© 1997 American Heart Association, Inc.
Articles |
Uptake of Chylomicrons by the Liver, but Not by the Bone Marrow, Is Modulated by Lipoprotein Lipase Activity
From the Gladstone Institute of Cardiovascular Disease (M.M.H., K.H.W., R.W.M., T.L.I.), the Departments of Pathology (K.H.W., R.W.M., T.L.I.) and Medicine (R.W.M.), and the Cardiovascular Research Institute (M.M.H., K.H.W., R.W.M., T.L.I.), University of California, San Francisco; and the Department of Medicine, College of Physicians & Surgeons of Columbia University, New York, NY (I.J.G.).
Correspondence to Thomas L. Innerarity, PhD, Gladstone Institute of Cardiovascular Disease, PO Box 419100, San Francisco, CA 94141-9100.
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Abstract |
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Abstract We have shown that chylomicrons are catabolized by the liver and bone marrow in rabbits and marmosets. In the present investigation, we studied the role of various apolipoproteins and lipoprotein lipase in the clearance of these particles by the liver and bone marrow in rabbits. Incubation of chylomicrons with purified apolipoprotein (apo) E or C-II resulted in more rapid clearance of these particles from the plasma, whereas incubation of chylomicrons with apoA-I, apoC-I, apoC-III1, or apoC-III2 did not affect their clearance rates. Analysis of tissue uptake revealed that the increased plasma clearance rate of chylomicrons enriched with apoE or apoC-II was primarily due to enhanced uptake by the liver. The uptake of chylomicrons by the bone marrow increased after their enrichment with apoA-I but decreased after their enrichment with apoC-II. Because apoC-II is a cofactor for lipoprotein lipase, we hypothesized that the increased clearance rates were due to faster hydrolysis of chylomicrons and rapid generation of chylomicron remnants. To test this hypothesis, lipoprotein lipase activity was inhibited by injection of an anti–lipoprotein lipase monoclonal antibody. Inhibition of lipoprotein lipase retarded clearance of chylomicrons from the plasma and decreased their uptake by the liver but did not affect their uptake by the bone marrow. These studies suggest that bone marrow can take up chylomicrons in the absence of lipoprotein lipase activity and provide an explanation for the presence of foam cells in the bone marrow of type I hyperlipoproteinemic patients.
Key Words: apolipoproteins • lipoproteins • apoE • apoC-II • apoA-I
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Introduction |
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Chylomicrons are the major lipoproteins synthesized by the intestine and are essential for the transport of dietary fat and fat-soluble vitamins. Chylomicrons are secreted into the mesenteric lymph and enter the circulation via the thoracic duct. During blood circulation, the triglycerides in the cores of these particles are hydrolyzed by the action of endothelial cell–bound lipoprotein lipase (LPL). This enzyme requires a cofactor, apolipoprotein (apo) C-II. The remnant particles arising from the action of LPL acquire apoE from the plasma and are cleared primarily by the liver.1 2 3 We have demonstrated that bone marrow also plays a major role in the catabolism of chylomicrons in rabbits and marmosets.4 5 Recently, clearance of chylomicrons by the bone marrow has been demonstrated in humans.6 7
The uptake of chylomicron remnants by the liver has been hypothesized to involve sequestration in the space of Disse, processing at the cell surface, and internalization by parenchymal cells via receptor-mediated endocytosis.2 3 Cell-surface heparan sulfate proteoglycans and hepatic lipase also play major roles in the initial binding of apoE-enriched remnant lipoproteins to various cells, including hepatocytes.8 9 10 11 12 Likewise, LPL has been shown to mediate the enhanced uptake of remnant lipoproteins.13 Endocytosis of remnant lipoproteins can be mediated by LDL receptors14 and the LDL receptor–related protein.15 16 17 18 The apoE acquired by these particles during blood circulation or by addition of apoE to the particles in the space of Disse may play a significant role in the sequestration and internalization of the particles.2 3 In contrast, the mechanism of chylomicron uptake by bone marrow and the factors that modulate this uptake are poorly understood. Macrophages in bone marrow are known to internalize chylomicrons,4 5 6 7 but the ligands and receptors involved in this process are not known. Chylomicron uptake in bone marrow has been speculated to be important for the delivery of retinols because of their critical role in tissues with intense proliferative activity.19 20
A deficiency in LPL or its cofactor apoC-II (type I hyperlipoproteinemia) results in the accumulation of chylomicrons in the plasma, suggesting that triglyceride hydrolysis is important in the clearance of these particles.21 Clinical manifestations of type I hyperlipoproteinemia include recurrent abdominal pain, pancreatitis, eruptive cutaneous xanthomatosis, and hepatosplenomegaly.21 The xanthomas and splenomegaly are caused by foam cells, which have also been found in the bone marrow of subjects with type I hyperlipoproteinemia.22 These observations suggest that chylomicrons are taken up by macrophages in these tissues. However, it is not known whether the chylomicron uptake in the bone marrow of these subjects is a normal process that is merely exaggerated with LPL deficiency because of the accumulation of particles in the plasma. This possibility was evaluated by injecting monoclonal antibodies that inhibit LPL into rabbits and creating a transient type I hyperlipoproteinemic phenotype. Our data suggest that chylomicron uptake by the bone marrow is a normal process that does not require hydrolysis of these particles by LPL.
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Methods |
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Preparation of Lipoproteins
Chylomicrons were labeled in vivo with [3H]retinol and [14C]cholesterol, collected from the thoracic ducts of dogs as described earlier,4 5 and purified by ultracentrifugation (SW 28 rotor, 28 000 rpm for 90 minutes at 20°C).4 5 In chylomicrons, >70% of the [14C]cholesterol and >90% of the [3H]retinol were esterified.
Purification of Bovine Milk LPL
LPL was purified from fresh bovine milk by the method of Socorro
et al23 as described by Saxena et al.24
Unpasteurized milk was adjusted to 0.4 mol/L NaCl by addition of solid
NaCl and centrifuged at 3000g at 4°C to remove the
cream. Heparin-agarose gel (Bio-Rad; 80 mL) was added to the skim milk
(3.5 L) and incubated for 18 hours at 4°C on a platform rocker. The
gel was washed twice, first with 10 mmol/L Tris-HCl buffer (pH
6.8, containing 0.4 mol/L NaCl) and then with the same buffer
containing 0.75 mol/L NaCl. The gel was transferred to a column
(2.5x20 cm), and LPL was eluted with 10 mmol/L Tris-HCl buffer,
pH 6.8, containing 1.5 mol/L NaCl. The enzyme was stored at -70°C
until use.
Assay of LPL Activity
LPL activity was measured with the emulsion described by
Nilsson-Ehle and Schotz.25 The enzymatic reaction was
allowed to proceed for 1 hour in a 37°C water bath. Released fatty
acids were extracted as described by Belfrage and
Vaughan.26 One milliliter of the aqueous phase was mixed
with 5 mL of scintillation fluid (Hydrofluor, National
Diagnostics), and radioactivity was determined with a model
1800 liquid scintillation counter (Beckman Instruments).
In Vivo Inhibition of LPL
Rabbits were restrained, and an ear artery and vein were
catheterized. A zero-time blood sample was obtained, followed by
intravenous injection of either a control monoclonal
antibody (Cappel) or a monoclonal anti-LPL (5D2) IgG (1 mg; Washington
Research Foundation) into an ear vein. Five minutes later, chylomicrons
(100 mg triglyceride per kilogram of body weight) were
injected intravenously. Blood samples were collected from
an ear artery at designated times. Thirty minutes after the injection
of chylomicrons, euthanasia solution was administered and tissues were
collected. Plasma and tissues were analyzed for radiolabels as
described earlier.4 5
Purification of Apolipoproteins
Rabbit apoE was purified from cholesterol-fed
rabbits.27 The plasma from these rabbits was adjusted to
d=1.02 g/mL with KBr28 and
ultracentrifuged (60 Ti rotor, at 59 000 rpm for 18 hours at
4°C; Beckman Instruments). The d<1.02 g/mL lipoprotein
fraction was collected, recentrifuged once to remove plasma
contaminants, dialyzed extensively against distilled water containing
2 mmol/L EDTA (pH 7.4), lyophilized, and delipidated with
chloroform/methanol (2:1, vol/vol). The apolipoproteins were
solubilized with 6 mol/L guanidine containing 0.1 mol/L Tris-Cl, pH
7.4, and 2 mmol/L EDTA. ApoE was purified by gel filtration on
Sephacryl S-300 HR (Pharmacia) as previously described for human
apoE.29 Apolipoproteins were purified from normal human
HDLs (d=1.063 to 1.21 g/mL) in a similar manner. Human
apolipoproteins C-I, C-II, C-III1, and C-III2
from type IV hypertriglyceridemic patients
were purified by gel filtration on Sephacryl S-300 HR and
high-performance liquid chromatography ion
exchange as previously described.30
Effect of Apolipoproteins on Lipoprotein Catabolism
Chylomicrons (50 mg triglyceride per kilogram of
body weight) were incubated with or without purified apolipoproteins (1
mg protein per kilogram of body weight) at 37°C for 1 hour and stored
on ice until injection. Metabolic studies were performed as
described earlier.4 5
Biochemical Analyses
The protein concentration was determined by the method of Lowry
et al.31 The concentrations of cholesterol and
triglyceride were determined with an Abbott Spectrum
high-performance diagnostic system using standards
in aqueous solution (New England Reagent Laboratory).
Statistical Analysis
The statistical significance of differences in plasma clearance
and tissue uptake of chylomicrons and chylomicrons incubated with
purified apolipoproteins was determined with the t test. All
statistical calculations were performed on a personal computer using
software written by Glantz.32
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Results |
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Effect of Purified Apolipoproteins on the Catabolism of Chylomicrons
In vivo clearance of radiolabeled chylomicrons incubated with purified apolipoproteins is summarized in Table 1
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Incubation of chylomicrons with apoA-I, apoC-I, apoC-III1,
or apoC-III2 did not significantly affect their clearance
from plasma. However, incubation of chylomicrons with human apoC-II or
apoE caused a marked increase in initial clearance rates. For example,
at 2 minutes 
50% to 55% of chylomicrons alone or chylomicrons
incubated with apoA-I, apoC-I, apoC-III1, or
apoC-III2 remained in the plasma compared with only 30%
or 20%, respectively, of chylomicrons incubated with apoE or
apoC-II. The increased initial clearance rates of chylomicrons
incubated with apoE or apoC-II were mainly due to increased uptake by
the liver.
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Tissue uptake of radiolabeled chylomicrons incubated with purified
apolipoproteins is summarized in Table 2. At 20 minutes,
46% of the injected dose of [14C]chylomicrons had been
taken up by the liver. Similar hepatic uptake was observed for
chylomicrons incubated with apoA-I, apoC-III1, or
apoC-III2, and a slight decrease in uptake was observed for
chylomicrons incubated with apoC-I. In contrast, 63% or 64%,
respectively, of [14C]chylomicrons incubated with apoC-II
or apoE were taken up by the liver. Analysis of bone marrow
revealed that uptake of chylomicrons incubated with apoC-II was
decreased, whereas uptake of chylomicrons incubated with apoE was not
significantly different from controls. However, bone marrow uptake of
chylomicrons incubated with apoA-I was enhanced compared with that of
chylomicrons alone or those incubated with other apolipoproteins. The
role of apoA-I in the increased uptake of chylomicrons by the bone
marrow was not investigated further. Similar results were obtained with
[3H]chylomicrons; however, the liver and bone marrow
retained less [3H]retinol than
[14C]cholesterol.
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Effect of In Vivo Inhibition of LPL on Chylomicron
Metabolism
We speculated that the effect of apoC-II was due to increased
rates of triglyceride hydrolysis and hypothesized that
inhibition of LPL would decrease the rate of chylomicron clearance.
Monoclonal antibodies that inhibit LPL activity were used to test this
hypothesis. First, we studied the inhibition of LPL in
postheparin plasma by monoclonal antibodies in vitro and
estimated the amount of antibody required for in vivo inhibition. In
vivo inhibition of LPL was studied by injecting antibodies into
rabbits, assaying for the presence of inhibitory antibodies
in the plasma of these animals, and studying the resulting
triglyceride clearance. We then characterized the effect of
the inhibition of LPL activity on the plasma clearance of chylomicrons
in rabbits.
As shown in Fig 1, <10 ng of monoclonal antibody
against LPL (5D2) caused an 50% inhibition of LPL activity in 20
µL of postheparin plasma. At the highest concentration of
antibody used (>250-fold that required for 50% inhibition), the
maximal inhibition achieved was 80% of total lipolytic activity in
postheparin plasma. For in vivo inhibition of LPL, we
estimated that 50 µg of monoclonal antibody would inhibit >50% of
the enzyme activity in a normal rabbit weighing 3 kg. We then
injected 20 times this amount (1 mg) into each rabbit to obtain maximal
inhibition. The in vivo inhibition of LPL by this antibody was studied
by measuring the monoclonal antibody level in the circulation at the
end of the in vivo experiments and the decay of
triglycerides during the experiments.
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To measure the antibody level during in vivo metabolic studies, plasma was obtained 35 minutes after the monoclonal antibodies were injected intravenously and assayed for inhibitory activity by using a partially purified preparation of LPL. The plasma from animals injected with the anti-LPL antibody caused 89% to 92% (n=3) inhibition of LPL activity in in vitro assays as described in "Methods." The plasma from animals injected with control antibodies caused a 16% to 30% inhibition of LPL activity. These studies suggest that a substantial amount of injected antibody was still present in the circulation at the end of the experiment and likely inhibited most of the LPL activity in vivo.
Direct evidence that the antibody was indeed inhibiting LPL activity in
vivo was obtained by studying the rate of triglyceride
clearance. As shown in Fig 2, injection of chylomicrons
caused a similar increase in plasma triglycerides at 2
minutes in both the control IgG and the anti-LPL antibody–injected
groups. This increase represents the triglyceride
level 2 minutes after injection and does not account for the initial
clearance of injected chylomicrons that occurs within this time period.
Subsequent clearance of triglycerides was significantly
different, however, between the two groups. During the next 30 minutes,
30% of the triglycerides present 2 minutes after
injection were cleared from the plasma of control IgG–injected
animals. In contrast, <5% of the triglycerides were
cleared from the plasma of rabbits injected with the LPL
inhibitory antibody. Plasma cholesterol values
did not change significantly in these animals. These studies
demonstrated that the LPL monoclonal antibody indeed inhibited the
hydrolysis or clearance of triglycerides in the
chylomicrons, apparently by inhibiting LPL activity in vivo.
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As shown in Fig 3A and 3B, injection of LPL antibodies
inhibited chylomicron clearance from the plasma. The amounts of
chylomicrons cleared in the first 2 minutes were similar in both groups
of animals and probably represent sequestration of small
chylomicrons in the space of Disse.2 3 4 33 However, after
this time, the amount of radiolabeled chylomicrons remaining in the
plasma decreased more rapidly in control animals. At 30 minutes, plasma
levels of [3H]retinol and
[14C]cholesterol were 18% and 21%,
respectively, in controls compared with 40% and 38%, respectively,
in animals injected with LPL antibodies. The retarded clearance of
chylomicrons in the antibody-injected rabbits was apparently due to
decreased hepatic uptake of chylomicrons. At 30 minutes, the livers of
control animals contained 25% and 41% of the injected
[3H]retinol and
[14C]cholesterol, respectively, compared with
11% and 23% of chylomicrons in the animals receiving the LPL antibody
(Fig 3C and 3D). The decrease in uptake by the liver accounted for the
increased amounts of chylomicrons remaining in the plasma of these
animals. Chylomicron uptake by bone marrow (Figs 3C and 3D) was not
affected. The recovery of less [3H]retinol than
[14C]cholesterol was probably due to
catabolism of the retinol in the tissues and mobilization of its
metabolic products.4 5 These studies
suggest that inhibition of LPL specifically decreases the uptake of
chylomicrons by the liver but has no effect on the uptake of
chylomicrons by the bone marrow.
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Discussion |
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Our studies provide data on the roles of apolipoproteins and LPL in chylomicron catabolism and show that uptake of these particles by the rabbit liver is sensitive to LPL activity and the availability of apoE and apoC-II. Plasma clearance of chylomicrons enriched with apoE and apoC-II was increased in rabbits at the earliest time assessed (2 minutes), suggesting that enrichment accelerated the initial phases of chylomicron catabolism. This probably represents sequestration of these particles in the space of Disse.2 3 33
ApoC-II, a cofactor of LPL, probably enhanced lipolysis rates and the generation of remnants that are cleared more rapidly by the liver. The kinetics of apoC-II–mediated clearance was rapid, suggesting either that the rate of hydrolysis must have been enhanced very significantly or that apoC-II may also play some role in the targeting of these particles to the liver. These results also suggest that apoC-II levels may be rate limiting in the process of chylomicron clearance in rabbits, because addition of excess apoC-II accelerated this process.
ApoE is a ligand for the clearance of remnant lipoproteins,1 and addition of excess apoE increases the clearance of these particles.4 34 35 The increased rate of clearance of apoE-enriched chylomicrons was probably due to enhanced affinity of these particles for the heparan sulfate proteoglycans in the space of Disse2 3 8 9 and hepatic receptors.14 15 16 18 ApoE may also increase the rate of hydrolysis of the sequestered particles by hepatic lipase.36
The addition of apoC-I, apoC-III1, or apoC-III2 did not inhibit chylomicron clearance in vivo in rabbits, as was anticipated from previous studies. These apolipoproteins have been shown to inhibit the uptake of remnant lipoproteins in liver perfusion experiments,37 38 in studies involving the binding and uptake of apoE-enriched remnant lipoproteins by fibroblasts,30 39 and in transgenic mice that overexpress apoC-III.40 Only apoC-I significantly inhibited the clearance of [3H]retinol-labeled chylomicrons in rabbits. The lack of a major effect by these apolipoproteins on chylomicron clearance may be due to our use of insufficient amounts of apolipoproteins or differences in rabbits in vivo.
LPL plays important roles at two stages in the catabolism of
chylomicrons. First, LPL hydrolyzes triglycerides and
facilitates the generation of remnants. Inhibition of LPL activity
abolished the hydrolysis of triglycerides and decreased the
plasma clearance of chylomicrons, primarily due to a significantly
reduced uptake of these particles by the liver. These results agree
with those of several studies that have described the importance of
lipolytic hydrolysis of chylomicrons to remnants for hepatic
clearance41 42 and the accumulation of
triglyceride-rich particles in patients with type I
hyperlipoproteinemia, in whom either LPL or its
apoC-II cofactor is defective or absent.21 In contrast to
the results obtained with added apoC-II and the inhibition of LPL on
liver uptake, there was no effect on the uptake of chylomicrons by the
bone marrow. This finding suggests that hydrolysis of these particles
is not necessary for their uptake by bone marrow macrophages.
On the basis of these observations, we propose that chylomicron uptake
by the bone marrow occurs independently of LPL activity (Fig 4) and that the remnants generated by the action of LPL
are predominantly and preferentially cleared by the liver. The
clearance of chylomicrons by macrophages may be a major
mechanism for the clearance of dietary particles in patients with type
I hyperlipoproteinemia, who have an abundance
of foam cells in their bone marrow and spleen.22
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Second, LPL increases the binding of lipoproteins to heparan sulfate proteoglycans43 44 and enhances the uptake and degradation of triglyceride-rich lipoproteins by the LDL receptor–related protein.13 45 46 47 The receptor-binding activity of the enzyme is independent of enzyme activity and occurs at the carboxyl-terminal end of the molecule.48 The monoclonal antibody used in the present study recognizes the same epitope as in the carboxyl terminus. Thus, it is possible that inhibition of LPL could have affected its ability to interact with the LDL receptor–related protein and caused decreased clearance of chylomicrons. However, this possibility is considered unlikely because of the well-known effect of LPL on the hydrolysis of chylomicrons before their clearance by the liver.21 41 42
Catabolism of chylomicrons by the liver and bone marrow appears to involve two independent mechanisms. The liver has a high-affinity clearance and uptake pathway for chylomicron remnants that involves sequestration in the space of Disse, further lipolytic processing, and receptor-mediated uptake.2 3 ApoC-II accelerates the generation of these particles, whereas apoE enhances their targeting to the liver. Inhibition of LPL results in a significant decrease of hepatic clearance of chylomicrons. In bone marrow, chylomicron particles are taken up by macrophages;2 3 4 5 no evidence for their sequestration has been reported, however. The mechanism of uptake of remnants by bone marrow macrophages is unknown. In contrast to hepatic uptake, uptake of chylomicrons by the bone marrow is not significantly affected by changes in apoC-II or apoE levels or LPL activity. However, apoA-I appeared to increase chylomicron clearance by the bone marrow but had no effect on hepatic uptake. A more in-depth investigation is required to explore the effect of apoA-I on the uptake of chylomicrons by the bone marrow.
In summary, these studies demonstrate that activation of LPL increases the uptake of chylomicrons by the liver but has no effect on their uptake by the bone marrow, whereas inhibition of LPL activity decreases liver uptake without affecting bone marrow uptake. The normal uptake of chylomicrons by bone marrow macrophages may contribute to foam cell formation in type I hyperlipidemic patients.
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Acknowledgments |
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Partial support was provided by Grants-in-Aid from the California Affiliate and National Center (funded in part by a bequest from Ivan D. Savage) of the American Heart Association to M. Mahmood Hussain, National Institutes of Health grants HL21006 and HL45095 to Ira J. Goldberg, and program project grant HL41633 to Robert W. Mahley. We thank Walter J. Brecht, R. Dennis Miranda, Peter Lindquist, Yvonne M. Newhouse, and Lynne H. Shinto for technical support; Sylvia Richmond for manuscript preparation; Charles Benedict and Tom Rolain for graphics; and Gary Howard and Stephen Ordway for editorial assistance. All experiments were approved by the Committee on Animal Research, University of California, San Francisco.
Received April 26, 1996; accepted October 2, 1996.
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