia associated with hypoalbuminemia (plasma cholesterol, 348 mg/dL; plasma triglycerides, 78 mg/dL; plasma albumin, 2.7 g/L). The father of BR and RR was hypercholesterolemic but had normal plasma albumin concentration (plasma cholesterol, 290 mg/dL; plasma triglycerides, 180 mg/dL). He died at the age of 63 of hepatic metastasis of a colic carcinoma. The brother of BR and RR is also hypercholesterolemic without hypoalbuminemia (plasma cholesterol, 324 mg/dL; plasma triglycerides, 65 mg/dL).

At present, the physical examinations of BR and RR are normal, except that BR has edema in both legs and low blood pressure (100/70 mm Hg) and RR is overweight (BMI=30.4 kg/m2). BMI of BR is 23.3 kg/m2.

Control Subjects
The control group consisted of five healthy, normolipidemic women recruited from among the hospital staff (38.6±6.9 years old; BMI, 20.7±1.0 kg/m2; plasma cholesterol <230 mg/dL; plasma triglycerides <200 mg/dL). Informed consent from patients and control subjects was obtained. They took neither drugs nor oral contraceptives.

Control subjects did not differ significantly from analbuminemic patients in regard to their physical activity, smoking habits, and diet. Only one control subject was a smoker (10 cigarettes per day). Information on usual food intake was obtained through a 3-day dietary record. The average energy consumption, as well as the protein, carbohydrate, and fat contents of the diets in analbuminemic patients and control subjects did not differ significantly. Saturated fatty acids accounted for {approx}50% of the total fat intake in all the subjects studied.


*    Methods
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Blood Sampling
Venous blood was collected after an overnight fast into tubes containing 0.1 mg/mL Na2-EDTA and placed immediately on ice. Plasma was promptly separated by a 15-minute centrifugation at 3000 rpm and maintained at 4°C before lipid and lipoprotein analysis. Plasma aliquots for cholesteryl ester transfer, phospholipid transfer, and cholesterol esterification assays were kept at -20°C.

Analysis of Lipoprotein Components
Total cholesterol, free cholesterol, triglyceride, and phospholipid concentrations were determined in total plasma and lipoprotein fractions by using an Abbott diagnostic VP analyzer with enzymatic reagents (Boehringer Mannheim). Cholesteryl ester mass content of lipoprotein fractions was calculated as the difference between total cholesterol and free cholesterol multiplied by 1.67, representing the sum of the esterified cholesterol and fatty acid moieties. Protein concentrations were measured by using the method of Lowry et al,24 with serum albumin as the standard. HDL cholesterol levels were determined after precipitation of plasma apoB-containing lipoproteins with phosphotungstic acid and magnesium chloride (Boehringer Mannheim). LDL cholesterol levels were calculated using the formula of Friedewald et al.25 Nonesterified fatty acid concentrations were determined by using an enzymatic kit (Wako Pure Chemicals Industries).

Preparation of Lipoprotein Fractions by Sequential Ultracentrifugation
Lipoprotein fractions were separated by flotation in an L8-65 ultracentrifuge (Beckman Instruments) according to a modification of the procedure of Havel et al.26 Densities were adjusted by using KBr solutions. VLDL, IDL, LDL, HDL2, and HDL3 were isolated step by step as the d<1.006-g/mL, 1.006<d<1.019-g/mL, 1.019<d<1.063-g/mL, 1.063<d<1.125-g/mL, and 1.125<d<1.250-g/mL plasma fractions, respectively. HDL2 and HDL3 fractions were washed by a second run of ultracentrifugation in solutions of d=1.125 g/mL and d=1.250 g/mL, respectively, to avoid contamination with plasma albumin.

Density Gradient Ultracentrifugation
Plasma lipoproteins were fractionated according to a continuous KBr gradient by using the general procedure described by Chapman and coworkers.27 Briefly, the density of the plasma samples was first adjusted to 1.210 g/mL by the addition of solid KBr. A discontinuous gradient was then constructed in cellulose nitrate tubes in a Beckman SW 41-Ti swinging-bucket rotor by using KBr solutions in the following order: 0.5 mL of a d=1.250-g/mL NaCl-KBr solution, 2 mL of plasma adjusted to d=1.210 g/mL, 3 mL of a d=1.120-g/mL NaCl-KBr solution, 2.5 mL of a d=1.063-g/mL NaCl-KBr solution, 1.5 mL of a d=1.019-g/mL NaCl-KBr solution, 1 mL of a d=1.006-g/mL NaCl solution, and 1 mL of distilled water. Tubes were immediately centrifuged at 40 000 rpm for 24 hours at 15°C in a Beckman L8-55 ultracentrifuge.

Isotopic Assay of Plasma Cholesteryl Ester Transfer Activity
Cholesteryl ester transfer activity was determined in total plasma according to the general procedure previously described.28 Briefly, the capacity of a plasma sample to promote the transfer of tritiated cholesteryl esters from a tracer amount of biosynthetically labeled HDL3 (3H-CE-HDL3) toward plasma apoB-containing lipoproteins was evaluated during the incubation at 37°C of total plasma (25 µL), 3H-CE-HDL3 (2.5 nmol of cholesterol), and iodoacetate (75 nmol) in a final volume of 50 µL. At the end of the incubation, apoB-containing lipoproteins were separated by using either ultracentrifugation or PAGE. In the former case, incubation mixtures were adjusted to d=1.068 g/mL, ultracentrifuged for 7 hours at 50 000 rpm (269 000g) in a 50.4 Ti rotor on an L7 ultracentrifuge (Beckman), and the d<1.068- and d>1.068-g/mL fractions were recovered.28 In the latter case, plasma lipoprotein fractions were separated by electrophoresis in 20- to 160-g/L polyacrylamide gels.29 Subsequently, gel fragments containing the different plasma lipoprotein fractions (VLDL+IDL, LDL, and HDL) were cut off and dissolved with NaOCl according to the procedure of Florentin et al.29 Lipoprotein fractions recovered by using either the ultracentrifugation or the PAGE method were mixed with a scintillation fluid (OptiPhase Hisafe 3, Pharmacia), and radioactivity was assayed for 5 minutes in a Wallac 1410 liquid scintillation counter (Pharmacia). Results were expressed as percentage of total radiolabeled cholesteryl esters recovered in each lipoprotein fraction.

Isotopic Assay of Plasma Phospholipid Transfer Activity
Phospholipid transfer activity was determined in total plasma by measuring the transfer of radiolabeled phosphatidylcholine from phospholipid liposomes (14C-PC-liposomes) to the plasma HDL fraction according to the method previously described30 and derived from the general procedure of Damen et al.31 Briefly, total plasma (30 µL), 14C-PC-liposomes (110 nmol of phosphatidylcholine), and iodoacetate (120 nmol) were incubated for 30 minutes at 37°C in a final volume of 80 µL. Phospholipid liposomes and apoB-containing lipoproteins were subsequently precipitated by addition of 60 µL of a 500-mmol/L NaCl, 215-mmol/L MnCl2, 445-U/mL heparin solution.30 Radioactivity in resulting supernatants was assayed as described above and phospholipid transfer activity was calculated as the rate of total radiolabeled phospholipids transferred from liposomes to plasma HDL after deduction of nonincubated control values.

LCAT Activity
LCAT activity in total plasma was evaluated by using two independent methods, which measured either the cholesterol esterification rate with an exogenous, radiolabeled substrate ("isotopic cholesterol esterification rate") or the decrease in plasma free cholesterol mass ("endogenous cholesterol esterification rate").

Isotopic Cholesterol Esterification Rate
LCAT activity in total plasma was evaluated by using the general procedure previously described.28 Briefly, 5 µL of a 3H-cholesterol–albumin emulsion (3H-cholesterol, 6.7 mCi/L; albumin, 50 g/L) and 50 µL of total plasma were mixed and preincubated for 1 hour at 4°C. Subsequently, mixtures were incubated for 3 hours at 37°C and nonesterified cholesterol remaining was precipitated by digitonin.32 The isotopic cholesterol esterification rate was calculated as the percentage of total radiolabeled cholesterol esterified during the 3-hour period compared with control in which plasma was replaced by Tris-buffered saline. Isotopic LCAT activity was expressed in percentage of radiolabeled cholesterol esterified per hour per milliliter of plasma (%·h-1·mL-1).

Endogenous Cholesterol Esterification Rate
Endogenous cholesterol esterification was determined by the previously described nonradioactive method,33 which measures the decrease in plasma free cholesterol during incubation for 40 minutes at 37°C. Endogenous cholesterol esterification rate was expressed in percentage of decrease in unesterified cholesterol per hour (%/h).

CETP Enzyme-Linked Immunosorbent Assay
CETP mass concentrations were measured by using a competitive enzyme-linked immunosorbent assay on a Biomek 1000 Biorobotic System (Beckman Instruments).34 CETP mass concentration values were determined in quadruplicate from a calibration curve obtained with a frozen plasma standard.

Native Polyacrylamide Gradient Gel Electrophoresis
The size of isolated LDL was determined by electrophoresis on nondenaturing 15- to 250-g/L polyacrylamide gradient gels according to the general procedure previously described.28 Gels were fixed and stained with Coomassie brilliant blue G before analysis on a GS-670 Gel Densitometer (Bio-Rad). The mean apparent diameter of LDL was determined by comparison with protein standards (Pharmacia High Molecular Weight Protein Calibration kit) and carboxylated latex beads (Duke Scientific).28

Agarose Gel Electrophoresis
The electrophoretic mobility of isolated LDL particles was determined by electrophoresis on 0.5% agarose gels (Paragon Lipo kit, Beckman), according to the method described by Sparks and Phillips.35 Mean migration distances were obtained by analysis of the gel on a Bio-Rad GS-670 imaging densitometer.

Precipitation of the Total Plasma Lipoprotein Fraction
Lipoproteins were removed from total human plasma by using a single-step adsorption method based on the ability of FSD to remove large particles, such as lipid emulsions and lipoprotein particles, from aqueous media.36 Briefly, total plasmas were treated for 10 minutes at room temperature with FSD (final concentration, 2.5 mg/mL) according to the general procedure previously reported.37 Under those experimental conditions, FSD allowed the removal of all plasma lipoprotein components, whereas no more than 5% of plasma albumin was coprecipitated.

Statistical Analysis
Data means were compared by using the Mann-Whitney U statistic. Correlations between various parameters were analyzed by using Spearman's rank correlation analysis.


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Plasma Parameters
Table 1Down presents the albumin and lipid levels in total plasma from three analbuminemic patients and five control subjects. Study patients presented markedly and significantly lower albumin levels than control subjects. Hypoalbuminemia was associated with significantly higher total cholesterol, LDL-C, and triglyceride concentrations compared with normolipidemic control subjects. Conversely, HDL-C tended to be reduced in hypoalbuminemic plasmas. Total NEFA levels in analbuminemic patients were within the normal range (Table 1Down). Plasma LDL:HDL cholesterol ratio was significantly higher in analbuminemic patients than in control subjects (Table 1Down).


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  		Table 1. Plasma Parameters in Analbuminemic Patients and Normal Subjects

Plasma Lipoprotein Composition
Distinct lipoprotein fractions (VLDL, IDL, LDL, HDL2, and HDL3) were isolated from total plasma by sequential ultracentrifugation and were assayed for protein, unesterified cholesterol, total cholesterol, phospholipid, and triglyceride as described in "Methods." As shown in Table 2Down, lipid:protein ratios were significantly increased only in LDL fractions of analbuminemic patients (3.23±0.20 versus 1.87±0.95, P=.036). Whereas the mass percentage of surface lipid components (phospholipid, unesterified cholesterol) in individual lipoprotein fractions was quite similar in the two groups, some differences appeared when comparing the neutral lipid (cholesteryl ester and triglyceride) contents. Indeed, cholesteryl ester content tended to be higher in lipoproteins from analbuminemic patients compared with normal control subjects, and the difference was statistically significant in the VLDL and LDL fractions. Triglycerides tended to be lower in analbuminemic VLDL and IDL but higher in analbuminemic HDL. However, differences did not reach the significance level. Overall, the esterified cholesterol:triglyceride ratio tended to be higher in analbuminemic apoB-containing lipoproteins, ie, VLDL, IDL, and LDL, but lower in analbuminemic HDL (Table 2Down). Again, because of the small number of subjects studied, the difference in the esterified cholesterol:triglyceride ratio between analbuminemic patients and normal subjects reached statistical significance only for the VLDL fraction (Table 2Down).


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  		Table 2. Plasma Lipoprotein Composition in Analbuminemic Patients and Control Subjects

Size and Density of LDL
To determine whether the significant increase in the lipid:protein ratio of analbuminemic LDL was associated with alterations in particle size and density, LDLs were separated on native polyacrylamide gradient gel and isolated from total plasma by density gradient ultracentrifugation (see "Methods"). Compared with LDL from control individuals, LDL particles from analbuminemic patients tended to be of larger size (26.6±0.2 versus 27.0±0.5 nm, respectively; NS). In addition, the mean density of LDL from analbuminemic patients was significantly lower than the mean density of LDL from control subjects (1.041±0.041 versus 1.045±0.001 g/mL, respectively; P=.036).

Distribution of NEFA Among Plasma Lipoprotein Fractions
To investigate whether hypoalbuminemia was associated with alterations in the plasma distribution of NEFA, plasma lipoproteins were precipitated by using FSD, and NEFA contents of lipoprotein and nonlipoprotein plasma fractions were determined as described under "Methods." Interestingly, in spite of similar total NEFA levels in plasmas of both analbuminemic patients and control subjects, strong differences appeared when comparing the plasma NEFA distribution in the two groups. Indeed, the bulk of plasma NEFA, representing 59±3% (mean±SD of three determinations), 68±3%, and 88±20% of the total, was located in the lipoprotein fraction of BR, RR, and ZA, respectively. In contrast, only a minor proportion of total NEFA, not exceeding 10% of the total, was located in lipoproteins from control subjects.

The precise distribution of plasma NEFA was further studied after separation of lipoprotein fractions by sequential ultracentrifugation (see "Methods"). In agreement with data obtained after precipitation of plasma lipoproteins with FSD, most of the NEFA in analbuminemic plasmas was bound to the ultracentrifugally isolated LDL, HDL2, and HDL3 fractions. In contrast, only a small percentage of total NEFA was recovered in the triglyceride-rich lipoprotein fractions, VLDL and IDL, from both analbuminemic and control plasmas (Fig 2Down). In accordance with a higher NEFA content of analbuminemic LDL compared with normolipidemic counterparts (33.9±4.3 versus 3.2±2.3% of total plasma NEFA, respectively; P=.025), the mean distance of migration of LDL particles toward the anodic end of agarose gel was significantly higher when isolated from anabuminemic than normolipidemic plasma (7.1±0.3 versus 5.4±0.4 mm, respectively; P=.036) (Fig 3Down). The distance of migration of plasma LDL in agarose gel correlated positively with its NEFA content (P=.78; P=.04).



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  		Figure 2. Distribution of NEFAs among plasma lipoprotein fractions. Plasma lipoprotein fractions (VLDL, IDL, LDL, and HDL) were isolated by sequential ultracentrifugation and NEFAs were assayed as described under "Methods." The results are expressed as percentage of total plasma NEFA bound to each lipoprotein fraction in the three analbuminemic patients (ZA, BR, RR) and the five control subjects. Values for each analbuminemic patient are mean of triplicate determinations. Values for the control population are mean±SD of five normolipidemic subjects.



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  		Figure 3. Agarose gel electrophoretic profiles of LDL isolated from analbuminemic and control plasmas. Plasma LDL was isolated by sequential ultracentrifugation, and its electrophoretic mobility was determined as described under "Methods." Electrophoretic profiles of LDL from analbuminemic and control plasmas were obtained by image analysis of the agarose gel.

LCAT Activity in Analbuminemic and Control Plasmas
LCAT activity was determined by two independent methods, which measured either the esterification of exogenous radiolabeled unesterified cholesterol (isotopic cholesterol esterification rate) or the esterification of endogenous unesterified cholesterol (endogenous cholesterol esterification rate; see "Methods"). Whereas the isotopic cholesterol esterification rate was markedly decreased in the three analbuminemic patients (38.1±12.8%·h-1· mL-1 versus 117.2±19.9%·h-1 · mL-1 in control subjects, P=.036), the endogenous cholesterol esterification rate was normal (8.75±1.96%/h versus 7.27±2.62%/h in control subjects, NS).

Phospholipid Transfer Activity in Analbuminemic and Control Plasmas
The phospholipid transfer activity was determined by measuring the transfer of radiolabeled phosphatidylcholine from phospholipid liposomes to the plasma HDL fraction (see "Methods"). The difference in plasma phospholipid transfer activity between analbuminemic patients and control subjects was not statistically significant (358±55%·h-1·mL-1 versus 464±35%·h-1·mL-1, NS).

Isotopic Transfer of Cholesteryl Esters in Analbuminemic and Control Plasmas
Fig 4Down shows the time-dependent transfer of radiolabeled cholesteryl esters from HDL3 to apoB-containing lipoproteins measured in analbuminemic patients and control subjects. The rate of cholesteryl esters transferred toward the d<1.068-g/mL plasma fraction increased progressively during the first 3 hours of incubation and tended to reach a plateau for incubation times exceeding 4.5 hours (Fig 4Down). During the period studied, cholesteryl ester transfer activity in analbuminemic patients was constantly and significantly higher than in normolipidemic control subjects (P=.036). As measured after 3 hours of incubation, mean cholesteryl ester transfer activity, expressed in percentage of radiolabeled cholesteryl esters transferred from HDL3 to apoB-containing lipoproteins per hour per milliliter of plasma, was significantly higher in analbuminemic plasmas than in normal control plasma (473.6±107.3 versus 227.5±84.0%·h-1·mL-1, respectively; P=.036).



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  		Figure 4. Isotopic transfer of cholesteryl esters from HDL3 to the d<1.068-g/mL plasma fraction. Cholesteryl ester transfer activity was determined as the percentage of total radiolabeled cholesteryl esters transferred from a tracer dose of exogenous HDL3 toward the d<1.068-g/mL plasma fraction in three analbuminemic patients (ZA, BR, RR) and five control subjects. Values for each analbuminemic patient are mean±SD of triplicate determinations. Values for the control population are mean±SD of five normolipidemic subjects.

As observed by using PAGE, significant increase in the transfer of radiolabeled cholesteryl esters toward LDL but not toward the VLDL+IDL plasma fraction accounted for the rise in cholesteryl ester transfer activity in analbuminemic plasmas (Table 3Down).


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  		Table 3. Repartition of Isotopic Transfers of Cholesteryl Esters From HDL Toward the Plasma Apolipoprotein B–Containing Lipoprotein Fractions

CETP Mass
To determine whether increased CETP mass might also account for the increased transfer of neutral lipids between lipoproteins, plasma CETP concentrations were measured by using a specific enzyme-linked immunosorbent assay. CETP mass was higher in analbuminemic patients than in control subjects, but the difference did not reach the significance level (5.18±0.82 mg/L versus 3.13±1.19 mg/L, P=.07).

Effect of Albumin Supplementation on the Isotopic Transfer of Cholesteryl Esters From HDL3 Toward the d<1.068 g/mL Plasma Fraction
In vitro albumin is able to remove NEFA from lipoprotein substrates when added to normal or hypoalbuminemic plasmas.19 In the present study, we made use of the high binding capacity of albumin for NEFA to confirm that increased cholesteryl ester transfer activity was, at least in part, due to high levels of lipoprotein-bound NEFA. To this end, analbuminemic and control plasmas were supplemented with increasing amounts of fatty acid–poor albumin. Compared with nonsupplemented plasma counterparts, changes in cholesteryl ester transfer activity after supplementation of total plasma with 5, 10, 15, and 20 g/L of fatty acid–poor albumin were -28.3±16.4, -42.2±20.7, -47.1±25.6, and -50.1±23.7%·h-1·mL-1 in control plasmas, respectively. In analbuminemic plasmas, changes in cholesteryl ester transfer activity after supplementation of total plasma with 5, 10, 15, and 20 g/L of fatty acid–poor albumin were -54.4±46.6, -92.4±46.6, -122.2±31.1, and -144.6±66.2%·h-1·mL-1, respectively. Differences in the reduction of cholesteryl ester transfer activity between control and analbuminemic plasmas were statistically significant for the two highest albumin concentrations studied, 15 and 20 g/L (P=.05 and P=.027, respectively).

Specific activity of CETP in albumin-supplemented plasmas was calculated as the ratio of plasma cholesteryl ester transfer activity to plasma CETP mass concentration and expressed in percentage of total radiolabeled cholesteryl esters transferred per hour per microgram of CETP (%·h-1·µg-1). Specific CETP activity in analbuminemic plasmas was higher than in control plasmas (93.4±10.1 versus 78.1±15.9%·h-1·µg-1, respectively), but the difference did not reach the significance level. When analbuminemic plasmas were supplemented with increasing concentrations of fatty acid–poor albumin, mean specific CETP activity decreased markedly, with an approximately linear progression along the albumin concentration range studied (Fig 5Down). In contrast, mean specific CETP activity in normal plasmas was substantially reduced with low levels of fatty acid–poor albumin (5 and 10 g/L) but subsequently did not decrease further (Fig 5Down). For the highest fatty acid–poor albumin concentration studied (20 g/L), specific CETP activities measured in analbuminemic and control plasmas were remarkably similar (66.1±7.7 versus 61.7±15.1%·h-1·µg-1, respectively). When plotted against the added fatty acid–poor albumin concentration, the difference between specific CETP activity measured in both analbuminemic and normal plasmas decreased progressively, reaching virtually the zero value when 28 g/L of fatty acid–poor albumin was added to total plasmas (see Fig 5Down).



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  		Figure 5. Effect of supplementation of total plasma with fatty acid–poor albumin on specific activity of CETP. The specific activity of plasma CETP is calculated as the ratio of plasma cholesteryl ester transfer activity to plasma CETP mass concentration and expressed in percentage of radiolabeled cholesteryl esters transferred from exogenous HDL3 toward the apoB-containing lipoproteins per hour per microgram of CETP. Values are means of three analbuminemic plasmas ({bullet}) and five normal control plasmas ({circ}). Differences between analbuminemic and control samples have been calculated and plotted against the added concentration of fatty acid–poor albumin (see inset graph).


*    Discussion
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The results of the present study revealed for the first time that the hyperlipidemic state associated with analbuminemia can relate at least in part to a significant increase in plasma cholesteryl ester transfer activity. Consistent observations were made by measuring the exchange of radiolabeled cholesteryl esters between HDL and VLDL+LDL fractions and the plasma CETP mass concentration. In accordance with a previous study from our laboratory in which NEFAs were shown to modulate CETP activity in normolipidemic plasma,38 the increased cholesteryl ester transfer activity in hypoalbuminemic plasmas was explained in part by the redistribution of NEFA from albumin toward the plasma lipoprotein particles.

Analbuminemia is a rare genetic disease that is associated with corneal arcus9 12 and premature atherosclerosis.3 5 6 13 It is also associated with a mild hypertriglyceridemia6 9 14 and a strong hypercholesterolemia6 7 9 10 14 15 that is mainly due to a rise in LDL cholesterol levels.15 In agreement with previous reports, the three analbuminemic patients of the present study showed abnormally high plasma cholesterol levels in association with corneal arcus in one of them.14 15 Moreover, we observed that the cholesteryl ester:triglyceride ratio in the apoB-containing lipoprotein fractions, ie, VLDL, IDL, and LDL, tended to be higher in analbuminemic patients than in normolipidemic control subjects, with only the ratio in VLDL reaching the significance level. In contrast, the cholesteryl ester:triglyceride ratio tended to be reduced in HDL from analbuminemic patients. The plasma LDL:HDL cholesterol ratio was significantly higher in analbuminemic plasmas. We demonstrated that alterations in the plasma lipoprotein profile were characterized by a marked, significant increase in the lipid:protein ratio of analbuminemic LDL, which was associated with changes in the physical properties of the particles. Indeed, we observed that analbuminemic LDL tended to be both of larger size and lower density compared with normolipidemic LDL. In addition, the electronegativity of analbuminemic LDL was significantly higher than that of normolipidemic LDL, reflecting its higher NEFA content.

It is commonly admitted that dyslipidemia associated with hypoalbuminemic states, such as congenital analbuminemia or nephrotic syndrome, is primarily induced by a hepatic oversynthesis of apoB-containing lipoproteins in response to the decreased oncotic pressure.39 40 However, recent observations suggested that the enrichment of individual LDL particles with cholesterol also contributed to elevated LDL-C levels in nephrotic syndrome.41 It is suggested, therefore, that not only an increased number of apoB-containing lipoprotein particles but also a net increase in their cholesterol content may be involved in the pathophysiology of hyperlipidemia associated with analbuminemia. In support of the latter view, we observed in the present study that LDL particles from analbuminemic patients compared with control subjects were enriched with cholesteryl esters.

Other studies achieved with analbuminemic patients,14 15 nephrotic patients,42 43 and analbuminemic rats,44 45 suggested that alteration in LCAT activity might be involved in the lipoprotein abnormalities associated with hypoalbuminemia. However, controversial observations were reported, and the hypoalbuminemic state was associated with increased,15 42 43 44 45 normal,14 42 46 or decreased42 46 plasma cholesterol esterification rate. The data presented here show that LCAT activity in analbuminemic plasmas was significantly decreased when measuring the esterification rate with an exogenous substrate but was normal when measuring the endogenous cholesterol esterification rate with the method of Albers and coworkers.33 In fact, as suspected by others,45 the decrease in exogenous cholesterol esterification rate might relate to variations in plasma lipoprotein levels, and then to differences in the ratio of added radiolabeled cholesterol to the plasma unesterified cholesterol pool. Therefore, on the basis of measurements of endogenous cholesterol esterification rates, it appears that the lipoprotein disorders associated with the hypoalbuminemic state in the present study are unlikely to result from alteration in plasma LCAT activity.

Since similar lipoprotein modifications, ie, increased cholesteryl ester:triglyceride ratio in triglyceride-rich lipoproteins and increased plasma LDL:HDL cholesterol ratio, were also observed in physiopathological conditions under which plasma CETP activity is enhanced,47 an abnormally elevated plasma CETP activity in analbuminemia was suspected. CETP activity was clearly higher in analbuminemic patients than in normal subjects in our study by measuring the isotopic transfer of cholesteryl esters from HDL to the plasma apoB-containing lipoproteins. It is noteworthy that CETP activity was measured by using radiolabeled HDL substrates that presumably did not contain the NEFA found in analbuminemic HDL. Therefore, an underestimation of the influence of lipoprotein-associated NEFA on CETP activity cannot be excluded. In contrast to neutral lipid transfer, phospholipid transfer rates were not significantly modified in analbuminemic plasma compared with normal control plasma.

In total human plasma, cholesteryl ester transfer activity values reflect the activity of the CETP protein as modulated by endogenous plasma factors, among them the concentration and composition of lipoprotein particles.47 48 Therefore, to determine the mechanism that may account for the increased cholesteryl ester transfer activity in analbuminemic patients, we searched for alterations in both CETP mass and putative CETP modulators in total plasma. As measured by using a specific enzyme-linked immunosorbent assay,34 CETP concentrations tended to be higher in analbuminemic plasmas than in normolipidemic counterparts. Due to the small number of analbuminemic patients studied, these differences did not reach the significance level. However, mean CETP concentration values in analbuminemic plasmas were clearly beyond the normal upper limit recently reported by using the same immunoassay.34 Increased plasma CETP mass is in good agreement with previous observations of Moulin and coworkers,20 who reported a significant rise in plasma CETP concentration in patients with nephrotic syndrome, another hypoalbuminemic state. The rise in CETP concentration in analbuminemic patients might relate to the well-known overproduction of a number of proteins by the liver in hypoalbuminemic states.20 43 Whether CETP is part of these overproduced proteins remains to be established.

In addition to high plasma CETP mass and elevated concentrations of triglyceride-rich lipoprotein acceptors,48 enhanced plasma cholesteryl ester transfer activity in analbuminemia might relate to significant increases in potential plasma CETP activators, among them the negatively charged lipoprotein-bound lipolytic products.21 47 49 50 51 In agreement with previous data,15 19 we observed that most NEFA is abnormally bound to analbuminemic lipoproteins, mainly LDL. In addition, Joles and coworkers45 recently demonstrated that the lysophosphatidylcholine content of plasma lipoproteins, another negatively charged lipid product, is also strongly increased in hypoalbuminemia. It results, therefore, that high amounts of lipoprotein-bound, negatively charged molecules, normally bound to plasma albumin, may facilitate the interaction of plasma CETP with analbuminemic lipoprotein substrates, resulting in a significant increase in neutral lipid transfer activity. In support of the latter view, we observed that specific activity of CETP tended to be higher in analbuminemic patients than in control subjects, and cholesteryl ester transfers were specifically and significantly directed toward LDL, the main NEFA carrier in analbuminemic plasmas.

The possibility that lipolytic products can enhance CETP activity was verified by supplementation of plasmas with fatty acid–poor albumin. Whereas in normolipidemic control plasma the CETP activity was only slightly reduced after albumin supplementation, the albumin-mediated decrease in cholesteryl ester transfers was much more pronounced in analbuminemic plasmas. In accordance with in vitro studies in which the ability of NEFA to modulate CETP activity was canceled in the presence of fatty acid–poor albumin,21 51 striking reduction of plasma cholesteryl ester transfer activity with fatty acid–poor albumin strongly suggests that lipoprotein-bound NEFA may constitute potential activators of lipid transfers in analbuminemic patients. Since plasma CETP activity tended to return to a basal, normal level when plasma albumin concentration was normalized, the elevation of CETP activity associated with analbuminemia appeared to be directly linked to increased NEFA content of plasma lipoproteins. In other words, the results of the present study strongly suggest that some of the lipoprotein disorders associated with analbuminemia might relate to enhanced plasma CETP activity, resulting itself from the hypoalbuminemic state. In support of the latter view, high plasma cholesterol values were shown to return to the normal level following albumin infusion in analbuminemic patients.4 6

In conclusion, the present study demonstrated that analbuminemia is associated with increased plasma cholesteryl ester transfer activity. It gave new insights into the mechanisms that may account for the previously reported relationship between hypoalbuminemic states and increased risk for coronary artery disease.16 17 18 By stimulating cholesteryl ester transfers from the "antiatherogenic" HDL toward the "proatherogenic" apoB-containing lipoproteins, lipoprotein-bound NEFA may represent a risk factor of atherogenicity.


*    Selected Abbreviations and Acronyms
 
apoB = apolipoprotein B
BMI = body mass index
CETP = cholesteryl ester transfer protein
FSD = fumed silicon dioxide
HDL-C = HDL cholesterol
LCAT = lecithin:cholesterol acyltransferase
LDL-C = LDL cholesterol
NEFA(s) = nonesterified fatty acid(s)
PAGE = polyacrylamide gradient gel electrophoresis


*    Acknowledgments
 
This investigation was supported by the Université de Bourgogne, the Conseil Régional de Bourgogne, the Institut National de la Santé et de la Recherche Médicale (INSERM), and the Fondation pour la Recherche Médicale. Françoise Berneau and Caroline Rousseau are greatly acknowledged for their secretarial assistance.

Received June 2, 1995; accepted November 30, 1995.


*    References
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*References
 

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