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					CLIN.CHEM.38/6, 793-797 (1992)

Apolipoprotein A-Containing Lipoprotein Particles: Physiological Role, Quantification,
and Clinical Significance
J. C. Fruchart’ and G. Ailhaud2

High-density lipoprotein (HDL) particles are made up of                        On the basis of their hydrated density, two main sub-
two major populations of particles, differing in composition                   fractions have been identified: HDL2 and HDL3 (4); each
and metabolism. Both contain apolipoprotein (apo) A-I but                      of these subfractions can be further fractionated      into
only one contains apo A-Il. Lipoprotein particles that                         discrete subclasses by different techniques (5, 6).
contain only apo A-I (LpA-l particles) can increase cellular                      Some    authors    have suggested that   the low HDL
cholesterol efflux from cultured cells in vitro. LpA-I:A-ll                    concentrations     observed in CAD were mainly    due to a
particles, however, do not increase cholesterol efflux.                        decrease    of HDL2 and particularly   of the subfraction
LpA-l:A-lI can be determined directly with an enzyme-                          HDL2b (7).
linked differential antibody immunosorbent assay. LpA-l is                       HDL metabolism        has not yet been     fully   characterized,
determined by differential electroimmunoassay: in the                          and no specific functions     have been assigned to the HDL
presence of a large excess of anti-apo A-lI, LpA-I:A-ll                        subfractions, which are      defined by physical ultracentrif-
particles are retained in one peak, whereas LpA-l mi-
                                                                               ugal flotation criteria.      HDL particles apparently            are
grates as a second peak. Both lipoprotein forms of apo                         produced in the liver        and the intestine (8) and are
A-I-containing particles are present mainly in HDL, but the
                                                                               continuously      being  converted    in plasma (3, 5). More-
relative proportion of LpA-l is greater in HDL2 than in                        over, surface material derived from the catabolism of
HDL3. Concentrations of LpA-l in plasma samples from
                                                                               triglyceride (TG)-rich lipoproteins appears to contribute
normolipemic subjects average -10% higher in women                             to their synthesis (9). Several studies have shown that
than in men. The lower ape A-I concentrations in patients                      HDL can promote reverse cholesterol           transport,    a chain
with significant coronary artery disease reflect a decrease                    of metabolic reactions that remove excess cholesterol
in the LpA-I particles. Data obtained in octogenarians also
                                                                               from peripheral tissues and transport             cholesterol, di-
support the possibility that LpA-l might represent the
                                                                               rectly or indirectly, with other lipoproteins to the liver
anti-atherogenic fraction of HDL. Moreover, the concen-
                                                                               (10, 11). This process involves several steps. Interactions
tration of LpA-l in children of parents with premature
                                                                               between HDL3 and HDL-binding               sites are generally
coronary heart disease was lower than that of a control
                                                                               believed to facilitate egress of cholesterol from cells to
group without any family history of this disease. Nutrients
                                                                               the plasma lipoproteins        (12, 13) and particularly         to a
and hypolipidemic drugs seem to affect the two kinds of                        small pre-f3-migrating HDL (14). This incorporation of
particles differently.                                                         free cholesterol into acceptor lipoproteins,           facilitating
Additional   Keyphrases:    sex- and age-related         effects   .   heart
                                                                               its esterification by lecithin:cholesterol        acyltransferase
disease      cholesterol transport   .   dyslipoproteinemia                    (LCAT, phosphatidylcholine-sterol          acyltransferase,       EC
                                                                      and cholesteryl ester transfer protein (CETP),
   Epidemiological and clinical studies showing an asso-                       mediates transfer to very-low-density           lipoproteins and
ciation between decreased concentrations of high-densi-                        exchange for TG (15, 16).
ty-lipoprotein (HDL) cholesterol and increased risk of                            In this complex pathway, reverse conversion of HDL2
premature coronary artery disease (CAD) (1, 2), have                           and HDL3 takes place. Supply of surface material con-
generated interest in the mechanism through which                              verts small, dense HDL3 to HDL2, whereas the action of
HDL prevents atherosclerosis.3                                                 hepatic lipase (EC on TG-rich HDL2 causes
   Human HDL consists of a collection of particles dif-                        reverse conversion      of HDL2 to HDL3 (17).
fering in size, density, and apolipoprotein content (3).                          LCAT deficiency leads to an increase of HDL3 in
                                                                               plasma      (18); CETP deficiency induces an increase of
   1 SERLIA  et INSERM U325, Institut    Pasteur,   1,   rue   du Pr. Cal-     HDL and particularly         of cholesteryl ester-rich HDL2
mette,   59019 Lille Cedex, France.                                            (19); hepatic lipase deficiency results in the accumula-
   2                                            des
             de Biochimie du CNRS, Facult#{233} Sciences, Parc
                                                                               tion of TG-rich HDL2 (20).
Valrose, 06108 Nice Cedex 2, France.
   3Nonstandard     abbreviations: HDL, high-density lipoprotein;                 Recent studies with selected imznunosorption                 tech-
apo, apolipoprotein; LpA-I, lipoprot.ein containing apo A-I; LpA-              niques designed to isolate subpopulations of lipoproteins
I:A-il, lipoprotein containing both apo A-I and apo A-il; TG,                  have shown that HDL cannot be regarded as homoge-
triglyceride; CAD, coronary artery disease; CETP, cholesteryl                  neous particles containing apolipoproteins           (ape) A-I and
ester transport protein; and LCAT, lecithin:cholesterol acyltrans-
ferase.                                                                        A-U. The distribution of particles within HDL is heter-
   Received March 25, 1991; accepted January        9, 1992.                   ogeneous not only with respect       to their hydrated density

                                                                                               CLINICAL CHEMISTRY, Vol. 38, No. 6, 1992              793
but also in relation to their apolipoprotein composition            metabolic entity, have been confirmed in other studies
(3, 21, 22). It is now recognized that HDL contains at              (36,37).
least two types of ape A-I-containing      lipoprotein parti-          The ligands that recognize the cell surface HDL-
cles, which might have different metabolic functions                binding sites have been identified as ape A-I, ape A-N,
(23, 24) and clinical significance   (25). One species con-         and ape A-il (38,39). We proposed (39) that ape A-I and
tains as the main protein components both ape A-I and               ape A-N play the role of agonists and ape A-il that of
A-il (LpA-I:A-il); in the other species, ape A-Il is absent         antagonist of cholesterol efflux. Slotte et al. (40) sug-
(LpA-I). The definition of such lipoprotein particles by            gested that adding HDL3 to human fibroblasts or bovine
their apolipeprotein content has been proposed to be                endothelial cells induces a protein kinase C-dependent
more appropriate for studying the chemical complexity               translocation   of cholesterol from intracellular    mem-
and metabolic functions of the plasma lipoprotein        sys-       branes to the cell surface. We recently demonstrated
tem.                                                                (37) that cholesterol efflux from adipose cells is coupled
   Our purpose in this review is to describe     the recent         to diacylglycerol production and protein kinase C acti-
progress made in isolation, characterization,    quantifica-        vation. The fact that the binding of ape A-Ildimyris-
tion, and determination     of the clinical significance       of   toylphosphatidylcholine    complexes, but not that of ape
LpA-I and LpA-I:A-II.                                               A-Hldimyristoylphosphatidylcholine       complexes,   pro-
                                                                    duces diacylglycerol strongly supports the role of ape
Isolation and Composition of LpA-I and LpA-I:A-lI                   A-U as an antagonist in the production of cholesterol
   LpA-I and LpA-I:A-il are currently purified from total           efflux. In support of this interpretation, we recently
plasma by sequential immunoaffinity      chromatography             showed (35) that LpA-I:A-il can inhibit the LpA-I-
(22,26,27).   Some authors do not find any difference in            promoted cholesterol efflux of cholesterol-preloaded ad-
lipid composition between LpA-I and LpA-I:A-il (22),                ipose cells.
but others have claimed that the percentage      of TG and
the cholesteryl ester/total cholesterol ratio are lower in          Quantitative Determination of LpA-I and LpA-I:A-lI
LpA-I than in LpA-I:A-il (27-29). The lipid/protein ratio              Several methods have been developed for direct quan-
appears to be higher in LpA-I than in LpA-I:A-il (28).              tification of ape A-I-containing particles in human
The molar ratio of ape A-I to ape A-il in LpA-I:A-il is             plasma: immunoprecipitation (41), two-phase electroim-
1.5. Small quantities of ape A-IV, Cs, D, E are found in            munoassay (42), and enzyme-linked differential-anti-
both fractions (30,31).                                             body immunosorbent assay (26). These methods are well
   Of considerable significance is the finding that pro-            adapted for use in research laboratories but are time-
teins stimulating reverse cholesterol transport (LCAT,              consuming and inaccurate. The recent development of a
CETP) and other proteins such as ape J are mainly                   differential electroiminunoassay    allows the direct mea-
present in LpA-I and not in LpA-I:A-fl (23,30,32).                  surement of LpA-I. By using a large excess of anti-A-il
                                                                    antibodies,  LpA-I:A-II particles are retained in one peak
Physiological Role in LpA-l and LpA-I:A-II                          and LpA-I migrates as a second peak (43). This new
   Our understanding     with respect to the metabolism of          system can provide specific and reproducible determina-
ape A-I-containing       particles is limited. However,             tions of LpA-I in human plasma.
Brewer et al. (28) have shown recently that both ape-
lipeprotein particles are synthesized by the liver but              Clinical Significance of LpA-I and LpA-I:A-II Measurements
that LpA-I particles are produced by the intestine only.               Coronary Artery Disease. Concentrations of LpA-I but
The metabolic interrelationship between the two sub-                not LpA-I:A-il were lower in normolipemic patients
populations is not well established, but apparently                 with angiographically documented       CAD (44) than in a
LpA-I particles are catabolized at a faster rate than are           group of asymptomatic subjects and a group of patients
LpA-I:A-il particles (33). One of the key questions is              with arteriographically normal coronary arteries (25).
whether LpA-I and LpA-I:A-il have different physiolog-              However, in a similar study where the patient group
ical roles (34).                                                    had higher TG concentrations than the control subjects,
   To gain some insights into the mechanisms      by which          we found that both LpA-I and LpA-I:A-il were dimin-
cholesterol movement takes place in peripheral cells,               ished in CAD patients to a similar degree [one can
researchers have used cultured adipose cells as a model.            postulate that the decrease in LpA-I:A-il particles in
Indeed, the fact that adipose tissue has the ability to             hypertriglyceridemic     patients may be related to the
accumulate, store, and, when needed, mobilize a large               decreased formation of such particles during lipelysis
pool of unesterified   cholesterol means that these cells           (45, 46)]. A recent study of patients before coronary
meet the requirement for the study of reverse choles-               bypass surgery concluded that their concentrations of
terol transport (29). In studies of cholesterol efflux              both LpA-I and LpA-I:A-II were lower than in control
mediated    by ape A-I-containing particles in mouse adi-           subjects (46). However, discrimination analysis indi-
pose cells, after cholesterol preloading with low-density           cated that LpA-I was the more powerful discriminating
lipeproteins, long-term exposure to LpA-I particles pro-            factor in this hypertriglyceridemic population.
moted cholesterol efflux, whereas no efflux was observed               A case control study of ape A-I-containing particles
in the presence of LpA-I:A-II (35). These results, which            has been performed in three populations with contrast-
emphasize that LpA-I:A-U particles behave as a distinct             ing risks for CAD (ECTIM Study) (47). Male patients

794                    V
      CLINICALCHEMISTRY, ol.38, No.6, 1992
with myocardial         infarction     and control subjects were     preliminary    results obtained    in clinical and epidemio-
recruited in two French centers (Strasbourg              and Tou-    logical studies, it is obviously interesting to study the
louse) and a Northern           Irish center (Belfast). The stan-    effect of drug therapy on lipeprotein particles as defined
dardized mortality rates in Belfast, Strasbourg, and                 by their apolipeprotein composition. Two main ques-
Toulouse were respectively 348, 102, and 78 per 100 000              tions may be raised concerning the effect of drugs: Do
for the tested population. LpA-I and LpA-I:A-il concen-              compounds     with various mechanisms         of action lead to
trations were lower in the patients than in the control              different effects on ape A-containing particles? Is there
subjects, but the difference in LpA-I concentrations                 any relationship between      the pharmacological modula-
between the three populations was statistically signifi-             tion of a particular lipeprotein family and the change in
cant: LpA-I for the controls and the myocardial infarc-              cardiovascular morbidity and mortality? We now have
tion cases was much lower in Belfast than in the French              additional information to more accurately answer the
centers. In this study, the multivariate analysis sug-               first question, but further investigation is certainly
gested that the LpA-I/HDL cholesterol ratio was very                 needed to answer the second one.
significant.                                                             Atmeh et al. (42) showed that LpA-I may be increased
   Recently it has been also observed that the concentra-            by the use of nicotinic acid, whereas probucol leads to a
tion of LpA-I (but not of LpA-I:A-il) in children whose              decrease    in this particle. In contrast,       nicotinic     acid
parents have a premature form of CAD is lower than in                decreased LpA-I:A-il, and probucol had no major effect
a control group with no familial history of CAD                      on its concentration. We have recently shown (Table 1)
(Amouyel, Isorez, Bard, Goldman, Zylberberg, and Fru-                that fenofibrate decreases LpA-I and increases LpA-I:A-
chart, ms. submitted). The relevance of these observa-               il, whereas hydroxymethylglutaryl-CoA             reductase     in-
tions requires further investigation.                                hibitors (simvastatin      and pravast.atin), as well as
   Longevity.    Assuming that octogenarians, who have               cholestyramine, increase both particles (55-58). Also,
survived    periods of life during which the incidence of            we recently found (unpublished data) that estradiol may
CAD is very high, should have several protective factors             increase   the LpA-I concentration in postmenopausal
against CAD, we compared in octogenarians                     and    women without altering the LpA-I:A-il concentration.
younger control subjects (ages 30-50 years) the concen-              Because it has been suggested that LpA-I may represent
trations of ape A-I-containing particles: LpA-I was sig-             the particle that is involved in cholesterol efflux from
nificantly increased and LpA-I:A-il was clearly lower in             peripheral cells, we speculate that the increasing effect
the octogenarians (48).                                              on LpA-I may petentiate the beneficial cardiovascular
   Brewer et al. (28) investigated LpA-I and LpA-I:A-il              effect of low-density lipoprotein cholesterol reduction
in a kindred with hyperalphalipeproteinemia                and de-   also seen with these compounds. Inversely, the decreas-
creased risk of CAD. The selective increase in LpA-I in              ing effect obtained with fenofibrate might be considered
the 60-year-old putative homozygote proband with a                   as a potentially harmful effect. However, kinetic studies
family history of longevity supports the concept that                are necessary to determine whether the increasing ef-
these particles may represent the anti-atherogenic frac-             fect of the hydroxymethylglutaryl-CoA         reductase     inhib-
tion of HDL.                                                         itors and cholestyramine        is due to oversynthesis          or
   Dyslipoproteinemias.         Some dyslipoproteinemias have        undercatabolism and whether the decreasing effect of
specific profiles of ape A-I particles. For instance, type           fenofibrate is due to undersynthesis or overcatabolisin.
ifi dyslipeproteinemia,         a disorder with accelerated ath-     The clinical importance of the effect of drugs on LpA-I
erosclerosis, is characterized         by a decrease of LpA-I and    may depend on these findings.
an increase of LpA-I:A-il (49, 50). Non-insulin-depen-
dent diabetes mellitus is characterized by a specific                   The introduction of new immunological methods that
decrease in LpA-I (51). The HDL decrease observed in                 allow the separation of various ape A-I-containing lipo-
patients with chronic renal failure who have to undergo
hemodialysis is mainly due to a decrease in LpA-I:A-il                 Table 1. Changes In Apo A-i-Containing Lipoprotein
(52).                                                                           PartIcles under Different Therapies
  Diet.   Diet also modifies LpA-I concentration. In a
                                                                                                                       Cones, mgL
study of the effect on LpA-I of a high polyunsaturated/
saturated   fatty acid ratio (53), a ratio value of 1.1 led to        Drug Trsstm.nt               Base              Wisk 6(8)               Week     10(12)

a decrease in LpA-I in comparison with a ratio of 0.2.               LpA-I
Chronic alcohol consumption was shown to lead to an                  Simvastatin                    440                 +25’
increase in LpA-I:A-il, whereas LpA-I decreased (54);                Fenofibrate                    440                -128’                    _151b

moderate alcohol intake, however, increased both types               Cholestyramine                 450               (+217                    (+151’)
of these particles (W. Valmaki et al., Arteriosclerosis, in          Pravastatin                    430               (+130                      (+48)
press). The interpretation of such changes is difficult              LpA-I:A.I!
because the decrease in LpA-I may be due to overcatab-               Simvastatin                    860                 +54                         +18
olism or undersynthesis. Only kinetic studies can an-                Fenofibrate                    780                +l39b                    +223’

swer this crucial question, and the clinical importance              Cholestyramine                 930               (+ 118)                  (+412
                                                                     Pravastatin                    960               (+249’)                  (+326’)
of this effect may depend on this mechanism.
                                                                       Significantly different from baseline:   ‘P   <0.05,   b   P <0.01 (Wllcoxon test).
   Effects of drugs on apo A-I particles. Considering the

                                                                                        CLINICALCHEMISTRY, ol. 38, No. 6, 1992 795
protein particles reveals the existence of subpopulations                  istics of human lipoproteins     isolated by selected affinity immu-
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                                                                           proteins. J Lipid Res 1986;27:1135-44.
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796       CLINICAL CHEMISTRY, Vol.38, No. 6, 1992
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