© 1997 American Heart Association, Inc.
Articles |
Lipid Binding of Apolipoprotein CII Is Required for Stimulation of Lipoprotein Lipase Activity Against Apolipoprotein CII–Deficient Chylomicrons
From the Department of Medical Biochemistry and Biophysics, Umeå University, Umeå, Sweden (G.O.), and the Department of Medicine, University Hospital Eppendorf, Hamburg, Germany (U.B.).
Correspondence to Gunilla Olivecrona, Department of Medical Biochemistry and Biophysics, Umeå University, S-901 87 Umeå, Sweden. E-mail Gunilla.Olivecrona{at}medchem.umu.se
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Abstract |
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Abstract Human apolipoprotein CII (apo CII) consists of 79 amino acid residues. The amino-terminal two thirds of the molecule binds to lipid through the formation of amphipathic helixes, while the carboxy-terminal third is engaged in activation of lipoprotein lipase (LPL). On the basis of studies in model systems, it was previously concluded that fragments of apo CII spanning residues 51-79 were sufficient for activation, although they do not bind to lipid. In the present study, we used chylomicrons from an apo CII–deficient patient to reinvestigate this possibility, with a physiologically relevant substrate. Human LPL expressed very low activity against these chylomicrons. Addition of apo CII caused an immediate >100-fold increase in lipase activity. The apo CII fragment 50-79 caused very little stimulation, though with some synthetic lipid substrates, this fragment was fully effective. LPL bound to the chylomicrons even in the absence of apo CII but apparently in a nonproductive manner. In accord with this finding, the main effect of apo CII was on the VMAX for the reaction, with little or no change in the apparent KM. We conclude that the lipid-binding part of apo CII is needed for activity of LPL against chylomicrons. This idea is in accord with previous studies with lipid monolayers, which showed that the lipid-binding part is necessary for activation of the enzyme at high surface pressures.
Key Words: apolipoprotein CII • lipoprotein lipase • chylomicrons • lipid binding
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Apolipoprotein CII (apo CII) plays an important role in plasma lipid metabolism as an activator for lipoprotein lipase (LPL).1 2 3 4 5 This fact is illustrated by the massive hypertriglyceridemia that is seen in individuals with inherited defects in the synthesis of apo CII.6 7 8 Infusion with normal plasma (ie, with apo CII–containing lipoproteins) can transiently normalize plasma triglyceride (TG) levels in these individuals.9 10 A number of mutations affecting the apo CII gene have been identified and characterized.7 All mutations that have been described so far result in either very low levels of plasma apo CII or major structural changes in the protein, eg, prematurely truncated forms. No single–amino acid substitution leading to the loss of apo CII activity has yet been reported.
Human apo CII contains 79 amino acid residues.11 Studies with fragments of apo CII have demonstrated that the carboxy-terminal third of the molecule contains the structures needed for interaction with LPL and for enzyme activation, whereas the amino-terminal part probably forms amphipathic helixes that "anchor" the protein to the lipid particle.3 12 Synthetic fragments of apo CII spanning residues 50-79 do not bind to liposomes or other lipid/water interfaces.12 13 14 Nevertheless, these fragments, and even shorter ones, are able to stimulate LPL activity.3 12 14 15 Studies of the solution structure of fragment 50-79 by two-dimensional proton nuclear magnetic resonance have shown strong potential for helix formation in a region spanning residues 55-77.14 This region is interrupted by a segment with less-defined structure around residues 60-65. Functional studies of very short fragments have indicated that the region around Tyr-63 is of crucial importance for activation of the lipase.3 12
The detailed mechanism of activation of LPL by apo CII is not yet well understood.3 4 5 Apo CII is an integral part of the lipoproteins, yet LPL can also bind to many types of lipid particles in the absence of apo CII.5 It is therefore assumed that interaction occurs after LPL has bound to the lipoprotein particle and that apo CII somehow changes the orientation of LPL with regard to individual lipid molecules in a favorable way.5 The dependence of the lipase on apo CII for activity varies with the nature of the lipid substrate.3 4 5 In most model systems, the enzyme exerts rather high activity even without apo CII.5 16 There are reports that indicate that this is also the case with apo CII–deficient lipoproteins.17 18 19 20 It is difficult to understand how such a moderate impairment of TG hydrolysis in apo CII–deficient individuals could cause the dramatic accumulation of TG-rich lipoproteins in the plasma. In three kinetic studies using apo CII–deficient lipoproteins,17 18 20 it has been concluded that the main effect of apo CII is to increase affinity of the enzyme for the lipid particles, which is expressed as a decrease in the apparent KM. This notion implies that at the very high substrate levels usually found in apo CII–deficient individuals, the impairment of lipolysis due to the lack of apo CII should be overcome.
In the present study, we used chylomicrons from an apo CII–deficient individual and intact apo CII, as well as fragment 50-79, to probe whether or not the lipid-binding ability of the activator is required for activation with this, the physiologically most relevant, substrate.
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Methods |
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Chylomicrons
Apo CII–deficient plasma was obtained from a previously described patient.21 She is homozygous for the apo CIIHamburg mutation, which leads to an almost complete lack of apo CII in the plasma and massive derangement of the lipoprotein pattern.10 The patient was on a fat-restricted diet and had no pancreatitis at the time of these experiments. Fasted blood was drawn into EDTA-containing tubes and plasma was isolated at 4°C. Chylomicrons were obtained as a floating layer after centrifugation (30 minutes, 30 000 rpm, 4°C). They were gently suspended in the original plasma volume of 10 mmol/L Tris-Cl–0.15 mol/L NaCl, pH 7.4, and then floated once again by centrifugation as described above. The lipid layer was recovered and again suspended in buffer. For one preparation all components were determined by weight: 80% TGs, 4.5% free cholesterol, 3.0% cholesteryl ester, 10.5% phospholipids, and 2.0% protein. In five other preparations TGs, total cholesterol, and protein were determined and found to have weight ratios of 90.8±1.4%, 7.7%±1.2%, and 1.5±0.8%, respectively (mean±SD). Plasma TG levels in the samples obtained from the patient ranged between 13.1 and 32.2 mg/mL. The chylomicrons were kept at a concentration of
20 mg/mL at 4°C and used
within 5 days. Lipids were determined by enzymatic
colorimetric assays from Boehringer Mannheim.
Protein was determined by the method of Lowry et
al.22
Apolipoproteins
Apo CII was isolated from human plasma by adsorption to a lipid
emulsion followed by delipidation and separation from other
apolipoproteins by gel filtration and ion-exchange
chromatography as described.23 Stock
solutions of the purified apolipoprotein were made in 5 mol/L
urea–10 mmol/L Tris-Cl, pH 8.2. The concentration of apo
CII was 0.5 mmol/L (=1/1). Dilutions were made in the
urea-containing buffer. Carboxy-terminal fragment 50-79 of human apo
CII was kindly synthesized by Dr D. Wernic at Bio Mega Inc, Quebec,
Canada, and was the same preparation as previously used.14
The numbers (50-79) refer to the residue sequence of intact apo CII,
which was identical to that previously reported for human apo
CII.11 The fragment was dissolved in the urea-containing
buffer at a concentration of 0.5 mmol/L (=1/1).
LPLs
Bovine LPL was purified from milk23 and labeled
with Na[125I] as previously described.24
Human LPL was partially purified from postheparin plasma by
affinity chromatography on
heparin-Sepharose.25
Conditions for Incubations
Incubations were carried out in a total volume of 1 mL, of which
0.5 mL was 12% BSA (Sigma, fraction V) in 0.3 mol/L
Tris-Cl–0.2 mol/L NaCl, pH 7.4, with 20 µg heparin per
milliliter (at room temperature). For each experiment, chylomicrons or
plasma was added to the indicated concentration of TGs. Intact apo CII
or fragment 50-79 was added in a total volume of 5 µL of the
urea-containing buffer. For incubations without apo CII or its
fragment, 5 µL of the same buffer was used. Control experiments
showed that this amount of urea (25 mmol/L) had no effects
on the reaction. The volume was made up to 1 mL with water, and the
mixtures were preincubated for 5 to 15 minutes at 25°C before
addition of LPL. For each experiment, parallel incubations were made
without lipase. No significant lipolysis occurred in these samples. The
reactions were stopped at the indicated times by addition of organic
solvents, and the fatty acids were extracted and manually
titrated.26 Data points are the mean of duplicate
incubations. All experiments were repeated at least once with a
different batch of chylomicrons and with consistent results.
Owing to the variation in absolute numbers between experiments, only
data from a single experiment are shown. The intra-assay variation was
5%. One unit of lipase activity corresponds to the release of
1 µmol fatty acid per minute. The phospholipid-stabilized TG
emulsion Intralipid (10%) was from KABI-Pharmacia Parenterals.
Binding Experiments
Incubation mixtures of the same composition as detailed above
were incubated for 10 minutes at 25°C with 125I-labeled
LPL (20 000 to 100 000 counts per minute, corresponding to 2 to 10
ng). The total volume was 0.5 mL. Then 0.5 mL of 60% (wt/vol) sucrose
was added. The mixture was layered under 1 mL of 15% sucrose in 6%
BSA, 0.15 mol/L Tris-Cl, and 0.1 mol/L NaCl, pH 7.4, with
10 µg heparin per milliliter in centrifuge tubes (Beckman SW
60 rotor). The tubes were filled with a top layer of the same
composition but without sucrose (1.6 mL). After
centrifugation for 2 hours at 4°C (38 000 rpm), the
tubes were sliced into three layers of identical height (top, middle,
and bottom). Radioactivity in all fractions was counted and the sum was
set to 100%. The radioactivity in the top layer, containing the
floating lipid, is shown. The calculated recovery of radioactivity was
>90%.
Data Analyses
Data were analyzed by nonlinear regression using the
FIG.P program (BIOSOFT).
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Results |
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Bovine LPL exerted low, but significant, activity against the patient's chylomicrons. In several different experiments, this activity ranged from 1% to 5% of that obtained in the presence of optimal amounts of apo CII. Although not systematically studied, some variation in this basal activity was noted (data not shown). This result could have been due to differences in the particle composition and size, depending on the patient's nutritional status, which was not controlled. The basal activity appeared to increase slightly after storage of the chylomicrons at 4°C. A similar variation was noted for the level of lipolysis in whole plasma when LPL was added after storage (data not shown). Therefore, the chylomicrons were used for experiments within 1 week.
Fig 1
shows the effect of adding apo CII
to ongoing incubations of LPL with the patient's plasma (Fig 1, left)
or with isolated chylomicrons (Fig 1, right). The stimulatory effect
was immediate; other experiments showed that stimulation was obtained
within seconds. The degree of stimulation by intact apo CII was 25- to
30-fold. In contrast, addition of the same molar amount of fragment
50-79 caused a less-than-threefold increase in the reaction rate.
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) or apo CII fragment 50-79 (
), both at a concentration of
2.5 µmol/L.
In the next experiment, we studied the effect of increasing
concentrations of intact apo CII or of the fragment in incubations with
chylomicrons and either bovine or human LPL. The human lipase
consistently showed lower basal activity (in the absence of apo
CII) than did bovine LPL. In the experiment shown in Fig 2, the basal activity of human lipase was
almost zero. The relation between activation and concentration of
intact apo CII was similar for the two lipases. Half-maximal
stimulation was obtained with 0.1 µmol/L apo CII. With
fragment 50-79, in contrast, no stimulation was seen at this
concentration. With the two lowest dilutions of the fragment (1/5 and
1/1, corresponding to 0.5 µmol/L and 2.5
µmol/L, respectively), some stimulation was seen with both
lipases. Thus, there was a dramatic difference in the apparent affinity
of the LPLs for the fragment compared with the apparent affinity for
intact apo CII. In incubations under the same conditions but with the
synthetic phospholipid-stabilized TG emulsion Intralipid as the
substrate, the difference in apparent affinity was 30-fold (Fig 3). In contrast, with other test systems,
the fragment was as effective (on a molar basis) as intact apo
CII.14
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Fragment 50-79 lacks the lipid-binding part of apo CII and is therefore
not bound to lipid.14 27 The weak effect of the fragment
could be explained if stimulation with chylomicrons involved anchoring
of the lipase to the lipoprotein particle mediated by apo CII. We
therefore studied the binding of 125I-labeled bovine LPL to
the apo CII–deficient chylomicrons, with or without apo CII or the
fragment (Table). Binding in the absence
of apo CII was at least as high as that with Intralipid (50±7.3%
compared with 41±5.8%), and binding in both cases was moderately
stimulated by the presence of intact apo CII or the fragment. Thus, the
>20-fold increase in lipase activity against chylomicrons by apo CII
could not be explained by increased binding. A similar conclusion was
previously reached in binding experiments with
Intralipid28 and in those by Haberbosch et
al19 using apo CII–deficient chylomicrons as the
substrate.
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To obtain more information on the effect of apo CII with the patient's
chylomicrons as the substrate, we studied the dependence of the
lipolysis rate on the substrate concentration in incubations with a
10-fold difference in the amounts of apo CII (Fig 4A). The apo CII concentrations were
chosen to allow maximal and approximately half-maximal activity of the
lipase. The calculated KM values for TGs were
0.31 and 0.37 mg/mL, respectively. Thus, there was little or no
difference in the apparent substrate affinity of the lipase at the two
different concentrations of apo CII. The effect of apo CII appeared to
be mainly on the maximal catalytic rate (apparent VMAX) of
the lipase. In the experiment shown in Fig 4A, the total concentration of apo CII in
the system was held constant at all substrate concentrations. In the
experiment shown in Fig 4B, the relation between apo CII and the amount
of lipid (the surface concentration) was held constant for each
substrate curve. Thus, 8-fold more apo CII was added at 4 than at 0.5
mg TG per milliliter. The calculated apparent substrate affinity
(KM) was similar at higher apo CII–to-lipid
ratios (0.52, 0.51, and 0.62 mg/mL, with 2200, 733, and 244 ng
apo CII per milligram TG), but at the lowest ratio (82 ng apo CII per
milligram TG), the calculated apparent KM was
somewhat increased (1.33 mg/mL). Thus, we cannot exclude the
possibility that apo CII has some effect on the substrate affinity of
LPL, but the main effect appears to be on the maximal catalytic rate.
These results are in concert with the binding experiment (Table
).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The apo CII–deficient patient whose plasma was used in this study has a G-to-C substitution within the donor splice site of intron 2 in the apo CII gene (apo CIIHamburg).21 The patient is homozygous for this mutation and expresses low but significant amounts of apo CII, as detected by either immunoassay or two-dimensional electrophoresis.10 21 We have not directly studied whether the apo CII isolated from this patient is functional. We have demonstrated here that the activity of bovine LPL against chylomicrons from this individual was low. With human LPL, the activity was almost undetectable. This finding is in accord with the severe accumulation of plasma TGs that is seen in patients who are homozygous for this and other apo CII mutations. Such patients have symptoms resembling those seen in patients with complete LPL deficiency.7 Heterozygotes for apo CII deficiency usually have normal lipid levels in plasma, which demonstrates that apo CII is normally present in excess.7
With most model systems used for in vitro studies of LPL (emulsions, liposomes, and monolayers), the basal activity of the enzyme is higher than that obtained here with the apo CII–deficient chylomicrons. It follows that the enzyme under such conditions is less dependent on apo CII. This result was also previously reported with lipoproteins isolated from apo CII–deficient patients.17 18 19 20 In these studies the degree of maximal stimulation by apo CII was only 3- to 8-fold the basal activity. Human LPL has lower basal activities against model substrates than does bovine LPL.29 30 This difference in activity was also found in our present study with apo CII–deficient chylomicrons as the substrate. The molecular explanation for this difference is unknown.
We demonstrate here that apo CII fragment 50-79 is unable to effectively stimulate the action of LPL against chylomicrons. This finding is in sharp contrast to what has been previously found in studies with synthetic lipid substrates3 31 and even with apo CII–deficient VLDL.17 It appears as though the nature of the substrate as well as the physicochemical environment are both capable of influencing the ability of apo CII fragments to serve as effective stimulants of LPL. In monolayer studies, increasing the surface pressure to >28 mN/m inhibited the ability of fragments 51-79 and 56-79 to activate LPL.32 Vainio et al13 reported similar results with apo CII fragment 56-79. In a follow-up study by Balasubramaniam et al,15 the stimulating activity of fragment 56-79 could be restored by acylation of its amino terminus with a palmitoyl chain. They concluded that the lipid-binding region of apo CII plays an essential role in activation of LPL at high surface pressures. Because fragment 50-79 was almost ineffective with chylomicrons as the substrate, it can be speculated that the surface pressure on chylomicrons is higher than that for most synthetic lipid substrates and is also higher than that for VLDL.
Jackson and his collaborators used both triacylglycerol-rich lipoproteins from an apo CII–deficient patient20 and apo CII–deficient VLDL (Matsuoka et al18 ) in their studies of the mechanism of the stimulation of LPL by apo CII. In both studies they concluded that the stimulation was mainly due to a decrease in the apparent KM for the substrate particles, with little or no effect on the maximal catalytic rate of the enzyme (VMAX). These findings contrasted with what they and others found using synthetic lipid substrates, where the main effect appeared to be on VMAX rather than on the apparent KM.20 The previous results with apo CII–deficient lipoproteins, with the exception of the study by Haberbosch et al,19 implied that the main effect of apo CII would be to increase substrate affinity by anchoring the lipase to the lipid particles. We found herein with apo CII–deficient chylomicrons that LPL bound to the particles, even in the absence of apo CII. In concert with this finding, the overwhelming effect of apo CII was on the VMAX of the reaction. The conclusion from our data is that with chylomicrons as the substrate and under conditions that mimicked the physiological situation, the lipid-binding amino-terminal region of apo CII has a clear function for lipolysis. It is possible that fragment 44-79 is sufficient for this function, since Baggio et al9 reported that infusion of 18 mg of this fragment to an apo CII–deficient patient lowered plasma TG levels for several days Furthermore, fragment 44-79 showed increased helicity in the presence of phospholipids, whereas shorter fragments did not.33 In the study with lipid monolayers, Jackson et al32 found that fragment 44-79 was as efficient as intact apo CII in stimulating LPL at high surface pressures, whereas fragments 51-79 and 56-79 were inefficient. Taken together, these studies suggest that the lipid-binding potency of amino acid residues 44-50 is crucial for the physiological function of apo CII.
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Acknowledgments |
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This work was supported by grants from the Swedish Medical Research Council, by the Bank of Sweden Tercentenary Foundation, and by a BIOMED program grant from the European Community (No. PL921243).We are grateful for the technical assistance of Ann-Sofie Jakobsson and Solveig Nilsson.
Received January 26, 1996; accepted August 30, 1996.
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