Department of Medical Biochemistry and Biophysics, Umeå University, S-901 87 Umeå, Sweden
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ABSTRACT |
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Several laboratories have shown that when rats are fasted, the amount of lipoprotein lipase (LPL) at the vascular endothelium in heart (monitored as the amount released by heparin) increases severalfold without corresponding changes in the production of LPL. This suggests that there is a change in endothelial binding of LPL. To study this, 125I-labeled bovine LPL was injected. The fraction that bound in the heart was more than twice as high in fasted than in fed rats, 4.3% compared with 1.9% of the injected dose. Refeeding reversed this in 5 h. When unlabeled LPL was injected before the tracer, the fraction of 125I-LPL that bound in heart decreased, indicating that the binding was saturable. When isolated hearts were perfused at 4°C with a single pass of labeled LPL, twice as much bound in hearts of fasted rats. We conclude that fasting causes a change in the vascular endothelium in heart such that its ability to bind LPL increases.
perfusion; heparin; labeled lipase; lactoferrin; tissue distribution; lung
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INTRODUCTION |
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LIPOPROTEIN LIPASE (LPL) hydrolyzes triglycerides in plasma lipoproteins and thereby makes the fatty acids available for energy production, storage, or other metabolic reactions (19, 21, 31). Parenchymal cells in several tissues synthesize the enzyme (12). After processing and maturation into its active form, the enzyme is released from the cells and transported to the endothelium, where it becomes attached through interaction with oligosaccharide chains of heparan sulfate proteoglycans (10, 31). LPL can be released from the endothelium by heparin, and this has been used to evaluate the amount of LPL that is located there (8, 9, 25, 27, 35). On fasting, this amount decreases in the adipose tissue and increases in heart and red muscles (25). In adipose tissue this change in LPL activity is brought about by a posttranslational mechanism that determines whether newly synthesized LPL molecules will be processed into an active form (6, 18). This mechanism does not seem to operate in the heart (4, 6). Here, there is little or no change in total activity (8) or in LPL mRNA or mass (6) during fasting, but perfusion with heparin demonstrates a large increase in the amount of LPL at the endothelium (9, 25, 27, 35). After the perfusion the heart has much reduced ability to degrade lipoproteins, indicating that the LPL that is available for release by heparin is also the LPL that is available for interaction with lipoproteins from blood ("functional LPL") (9, 35).
A possible explanation for the increased functional pool of LPL in heart during fasting would be an increased number or affinity of endothelial binding sites for the enzyme. If so, LPL transferred from parenchymal cells to the endothelium should remain longer in the heart before it escapes into the circulating blood, and more LPL from blood would bind in the heart. Iodinated LPL has previously been used to study the binding of LPL in cell culture systems (33, 37), in tissue perfusion (14, 16), and in whole body experiments (44). The latter studies showed that the enzyme is rapidly cleared from blood. About 40% located in the liver, where the enzyme loses its activity and is degraded (16, 42, 44). The enzyme that located in extrahepatic tissues, on the other hand, retained its activity and could be released back to blood by heparin (44), suggesting that it had bound to normal sites for functional LPL. In the present study, we first compared the binding of injected 125I-LPL in tissues of fed and fasted rats. There was a marked increase of binding in hearts of fasted rats, and we have characterized this in some detail. We have also studied binding of the enzyme in perfused hearts.
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MATERIALS AND METHODS |
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Materials. Heparin (5,000 IU/ml) was from Lövens (Malmö, Sweden), Hypnorm was from Jansen (Bersee, Belgium), and midazolam (Dormicum) was from Roche, Switzerland. Leupeptin and pepstatin were from The Peptide Institute (Osaka, Japan). Bovine serum albumin (BSA), bovine lactoferrin, aprotinin (Trasylol), and Triton X-100 were from Sigma (St. Louis, MO).
Buffers . Medium A, used for heart perfusions, contained (in mM) 136 NaCl, 5.4 KCl, 0.81 MgSO4, 0.98 MgCl2, 0.44 KH2PO4, 1.33 Na2HPO4, 1.3 CaCl2, 5 glucose, 10 HEPES, and 1% BSA, pH 7.4. Buffer B, used for protein labeling, contained 20 mM Tris, 20% glycerol, and 0.1% Triton X-100 (pH 7.4). Buffer C, used for the stock solution of bovine LPL, contained 10 mM Bis-Tris and 1 M NaCl, pH 6.5. Buffer D, used to prepare tissue homogenates, contained 25 mM NH3, 5 mM Na2EDTA, and per ml 10 mg BSA, 10 µg leupeptin, 1 µg pepstatin, 25 kallikrein inhibitor units Trasylol, 10 mg Triton X-100, 1 mg sodium dodecylsulfate, and 5 IU heparin, pH 8.2. HCl was used to adjust the pH.
Preparation of 125I-labeled LPL and lactoferrin.
LPL, which was purified from bovine milk (1) and stored in
buffer C, and lactoferrin were radiolabeled according to the lactoperoxidase/glucose oxidase method as described in Ref. 44. The
reaction mixtures were applied to heparin-Sepharose columns (3 ml) to
separate the proteins from unreacted iodine. The columns were eluted
with linear salt gradients from 0.1 to 2.0 M NaCl in buffer B
(120 ml). For LPL, the fractions that contained the catalytically
active enzyme were collected. BSA was added to a final concentration of
2 mg/ml. The labeled preparations were stored at 70°C. The
specific activity for LPL was ~10,000
counts · min
1
(cpm) · ng
1.
Radioactivity was measured in a Wallac 1,480 WIZARD 3 gamma counter
(Turku, Finland).
Animal procedures. Male Sprague-Dawley rats were purchased from Møllegaard breeding center, Ejby, Denmark. During the first part of our study, we used rats that weighed ~180 g on arrival. After a 1-wk acclimatization, their average weight in the fed state was ~230 g. Later we turned to younger rats to save LPL in the experiments on saturation of the binding. These rats weighed ~70 g on their arrival, and after 1 wk of acclimatization they weighed 90-100 g in the fed state. The rats were allowed free access to standard laboratory chow (Laktamin AB, Stockholm, Sweden) and tap water. They were housed in a 12:12-h light-dark cycle, where the light period was from 6 AM to 6 PM. Rats designated to be in a fed state were killed at 6 AM. Fasting started at 6 AM and lasted for 24 h, if not otherwise stated. For experiments in which rats were to be refed ad libitum, fasting started at 7 PM and continued for 24 or 29 h. Refeeding started at 7 PM after 24 h of fasting and continued for 5 h. All rats were anesthetized with Hypnorm (50 µl/100 g body wt im) and with Dormicum (50 µl/100 g body wt im). For injection, tracer amounts of 125I-LPL or 125I-lactoferrin were diluted into heat-inactivated rat serum (56°C for 30 min) at pH 7.4 and kept on ice. The total amount of radioactivity injected was ~106 cpm (~100 ng of LPL), and the volume was 0.2 ml. In experiments designed to test whether the binding of exogenous LPL was saturable, we injected unlabeled lipase in buffer C 1 min before the tracer. To keep the lipase soluble and in its active form, it is necessary to use a buffer with high salt concentration and to keep the solution cold. Injections were made in the left jugular vein, and blood samples were taken from the right jugular vein. The local animal ethics committee approved all experimental protocols.
Blood samples to be measured for LPL activity were collected in heparinized Eppendorf tubes and put directly on ice. Plasma was obtained by centrifuging the blood samples at +4°C and was then stored atHeart perfusion.
The coronary vessels were perfused through the aorta by a
modification of the method previously described (26). After removal from the chest, the heart was immersed in ice-cold saline; the beat
ceased immediately. The aorta was rapidly cannulated, and residual
blood was removed by a flush of ice-cold saline. Then medium A
was infused at a constant flow of 8 ml/min for hearts from 200-g
rats, or 4 ml/min for hearts from 100-g rats. This gave a pressure of
40-60 mmHg in the perfusion system (e.g., pump and tubes). The
temperature of the medium was adjusted so that the liquid flowing away
from the heart was between 34 and 37°C. Under these conditions, a
regular heartbeat was quickly restored (usually 100-120 beats/min
and never <60). When this was obtained, the perfusion was shifted to
medium A plus 5 U/ml of heparin. Perfusate was collected on ice
for the times specified. One milliliter from each fraction was frozen
at 70°C for subsequent measurement of LPL
activity. Radioactivity was measured in another aliquot. After
perfusion, the hearts were blotted dry, cleaned from connective tissue,
weighed, and put directly on ice. 125I radioactivity was
determined within a few minutes, and the hearts were then frozen in
buffer D (9 vol) at
70°C for later assay of LPL activity.
Lipase assays. Frozen tissues in buffer were thawed and homogenized with a Polytron homogenizer (PT-MR 3000; Kinematica, Littau, Switzerland). The homogenates were centrifuged for 15 min at 3,000 rpm in a Heraeus Minifuge-T (Heraeus Christ, Oesterode, Germany). LPL activity was measured as detailed before (2). Two microliters of the supernatant, or 10 µl of plasma/perfusate, were assayed in a total volume of 200 µl. The substrate was an emulsion of 100 mg soybean triglycerides and 10 mg egg yolk phospholipids containing [3H]oleic acid-labeled triolein, kindly prepared by Pharmacia and Upjohn, Stockholm, Sweden. The incubation was at 25°C for 60 or 120 min. Samples in which low LPL activity was expected, preheparin plasma and perfusate, were incubated for 120 min, whereas samples with high expected LPL activity, tissue homogenate and postheparin plasma, were incubated for 60 min. For plasma samples, hepatic lipase was inhibited by antibodies (2). Control experiments showed that release of fatty acids was linear with the amounts of enzyme source and time, under the conditions used. One milliunit of enzyme activity corresponds to 1 nmol of fatty acid released per minute. All samples were assayed in duplicate.
Statistical analysis. Statistical comparisons between groups were done by Student's t-test.
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RESULTS |
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Tissue distribution of 125I-LPL and
125I-lactoferrin.
To explore whether the distribution of LPL between blood and tissue
binding sites changes on fasting, we injected labeled bovine LPL
intravenously in rats. For comparison, lactoferrin, a protein with
several binding properties similar to LPL [to heparin (24) and to
the LDL-receptor-related protein LRP (46)] was used. Both
proteins disappeared rapidly from the circulating blood (Fig.
1). Initially, lactoferrin disappeared even
faster than LPL, but after eight (lactoferrin) and ten (LPL) min,
comparable amounts remained in blood, ~9 and 5%, respectively. There
was no significant difference in clearance of the label between fed and
fasted rats for either of the two proteins.
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Can the exogenous LPL that binds in heart be released by heparin?
For this, we perfused hearts from rats that had been given
125I-LPL 10 min earlier with a heparin-containing medium
(Fig. 2). In the fasted rats, a burst of
125I radioactivity appeared early (Fig. 2A),
similar to the (endogenous) LPL activity (Fig. 2B). In the fed
rats, the released amounts of both labeled LPL and LPL activity were
less than in the fasted rats, and there was no initial burst. It should
be noted that the amount of labeled LPL was small compared with the
endogenous LPL. Total LPL activity in the 0- to 3-min perfusate was
100-400 mU. Of this, the labeled LPL contributed 1 mU.
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Effect of fasting on endogenous LPL in heart and blood.
The amount of LPL activity released from the heart by a 10-min
perfusion with heparin-containing medium was 1.3-fold (100-g rats) and
1.8-fold (200-g rats) higher in the fasted state (Table 3). The difference was even larger,
2.4-fold and 2.3-fold for the 100-g and 200-g groups, respectively,
when only the activity in the first peak (0-3 min) was compared
(data not shown). There was no statistically significant difference
between fed and fasted rats in the LPL activity that remained in the
heart after perfusion (residual activity, Table 3). Nor was there any
difference in the total LPL activity in heart (heparin release plus
residual). The heparin-releasable fraction accounted for 36% (100-g
rats) and 17% (200-g rats) of total heart LPL activity in the fed
state. This fraction rose to 47 and 30% when the rats were fasted.
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Is the binding saturable?
To test this, unlabeled bovine LPL was injected to give doses of
0-1,100 µg/100 g body wt, and 1 min later a trace dose of 125I-LPL (0.1 µg) was injected. The disappearance of the
tracer from blood was similar after loading the system with large
compared with small doses of unlabeled lipase (data not shown). After
10 min, 3-5% of the tracer remained in blood when the largest
dose of unlabeled lipase had been injected, compared with 2-8%
when only the tracer was injected. The fraction of the labeled material that located in the liver tended to increase somewhat with the dose
injected. The fraction of the tracer that located in the heart
decreased with the amount of unlabeled lipase injected, indicating that
binding of LPL is saturable (Fig. 3). There
was more label in hearts from fasted than from fed rats, and when data
points for injection of 400 µg LPL per 100 g body wt in Fig. 3 were
combined, the value for binding was twofold higher for hearts from
fasted rats (4.7 µg compared with 2.2 µg, P < 0.01). We
conclude that the capacity to bind exogenous LPL is increased in hearts
of fasted rats.
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Binding of LPL in the isolated perfused heart.
A single-pass perfusion at 4°C was performed to get a direct
measure of the binding sites without influences from redistribution or
metabolic events. Hearts from fasted rats bound more of the tracer than
hearts from fed rats did (Fig.
4). The difference was
1.9-fold and statistically significant (P < 0.05).
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DISCUSSION |
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The main conclusion from this study is that the ability of the vascular endothelium in heart to bind LPL changes with the nutritional state. It was previously known that the amount of heparin-releasable LPL in rat (9, 25, 35) and guinea pig (27) hearts increases markedly on fasting. There is no corresponding increase in tissue LPL activity (8, 27). Earlier studies evaluated LPL synthesis (26) and/or LPL mRNA levels (20, 34). The changes are small and cannot explain the large changes in heparin-releasable activity in going from the fed to the fasted state. Here we demonstrate that binding of exogenous LPL in heart increases by a similar proportion as found for endogenous heparin-releasable LPL. This indicates a new principle for regulation of LPL that would operate on the binding of the lipase to the endothelial sites rather than on the production of LPL in the parenchymal cells or on the delivery of lipase to the endothelium.
For comparison we also injected lactoferrin, which binds to heparin/heparan sulfate (22, 24) and competes with lipoproteins and LPL for binding sites in the liver and for binding to LRP and related receptors (11, 17, 22, 24). The pattern of distribution between tissues was quite different for lactoferrin compared with LPL. Lactoferrin located almost exclusively in the liver. In contrast, more than one-half of the injected LPL bound in extrahepatic tissues, as reported before (44). The difference in binding between LPL and lactoferrin was almost eightfold in the heart, and the large increase with fasting observed for LPL was not seen with lactoferrin. Hence, the increased binding of LPL is unlikely to reflect an increase of a general class of binding sites but suggests a more specific mechanism.
Chajek-Shaul et al. (15) reported that circulating LPL is higher in fasted compared with fed rats and suggested that plasma LPL is in equilibrium with LPL at endothelial sites in well-perfused tissues, such as heart. In contrast to their findings, there was no increase of plasma LPL in our fasted rats. Postheparin LPL, which should reflect endothelial LPL in the total body, was lower in the fasted than in the fed rats, as reported by Kuwajima et al. (25). Hence, the increased heparin-releasable LPL in heart of fasted rats in the present study was not secondary to an overall increase of LPL in a plasma-endothelium pool. This conclusion is in accord with the observation in humans that pre- and postheparin LPL activities generally do not correlate (41). The life cycle of an LPL molecule is probably as follows. It first moves from the parenchymal cells where it is produced to binding sites at the nearby endothelium. Then it moves slowly along the endothelial surface, jumping from binding site to binding site, but is retained close to the surface by long-range electrostatic forces (29). When it escapes into the circulating blood, it is rapidly taken up and degraded in the liver (16, 44). Thus plasma LPL does not reflect a system of reversible equilibria. It is a system of net flux, with synthesis in peripheral tissues and degradation in the liver.
Two groups have previously studied the binding of LPL in rat hearts by use of recirculating perfusion systems. One group found no difference between hearts from fed compared with fasted rats (14), and the other found no difference between hearts from diabetic and normal rats (28). We took another approach and injected a trace amount of LPL in vivo. A major difference between the systems is that blood, but not the perfusion medium, contains high concentrations of proteins such as apolipoprotein B (apoB) or apoE-containing lipoproteins and antithrombin 3 that will compete with LPL for binding to heparan sulfate. Because these competing molecules are not present in the perfusion systems, binding of LPL to nonspecific sites may overwhelm and mask the physiologically relevant binding to a limited class of more specific sites. An indication that this may in fact be the case is the observation by Chajek-Shaul et al. (14) that when hearts from fasted rats were perfused with low amounts of bovine LPL (0.1 µg/ml), the enzyme bound with displacement of endogenous LPL into the medium.
We used bovine LPL for our experiments. This is the commonly used model in LPL research because it is readily obtained from milk (32). Its properties are similar to those for LPL from other mammalian species with respect to kinetics, activation by apoC-II, and binding to heparin (32). Of special importance here, the specific activity of the bovine enzyme, 0.46 mU/ng protein, is almost identical to that for LPL from rat cardiomyocytes, 0.48 mU/ng protein (13). In support of the contention that the bovine enzyme served as an appropriate tracer in our experiments, most of the injected lipase that bound in the heart was rapidly released into the perfusion medium by heparin, similar to endogenous endothelial-bound LPL. In vivo, the small amounts of catalytically active LPL present in the circulation are bound to lipoproteins (43), and when LPL is added to plasma in vitro it binds to lipoproteins. The lipase injected here probably bound to lipoproteins, but this was not investigated.
The tracer dose that we injected was 0.1 µg. This gave a calculated initial concentration in plasma of ~17 ng/ml (in a 200-g rat), when the plasma volume is taken to be 6 ml. The amount of endogenous (active) LPL in plasma was ~7 ng/ml (3 mU/ml divided by 0.46 mU/ng). Hence, the tracer increased the concentration of circulating LPL by a factor of two to three, but the normal concentration was soon restored by rapid disappearance of the tracer. Compared with the amount of LPL at endothelial surfaces, the injected amount was small. Postheparin LPL activity was >1,800 mU, corresponding to ~4 µg, or >40 times the injected tracer. We therefore consider it unlikely that the tracer disturbed the system more than marginally.
To test whether the binding was saturable, we injected increasing doses of unlabeled LPL before the tracer. At the highest doses, ~2 µg and 5 µg bovine LPL bound in hearts from fed and fasted rats, respectively. These amounts can be compared with the amounts of endogenous LPL released by heparin in 3 min, 0.5-1 µg and 2-3 µg for fed and fasted rats, respectively. Hence, the amounts of exogenous LPL that bound were similar to the amounts of endogenous LPL present at the endothelium. The difference between fed and fasted rats was in both cases ~2 µg. We do not know whether the injected LPL bound to free binding sites or whether it bound by displacing some of the endogenous LPL. Probably most bound by displacement, as in the experiments by Chajek-Shaul et al. (14). It should be noted that in our experiments the plasma concentration of exogenous LPL was orders of magnitude higher than normal endogenous LPL. For instance, when 100 µg of bovine LPL were injected, the plasma concentration of LPL at the time when the hearts were excised must have been 2-3 µg/ml (5-10% remained in blood, Fig. 1) compared with the normal concentration of ~10 ng/ml. Endogenous LPL produced within the heart must have some advantage in binding compared with the injected LPL. One possibility is that endogenous LPL arrives at the endothelium in complex with some factor that contributes to its binding (38).
Postheparin LPL activity was more than twice as high in fed compared with fasted rats. Kuwajima et al. (25) perfused a number of rat tissues and found that heparin-releasable LPL in epididymal adipose tissue was seven times higher in fed compared with fasted rats. This agrees with measurements of total adipose tissue LPL activities in the two states (5). Heparin-releasable LPL in heart was about three times higher in fasted rats (25), similar to what we found here. The same difference was found in the red gastrocnemius muscle (25). These figures indicate a large change in the overall distribution of endothelial LPL when going from the fasted to the fed state. From our data we can estimate the contribution by heart in the two states. In fasted 200-g rats, heparin-releasable LPL in heart was 422 mU, and total plasma postheparin LPL was ~2,200 mU. In the fed state, the corresponding figures were 260 and 6,300 mU. From these figures the contribution by heart would be 11 and 4.1%, respectively. This is, however, an overestimation, because the liver (15, 44) will rapidly remove some of the LPL released to plasma by heparin. More realistic estimates of the contribution of heart to total body functional LPL are, therefore, 5 and 2% in fasted and fed rats, respectively. The figure for fasted rats is remarkable, when we consider that the heart makes up <1% of body weight. Already Borensztajn and Robinson in their classical study (9) calculated that the LPL activity in heart far exceeded what was needed for the estimated rate of uptake of lipoprotein fatty acids by the heart.
A reasonable overall interpretation of the present data is that the injected LPL can bind to an essentially unlimited number of unspecific binding sites at endothelial surfaces but that there are also a limited number of specific binding sites that vary with the nutritional state. This would be similar to what Stins et al. (40) found in their studies on the binding of LPL to cultured aortic endothelial cells and raises the question of the nature of the binding sites. The unspecific class likely represents heparan sulfate proteoglycans and perhaps other polyanions. One possibility for the more specific sites is that they involve the protein that Goldberg and colleagues [Sivaram et al. (39)] named HRP-116. This protein can bind to both heparin and LPL, thus reinforcing the binding, and has been reported to be an NH2-terminal fragment of apoB (38). Recent studies have shown that the heart synthesizes full-length apoB-100 and releases very low-density lipoprotein-like lipoproteins as a mechanism to rid itself of excess lipid (7, 30). It is tempting to speculate that part of the apoB synthesis results in generation of high affinity-binding sites for LPL that regulate the capacity of the heart to hydrolyze circulating lipoproteins.
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ACKNOWLEDGEMENTS |
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We thank Ann-Sofie Jacobsson for help with lipase assays.
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FOOTNOTES |
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This work was supported by Grants 03X-727 and 13X-12203 from the Swedish Medical Research Council.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: T. Olivecrona, Dept. of Medical Biochemistry and Biophysics, Umeå Univ., S-901 87 Umeå, Sweden (E-mail: Thomas.Olivecrona{at}medchem.umu.se).
Received 3 February 1999; accepted in final form 22 September 1999.
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