© 1997 American Heart Association, Inc.
Articles |
Lipoprotein Kinetics in Patients With Analbuminemia
Evidence for the Role of Serum Albumin in Controlling Lipoprotein Metabolism
From the Centre de Recherche en Nutrition Humaine, Hôpital G. & R. Laënnec, Nantes, France (C.M., K.O., P.M., D.D., T.M., M.K.); Service de Médecine Interne, Hôpital Henri Mondor, Créteil, France (S.B., B.J.); and Clinique d'Endocrinologie, Maladies Métaboliques et Nutrition, Hôtel Dieu, Nantes, France (P.M., M.K.).
Correspondence to Michel Krempf, Clinique d'Endocrinologie, Hôtel Dieu, 44093 Nantes cedex 01, France. E-mail mkrempf{at}micronet.fr.
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Abstract |
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Abstract In vitro data suggested that albumin is a key factor controlling apolipoprotein (apo) synthesis by hepatocytes. Studies in analbuminemic rats have shown an increase in secretion of apoB-containing lipoprotein from the liver. We studied the kinetic aspects of apoB- and apoAI-containing lipoprotein metabolism in two sisters with analbuminemia using a constant 14-hour infusion of leucine labeled with stable isotopes. Compared with control subjects, total cholesterol was higher in the two patients (432 and 461 versus 155±14 mg/dL), as was apoB (257 and 230 versus 72±7 mg/dL). Triglycerides were slightly increased (134 and 105 versus 89±9 mg/dL), whereas apoAI was lower (109 and 105 versus 124±6 mg/dL). VLDL–apoB production was higher, as was the production of IDL–apoB and LDL–apoB (32.8 and 36.0 versus 24.8±5.9, 32.1 and 27.2 versus 16.4±2.3, and 14.1 and 17.6 versus 10.3±1.2 mg · kg-1 · d-1, respectively). The fractional catabolic rate of all the apoB-containing lipoproteins was decreased (0.23 and 0.37 versus 0.48±0.05, 0.27 and 0.28 versus 0.62±0.08, and 0.012 and 0.009 versus 0.022±0.002 · h-1, respectively). A similar mechanism could explain the dyslipidemia observed in other conditions associated with low albumin levels, such as nephrotic syndrome.
Key Words: nephrotic syndrome • dyslipidemia • compartmental analysis • apoB • apoAI
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Introduction |
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The role of albumin in the control of apolipoprotein metabolism is not fully understood. Analbuminemia is a rare inherited disease characterized by very low or absent production of serum albumin. Patients exhibit only moderate edema and an increase in the plasma levels of other proteins such as immunoglobulin G and apolipoproteins.1 2 Subsequently, severe hypercholesterolemia and hypertriglyceridemia develop and may be responsible for the premature coronary heart disease reported in some cases.3 4 5 In Nagase rats, an animal model of congenital analbuminemia, hepatic overproduction of TG-rich particles, without any delay in their clearance, has been shown.6 No information is available on LDL kinetics in human analbuminemia, but data are available on patients with nephrotic syndrome, a kidney disease that is also associated with a reduced plasma albumin concentration; an increase in the production of LDL particles and a delay in their clearance depending on the level of TG concentration have been documented.7 8 9 To our knowledge, however, this has not been studied in patients with analbuminemia, and it must be pointed out that the kinetic lipid disturbances found in rats with experimental nephrosis are not always observed in Nagase rats.10 For example, a delay in the clearance of the TG-rich particles has been reported only in nephrotic animals, suggesting the urinary loss of a liporegulatory substance rather than an effect of low albumin concentration.6 To find out whether the circulating level of albumin controls apolipoprotein metabolism, we carried out lipid kinetic studies in two sisters with hereditary analbuminemia. We explored the kinetic aspects of the in vivo metabolism of apoB100 (apoB) and apoAI using a primed constant infusion of stable isotopes as previously reported.11 12 Results of the current study provide further insight into the role of albumin in controlling apolipoprotein synthesis in humans.
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Methods |
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Subjects
Patients
BR (patient 1) and RR (patient 2), two 25- and 32-year-old sisters, were investigated for severe and persistent hypercholesterolemia associated with hypoalbuminemia (albumin, 320 and 420 mg/dL, respectively). Review of the family history showed consanguineous unions. Both had normal blood pressure (120/80 and 116/75 mm Hg, respectively) as well as plasma osmolarity (278 and 286 mOsm, respectively), and both were in good general health. Neither had proteinuria or coronary heart disease; however, one maternal aunt, previously reported,5 also had analbuminemia (270 mg/dL), a myocardial infarction at 54 years of age, and dyslipidemia (TC, 348 mg/dL; TG, 78 mg/dL). The father and one of the patients' brothers also had hypercholesterolemia (father: TC, 290 mg/dL; TG, 180 mg/dL; brother: TC, 324 mg/dL; TG, 65 mg/dL) but with normal plasma albumin concentrations. The patients had been previously treated with 20 mg of pravastatin with no side effect; however, only mild efficacy was achieved (about 15% reduction of TC). They were never treated with probucol.
Control Group
The control group for the kinetic studies consisted of five
healthy, male, normolipidemic subjects (21 to 26 years old; body mass
index, 20 to 23 kg/m2). None had any disease on
physical examination, and all had a normal plasma albumin
concentration (4420±18 mg/dL).
Informed consent was obtained before the study according to protocols approved by the ethical committee of the University Hospital of Nantes Medical School.
Study Protocol
Subjects were instructed to consume a diet containing 45% of
daily caloric intake as carbohydrate, 35% as fat, and 20% as protein
for at least 1 week before the study. Analbuminemic patients
were taken off any medication known to affect lipid
metabolism at least 1 month before the study.
[2H3]Leucine (99.8% enrichment) was dissolved in a saline solution and tested for pyrogenicity and sterility before the study. After a 12-hour fast, the [2H3]leucine was administered as a priming dose of 10 µmol · kg-1 and was immediately followed by a constant infusion of 10 µmol · kg-1 · h-1 over a period of 14 hours. The subjects fasted during the entire study. Venous blood samples were withdrawn in EDTA tubes at baseline, every 15 minutes during the first hour, every 30 minutes during the following 2 hours, and finally hourly through the end of isotope infusion. Plasma was separated by centrifugation for 30 minutes at 4°C. Sodium azide and gentamicin were added into each plasma sample to a final concentration of 0.05% and 0.005%, respectively.
Analytical Procedures
Isolation and Preparation of Apolipoproteins
VLDL (d<1.006 kg/L), IDL (d=1.006
to 1.019 kg/L), and LDL (d=1.019 to 1.063
kg/L) were isolated from 4 mL of plasma by sequential
ultracentrifugation using standard
methods13 with a fixed angle rotor at 40 000 rev ·
min-1 for 22 hours at 10°C. Apolipoproteins
of lipoprotein fraction were concentrated following the method of
Mindham and Mayes.14 ApoB and apoAI were isolated from
other apolipoproteins by SDS–polyacrylamide gel
electrophoresis using a discontinuous gradient (4% to 5% to 10%).
Apolipoproteins were identified by comparing migration distances with
known molecular weight standards. Apolipoprotein bands were excised
from polyacrylamide gels and dried in vacuo for 2 to 3 hours.
The desiccated gel slices were hydrolyzed with 1 mL of 4N HCl at
110°C for 24 hours.
Isotopic Enrichment Determination
Hydrolysates were evaporated to dryness, and the amino acids
were purified by cation exchange chromatography using
Temex 50W-X8 resin. Amino acids were derivatized using
heptafluorobutyric anhydride before analysis by electron-impact
gas chromatography–mass spectrometry (Hewlett Packard
5891A gas chromatograph connected with a 5971A quadrupole mass
spectrometer). The chromatographic separations and mass
spectrometric analyses of leucine were done as previously
described.15 Isotopic abundances are reported as the
tracer/tracee mass ratio.16
Measurements of Lipids, ApoB, and ApoAI
ApoB and apoAI concentrations were measured in the plasma and in
lipoprotein fractions by immunonephelometry. The analytical precision
of the method (CV), assessed by triplicate measurements on 10 samples,
was 6.4%. Cholesterol and TG concentrations were measured
using commercially available enzymatic kits. The pool size of apoB (in
mg · kg-1) was calculated by
multiplying the apoB plasma concentration in each fraction by 0.045
(plasma volume of 4.5% body weight). This calculation could be used
for analbuminemic patients provided that their plasma volume
was not modified. For the apoAI pool size calculation, the
concentration of HDL apoAI was taken to be the plasma concentration of
apoAI (assuming that >95% of plasma apoAI is on
HDL).17
Modeling
Whole-body leucine turnover was calculated with the usual
steady-state equation from leucine plasma enrichments.18
The apoB leucine tracer/tracee ratio in VLDL, IDL, and LDL was
analyzed by multicompartmental modeling. The model used was a
minimal compartmental model for apoB metabolism (Fig 1
). In our experimental conditions, a
more complex compartmental model, previously used with a tracer bolus
experiment,11 did not provide a statistically better fit
of tracer/tracee ratio data.19 Our model included a
precursor pool from which apoB enters the VLDL compartment, VLDL–apoB
is converted into IDL–apoB, and IDL is converted into LDL–apoB. ApoB
can be removed from any compartment. Our model can estimate (1) the FCR
of VLDL as the sum of the rate constants of conversion of VLDL into IDL
and direct removal of VLDL, (2) the FCR of IDL as the sum of rate
constants of IDL conversion into LDL and direct removal of IDL, and (3)
the FCR of LDL as the rate constant of the removal of LDL from plasma.
We assumed a constant tracer/tracee ratio in the precursor pool during
the course of infusion to calculate the kinetic parameters.
This precursor pool tracer/tracee ratio was an adjustable
parameter in the optimization process. We assumed that each
subject remained in steady state; in this condition FCR equals FPR. The
fitting method was a program based on the numerical integration of
Runge-Kutta and Gauss-Marquardt optimization running on a 386
computer.20 The tracer/tracee curve of HDL–apoAI was
analyzed by fitting the data to a
monoexponential function (monocompartmental
analysis) as previously described.21 The following
function was used:
A(t)=Ap{1–exp[–k(t–d)]},
where A(t) was the HDL–apoAI leucine
tracer/tracee ratio at time t; Ap, the
tracer/tracee ratio at the plateau of the VLDL–apoB curve,
representing the tracer/tracee ratio of the hepatic
precursor pool; d, the delay time between the beginning of
the experiment and the appearance of the tracer in HDL–apoAI; and
k, the FCR of HDL–apoAI.21 The daily
production of apoB or apoAI (in
mg·kg-1 ·
d-1) was calculated as the product of FCR
by pool size of apoB or apoAI in the class of lipoprotein.
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Data for control subjects are expressed as the mean±SEM unless otherwise specified.
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Results |
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Lipids
The plasma levels of lipid, apolipoprotein, and albumin in patients and control subjects are shown in Table 1
. As expected, both patients had higher
cholesterol and apoB concentrations and lower apoAI
concentrations compared with control subjects. As shown in Table 2,
cholesterol, TG, and apoB
were higher in VLDL, IDL, and LDL in the two patients compared with
control subjects. Besides, both the cholesterol/apoB
mass ratio and cholesterol/TG mass ratio showed an
increase in cholesterol per VLDL and IDL particle. In these
same lipoprotein fractions, the TG/apoB mass ratio was lower in the
patients than in the control subjects, suggesting a decrease of TG per
VLDL and IDL particle. No difference between patients and control
subjects was observed for LDL composition.
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Kinetic Data
Enrichments in plasma free leucine reached a plateau value after
30 minutes and remained stable through the end of the study for
patients and control subjects (data not shown). The whole-body flux
rates of leucine were 73.9 µmol ·
kg-1 · h-1 for
RR, 81.6 µmol · kg-1 ·
h-1 for RB, and 84.2±3.2 µmol ·
kg-1 · h-1 for
the control subjects.
The tracer/tracee ratio curves in VLDL–, IDL–, and LDL–apoB for the
analbuminemic patients are shown in Fig 2, and those for control subjects are
shown in Fig 3. For control subjects, a
plateau of the tracer/tracee ratio was observed for VLDL and IDL but
not for LDL particles. For the patients, a plateau was observed only
for VLDL. The kinetic parameters of apoB are shown in Table 3, and apoB turnover rates in each model
pathways are shown in Fig 1
. The FCR of VLDL–apoB was lower in the two
patients compared with the control subjects, and the PR was increased.
The FCR for IDL–apoB and LDL–apoB was also decreased. The PRs of
IDL–apoB and LDL–apoB were markedly increased compared with those in
control subjects. The direct catabolic uptake of VLDL–, IDL–, and
LDL–apoB was decreased in the patients with analbuminemia (Fig 1).
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The tracer/tracee ratio curves for HDL–apoAI of patients and control
subjects are shown in Fig 4. Kinetic
parameters of HDL–apoAI calculated by
monoexponential regression are shown in Table 4.
The PR and FCR of apoAI from the two
patients were not different from those of control subjects.
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Discussion |
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To our knowledge, this study is the first to document an increase in VLDL–apoB secretion in analbuminemic patients. The production rate of IDL–apoB and LDL–apoB was also increased, whereas the catabolic rate of all lipoproteins was decreased. The PR and FCR of apoAI in HDL were not altered in analbuminemia. Changes in plasma lipids and differences in lipoprotein composition are similar to those found in a previous study22 in which these two patients were compared with a control group made up of women. Our five control subjects were men, and gender differences could have affected plasma lipid levels since estrogen lowers the level of LDL and raises that of HDL.23 Nevertheless, kinetic studies using normolipidemic men and women as control subjects have not shown any differences in apoB synthesis24 25 26 or HDL–apoAI catabolism,27 the main kinetic disturbances observed in this study.
Plasma leucine kinetics is commonly accepted as a good index of whole-body protein breakdown, and no difference in the total leucine flux was observed between patients and control subjects. Tracer/tracee ratios in plasma free leucine remained stable all through the study in patients and control subjects, showing that they were in steady-state condition. This suggests that the body could maintain a constant whole-protein breakdown. Nonoxidative leucine disposal, an index of whole-body protein synthesis, was not measured in the current study. However, because our patients had (1) a stable body weight and a presumably normal body protein store and (2) a normal rate of protein breakdown, it is unlikely that they had any alteration in their rate of whole-body protein synthesis. This is somewhat surprising since the synthesis of albumin represents a sizable fraction of overall protein synthesis.28 Kinetic disturbances of lipoprotein metabolism have been previously documented in nephrotic syndrome,7 9 29 30 31 another condition associated with low serum albumin levels. Although the albumin level is usually not as low compared with analbuminemia, it was never defined whether the hyperlipoproteinemia was a consequence of low plasma albumin level or of the urinary loss of factors regulating lipid metabolism. Because there is no proteinuria in inherited analbuminemia, this latter disease may be a good model to dissect out in the nephrotic syndrome, the role of low albumin plasma level per se in the regulation of apolipoprotein metabolism.
In vitro studies using liver slices or perfused liver from nephrotic rats have shown an increase in hepatic lipoprotein production.10 32 33 34 35 The high rate of VLDL production was related to hypoalbuminemia because similar results were reported in analbuminemic rats.6 35 36 The precise mechanism is not fully understood, but changes in oncotic pressure are probably involved since, like albumin, dextran and other oncotically active macromolecules are equally effective in correcting this abnormality.37 38 This effect of albumin probably occurs at a posttranscriptional level39 40 because no changes of mRNA apoB have been reported.41 Besides, it was recently shown that a low albumin concentration in HepG2 medium culture increased apoB synthesis and decreased LDL uptake, while apoAI secretion was unchanged.42 Our findings are very similar to these in vitro observations and highlight the key role of albumin in specific hepatic protein synthesis.
In the two analbuminemic patients, we observed increased production of VLDL–apoB compared with control subjects. The larger production observed in patient 2 compared with patient 1 could be related to the higher body mass index of patient 2, as previously reported.43 This increased production of apoB is similar to earlier data reported for patients with nephrosis.9 31 Because no proteinuria was found in our patients, these data collectively suggest that a low plasma albumin level may be one key determinant of VLDL overproduction in nephrotic syndrome. The delayed clearance of VLDL lipoproteins observed in our two patients differs from previous data reported in Nagase rats in which catabolism of the TG-rich particles was not impaired.6 This result in Nagase rats was surprising since a decrease in lipoprotein lipase activity was reported in these animals6 and therefore a delayed clearance should be expected. Our data are in good agreement with those of the endogenous apoB labeling study9 of human nephrotic syndrome and with previous observations of a delayed clearance of TG-rich particles in close relationship with a decrease in lipoprotein lipase activity.44 Because albumin increases lipoprotein lipase activity by binding free fatty acids, which are strong inhibitors of this enzyme, hypoalbuminemia could be a key factor in the low VLDL clearance.45 Another explanation for the delayed disappearance of VLDL could be related to their lipid composition since the same abnormalities were found in the analbuminemic and nephrotic patients.1 9 44 A higher ratio of cholesterol to TG in apoB-containing particles and an increase in the proportion of cholesterol ester relative to protein could explain the defective catabolism.46 47 However, the decrease in plasma albumin of nephrotic syndrome is not as high as observed in analbuminemia. Thus, it should be recognized that other factors, such as urinary loss of apoCII, could also play a key role in the decreased clearance of VLDL in nephrotic syndrome and could explain, at least in part, the high TG levels found in this kidney disease. The rate of production of IDL and LDL was dramatically increased in the analbuminemic patients. To our knowledge, the kinetic aspects of the metabolism of these two classes of lipoproteins had not been assessed before in analbuminemic animals or humans. In nephrotic syndrome, the increase of LDL production has been reported only in patients with combined hyperlipidemia, not in subjects with hypercholesterolemia only.7 A decrease in IDL and LDL removal was also observed in our analbuminemic subjects. Conflicting results were previously reported in nephrotic syndrome. Some studies have shown a decrease in LDL disappearance, whereas other studies have reported no abnormalities.7 8 9 29 30 31 In a recent study of nephrotic syndrome, this decrease in LDL clearance was related to the plasma TG level since patients with hypercholesterolemia alone showed a decreased clearance while patients with combined hyperlipidemia had a high FCR of apoB-containing particles.7 The similarities in the apoB kinetic disturbances and the fact that our patients had no large increase in plasma TG level suggested that they are probably similar to the nephrotic patients with hypercholesterolemia alone. This aspect of LDL catabolism rate may warrant further studies of the downregulation of LDL receptor. Because an increased production of cholesteryl-enriched apoB-containing particles was observed, a downregulation of LDL receptor could be expected because more cholesterol than normal was delivered to the liver; this decreased number of LDL receptors could, in turn, partly explain the defective catabolism of LDL.48 49 Another explanation for defective catabolism of LDL could involve a direct, specific effect of albumin, as previously suggested in vitro.42 Moreover, in our patients we cannot rule out an additional genetic defect on the apoB receptor, since two other members of the family who did not have analbuminemia presented with hypercholesterolemia. This association between analbuminemia and an apoB receptor defect has been reported in one family.50 Clearly, a molecular analysis could be useful for a better understanding of this defect in LDL clearance in our patients. Similar PRs and FCRs of apoAI in HDL were observed in analbuminemic patients and control subjects. We used a one-compartment model for analysis because a more complex model, previously used by Fisher et al,51 did not provide the best fit to the apoAI data. The model of Fisher et al was developed with data obtained over a very long time and included rises and falls in the tracer/tracee ratio in HDL–apoAI. We could not obtain reliable results by applying the model of Fisher et al to a constant tracer infusion over 14 hours. These data were similar to those of an in vitro study42 in which apoAI secretion from HepG2 cells was not altered by low albumin concentration in medium culture.
In conclusion, the findings of this kinetic study in two patients with analbuminemia confirm the finding of previous studies in cell culture and analbuminemic rats, that is, that a low plasma albumin level increases apoB production from the liver. However, we observed a decrease in the clearance of the TG-rich particles that was not reported in the analbuminemic rats. This kinetic profile of lipoprotein metabolism and the changes in lipid composition are similar to what has been reported for patients with nephrotic syndrome, especially patients with hypercholesterolemia alone. Our data suggest that the decrease in plasma albumin concentration per se may be responsible for apoB overproduction in nephrotic syndrome.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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We are grateful to Carole Le Valegant for excellent technical assistance. This study was supported in part by a research grant from Specia Laboratory (Rhone Poulenc-Rorer).
Received May 13, 1996; accepted October 9, 1996.
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References |
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