Download Lipoprotein Lipase in the Arterial Wall

Lipoprotein Lipase in the Arterial Wall
Linking LDL to the Arterial Extracellular Matrix and Much More
Markku O. Pentikäinen, Riina Oksjoki, Katariina Öörni, Petri T. Kovanen
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Abstract—For low density lipoprotein (LDL) particles to be atherogenic, increasing evidence indicates that their residence
time in the arterial intima must be sufficient to allow their modification into forms capable of triggering extracellular
and intracellular lipid accumulation. Recent reports have confirmed the longstanding hypothesis that the major
determinant(s) of initial LDL retention in the preatherosclerotic arterial intima is the proteoglycans. However, once the
initial atherosclerotic lesions have formed, a shift to retention facilitated by macrophage-derived lipoprotein lipase
(LPL) appears, leading to the progression of the lesions. Here, we review recent findings on the mechanisms enabling
LPL to promote LDL retention and extracellular lipid accumulation in the arterial intima, and we describe the structures
in the extracellular matrix that are held to be important in this process. Finally, the potentially harmful consequences
of LDL linking by LPL and of other LPL actions in the arterial intima are briefly reviewed. (Arterioscler Thromb Vasc
Biol. 2002;22:211-217.)
Key Words: lipoprotein lipase 䡲 extracellular matrix 䡲 lipoproteins 䡲 retention
T
N-terminal and the C-terminal folding domains, a binding site
for the cofactor apoC-II in the N-terminal folding domain,
and a binding site for LDL receptor–related protein in the
C-terminal folding domain.
The catalytically active LPL is a noncovalent 96-kDa
homodimer that is likely to be oriented in a head-to-tail
conformation.7 The dimeric form of the enzyme is stabilized
by its interaction with the heparan sulfate glycosaminoglycans (GAGs) present on the endothelial surface. As illustrated
by experiments with mice expressing heparin-binding defective LPL, binding of LPL to proteoglycans is important not
only for the stability of the enzyme but also for anchoring the
enzyme to sites at which its activity is required.8 Once the
enzyme is dissociated into monomers, its activity is lost.
Interestingly, monomers of LPL are present in significant
amounts in the circulation and also in extrahepatic tissues,
such as adipose tissue and the heart.9,10 In the circulation,
LPL monomers associate with the lipoprotein remnant particles and, in this way, may enhance their clearance by the
liver.9,11
The vast majority of the total LPL in the body is located in
the capillary endothelium. However, LPL is also found on the
arterial endothelium. This LPL, albeit a tiny fraction of the
total body LPL, has been suggested to have a role in
atherogenesis by creating, locally on the arterial endothelium,
remnant particles that can be deposited in the arterial intima.
As in the capillary bed, such remnants are generated from
triglyceride-rich lipoproteins of intestinal origin. Accordingly, this action of arterial LPL has been suggested to be a
postprandial phenomenon and so may link the fat-containing
he major lipolytic enzyme involved in the intravascular
metabolism of postprandial triglyceride-rich lipoproteins
is lipoprotein lipase (LPL).1 In adipose tissue and in muscle,
this enzyme is synthesized and secreted in catalytically active
form by adipocytes and myocytes, respectively, and is then
transported to the capillary endothelial surface. Its physiological function is to hydrolyze the triglycerides of chylomicrons
and VLDL and IDL particles on the luminal side of the
capillary endothelium, with release of free fatty acids, which
are stored as triglycerides (adipose tissue) or are oxidized for
production of energy (muscle). The majority of the so-formed
triglyceride-poor and cholesterol-enriched lipoprotein remnant particles are cleared by the liver. However, experiments
with transgenic mice expressing catalytically inactive LPL in
muscle indicate that peripheral tissues take up (remnants of)
lipoprotein particles via LPL.2
LPL belongs to the mammalian triacyglycerol lipase gene
family, which also contains pancreatic lipase, hepatic lipase,
and endothelial lipase. According to homology modeling3,4
based on the crystal structure of human pancreatic lipase,5
LPL has a larger N-terminal folding domain (amino acids 1 to
312) and a smaller C-terminal domain (amino acids 313 to
418). The catalytic site, consisting of Ser132, Asp156, and
His241, is localized in the N-terminal folding domain and is
covered by a lipid-binding lid. Interestingly, interaction of the
C-terminal folding domain with lipoprotein substrates has
been proposed to result in a conformational change in LPL
that leads to the opening of the lid, thus allowing the enzyme
to conduct its catalytic function.6 Other functionally important parts of LPL include heparin-binding sites located in the
Received August 16, 2001; revision accepted October 2, 2001.
From the Wihuri Research Institute, Helsinki, Finland.
Correspondence to Prof Petri T. Kovanen, MD, PhD, Wihuri Research Institute, Kalliolinnantie 4, 00140 Helsinki, Finland. E-mail
[email protected]
© 2002 American Heart Association, Inc.
Arterioscler Thromb Vasc Biol. is available at http://www.atvbaha.org
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Arterioscler Thromb Vasc Biol.
February 2002
Western diet with the development of atherosclerosis.12 A
second pool of arterial LPL is located subendothelially, ie,
within the inner layer of the artery, the arterial intima, where
lipids accumulate during atherogenesis. The present review
deals with this fraction of LPL and its potential relation to
intimal lipid accumulation and to some other processes that
are important in the development of atherosclerotic lesions.
Retention of LDL in the Arterial Intima
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The initial step in the development of atherosclerotic lesions
is suggested to be the retention of LDL.13–15 Kinetic studies
have provided evidence for sequestration of LDL in the
normal arterial wall in a pool that exchanges slowly with
plasma LDL. In atherosclerosis-prone areas, ie, in branch
points of normal arteries and also in injured or atherosclerotic
arteries, the size of this sequestered pool is increased.16 –19
The observed differences in LDL sequestration are correlated
with changes in the proteoglycan composition in arterial
branch sites20 and in early atherosclerotic lesions,21 which is
consistent with the idea that sequestration results, at least
partly, from the binding of LDL to proteoglycans in the
arterial intima. Direct experimental support for this idea has
come from experiments by Borén et al,22 who showed that if
the principal proteoglycan-binding site of apoB-100 is mutated, LDL retention in the normal arterial intima of mice is
virtually abolished. Importantly, Borén et al found that in
mice expressing proteoglycan-binding– defective human
apoB-100 compared with mice expressing wild-type human
apoB-100, the development of atherosclerotic lesions was
retarded.22 Although this experiment provides direct evidence
that LDL-proteoglycan interaction has a role in the initiation
and early development of atherosclerosis, it also reveals that
lipid-containing atherosclerotic lesions may develop even
when LDL-proteoglycan interaction is prevented.
Then, the same group made an important observation: Retention of the proteoglycan-binding– defective LDL to preformed
atherosclerotic lesions was found to be similar to that of
wild-type LDL.23 This finding must be interpreted to mean that
later during the process of atherogenesis, factors other than direct
binding to proteoglycans are involved in the retention of LDL to
the arterial intima. Because LPL can bind to GAGs (proteoglycans) and to LDL, LPL could be the factor mediating the
retention of the proteoglycan-binding– deficient LDL particles in
the proteoglycan-rich areas of atherosclerotic lesions.
Several experiments with genetically engineered mice have
attempted to elucidate the role of LPL in atherogenesis. In the
LDL receptor⫺/⫺ and the apoE⫺/⫺ mouse models of atherosclerosis with pronounced remnant hyperlipidemia, overexpression of LPL resulted in less extensive atherosclerotic
lesions than those found in their nontransgenic littermates.24,25 In contrast to mice with enhanced LPL activity,
apoE⫺/⫺ mice with heterozygous LPL deficiency, although
having enhanced hyperlipidemia, show a similar degree of
atherosclerosis26 or less atherosclerosis27 than do apoE⫺/⫺
mice with full LPL activity. The paradoxically lacking
atherogenic effect of remnant hyperlipidemia in these animals
could have been due to low LPL activity locally on the
arterial endothelium and in the arterial wall. However, in all
of the above-described experiments, the total body LPL
activity was either increased or decreased, making an un-
equivocal decision about the roles of arterial LPL in atherogenesis difficult.
With the advent of elegant novel techniques for producing
chimeric mice, it has become possible to assess the impact of
arterial wall LPL on atherosclerosis. Thus, by transplanting
either LPL⫹/⫹ or LPL⫺/⫺ fetal liver cells as the source of
hematopoietic cells (and, ultimately, of monocytes/macrophages infiltrating the arterial wall), Babaev et al28 were able
to show that cholesterol-fed C57Bl/6 mice with normal
expression of macrophage LPL developed more extensive
atherosclerosis than did mice with no expression of macrophage LPL. Using the same strain of mice but using bone
marrow transplantation, Van Eck et al29 showed that deficiency of macrophage LPL production during cholesterol
feeding led to a 50% decrease in serum cholesterol and apoE
and to a 52% decrease in the area of aortic fatty streak lesions.
Finally, Babaev et al,30 by transplanting either LPL⫹/⫹ or
LPL⫺/⫺ fetal liver cells into LDL receptor⫺/⫺ mice, showed
that macrophage LPL production enhanced the formation of
fatty streak lesions. In their experiment, development of
advanced atherosclerotic lesions was not affected by macrophage LPL production, which is consistent with the observed
scarcity of macrophages in this type of lesion. Collectively,
the above experiments showed that macrophage-derived LPL
exerts a proatherogenic effect by inducing aortic foam cell
formation, ie, formation of the earliest type of atherogenic
lesions, the fatty streaks.
Interaction of LPL With Different
Components of the Arterial Intima
Theoretically, LPL in the arterial intima could originate from
circulating LPL and/or from local synthesis by the various
cells present in the arterial intima. Because LPL has been
shown to be produced in the intima by macrophages and
smooth muscle cells31–33 and because virtually no LPL is
present in the intimas of mice deficient in macrophage LPL
production,28 –30 it appears that most of the LPL in the arterial
intima is derived from local synthesis, notably by the
monocyte-derived macrophages.26,32–35 Most interestingly,
immunohistochemical staining for LPL in the arterial intima
has shown that LPL is not only associated with intimal cells
but is also abundantly present within the extracellular matrix.31,32,34,36 Thus, the intima clearly differs from other
tissues in which the subendothelially synthesized LPL is not
stored within the stromal tissue but is effectively transported
to the luminal surface of the capillary endothelium. One
reason for this difference may be the lack of capillaries in the
arterial intima.
In vitro experiments have shown that LPL can bind to
heparan sulfate and dermatan sulfate GAGs but not to
collagen, fibronectin, vitronectin, or, surprisingly, chondroitin sulfate GAGs.37 However, differentiated macrophages
have been shown to synthesize oversulfated chondroitin
sulfate–rich proteoglycans that can bind to LPL.38 Moreover,
LPL has been shown to bind to chondroitin sulfate and
especially to dermatan sulfate–rich proteoglycans isolated
from the human aorta.39 In a recent study, we did not observe
any direct binding of LPL to collagen but found that the
collagen-binding small proteoglycan decorin was able to
efficiently link LPL to collagen.36 Binding of LPL to GAGs
Pentikäinen et al
Lipoprotein Lipase in the Arterial Wall
213
lipid-rich core, numerous inflammatory cells in the shoulder
region, and a relatively thin fibrous cap. In this lesion, LPL is
found diffusely throughout the superficial proteoglycan-rich
layer and is clearly absent from the deeper musculoelastic
layer of the intima. Similarly, versican and biglycan are
present throughout the upper layer of the intima. Decorin, in
turn, is present only in the core region of the plaque. Collagen
type I, again, is present in the core region and also in the
superficial part of the lesion, forming a thin fibrous cap.
Finally, LDL (apoB-100) is extensively deposited in the core
region of the plaque and also in the fibrous cap, colocalizing
with collagen I. Notably, apoB-100 is completely absent from
the highly cellular area between the core and the collagenous
cap, ie, the shoulder area, a finding compatible with the idea
that macrophages ingest and degrade the LDL particles.
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Interaction of LPL With Native and
Modified LDL
Figure 1. Distribution of LPL in a human coronary atheroma in
relation to LDL, proteoglycans, and collagen. Frozen sections of
an atheroma in a human coronary artery obtained at autopsy
was immunostained by indirect immunoperoxidase with use of a
rabbit polyclonal antibody to human LPL (kindly provided by Drs
M. Jauhiainen and C. Ehnholm, National Public Health Institute,
Helsinki, Finland), a mouse monoclonal antibody to human
apoB-100 (MB-47, a kind gift from Dr J. Witztum, University of
California, San Diego), rabbit polyclonal antibodies against
decorin (LF-30), biglycan (LF-51), and versican (LF-99, kind gifts
from Dr L. Fisher, National Institute of Dental and Craniofacial
Research, National Institutes of Health, Bethesda, Md), or a
mouse monoclonal antibody against collagen type I (MAB1340,
Chemicon). The chromogen was 3-amino-9-ethylcarbazole and
shows positive red-brown areas in each panel (hematoxylin
counterstaining). The top left panel shows the topography of the
visualized part of the coronary atheroma and different layers of
the arterial wall for purposes of orientation.
has been suggested to be mediated by 3 continuous clusters in
the N-terminal domain and a noncontinuous cluster in the
C-terminal domain of positively charged amino acids that are
brought together by folding of the enzyme.4 The dimeric
structure of LPL causes an increase in the affinity for heparin,
presumably because sites in both monomers can participate in
the binding of 1 heparin molecule.4
Although LDL can also bind to various types of proteoglycans with relatively similar affinities in vitro, a recent
study showed that the pattern of LDL retention closely
followed that of biglycan, a small proteoglycan.40 To elucidate the type of proteoglycan to which LPL binds in the
extracellular matrix of the arterial intima, we compared the
distribution of LPL with that of various proteoglycans in
sections of human atherosclerotic lesions. Figure 1 shows an
atherosclerotic lesion (atheroma or American Heart Association type IV lesion41) characterized by an almost acellular
The role of apolipoproteins in the interaction between LPL
and triglyceride-rich lipoproteins during hydrolysis of triglycerides has been studied extensively. Efficient hydrolysis of
triglyceride-rich lipoproteins depends on 1 of the several
apolipoproteins present on the surface of these particles,
namely, apoC-II, an activator of LPL. However, LPL has
been shown to also bind to artificial lipid emulsions lacking
apolipoproteins.42– 45 Thus, it appears that LPL can interact
directly with phospholipid molecules in the absence of
apolipoproteins. It has been proposed that the lipid-binding
region in LPL is constituted of the lid region containing
amphipathic ␣-helices of the N-terminal folding domain46
and of tryptophan residues in an exposed loop between the ␤
strands of the C-terminal folding domain (involving amino
acids 390 to 394).47 Interestingly, dimeric LPL lacking the
C-terminal domains binds to phospholipid vesicles as efficiently as native dimeric LPL but is totally unable to interact
with chylomicrons.48 On the other hand, although full-length
LPL binds to chylomicrons, VLDL, and LDL with similar
affinity,44 the C-terminal domain binds much more strongly
to chylomicrons and VLDL than to LDL.49 Thus, it appears
that the C-terminal domain of LPL is important for binding to
chylomicrons and VLDL, whereas the N-terminal folding
domain of LPL mediates the binding of LPL to phospholipid
vesicles and possibly also to LDL particles.
Results regarding the role of apoB-100 in the interaction of
LPL with LDL, which is not a physiological substrate for
LPL (unlike the triglyceride-rich lipoproteins), have been
conflicting. Goldberg’s group (Choi, Pang, and colleagues50 –52)
published data indicating that LPL interacts with the aminoterminal part of apoB-100. However, we found no evidence
to support an interaction of LPL with apoB-100 and could
even demonstrate enhanced binding of LPL to LDL that had
been treated with proteolytic enzymes to obtain degradation
of apoB-100 and subsequent loss of apoB-100 peptides.36
Moreover, in a very recent study, Borén et al53 studied this
issue extensively and found binding of LPL to LDL lipids
and, moreover, suggested that the binding of LPL to the
recombinant amino-terminal part of apoB-100 (apoB-17) can
be explained by the presence of lipids bound to this apolipoprotein. Finally, since 1 LDL particle contains only 1
apoB-100 polypeptide, the stoichiometry of the LPL-LDL
214
Arterioscler Thromb Vasc Biol.
February 2002
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Figure 2. Diagram showing the various effects of LPL in the arterial intima. TG indicates triglyceride; FFA, free fatty acid.
interaction (binding of up to 15 dimers per LDL particle)53
speaks against a specific interaction between LPL and apoB100 on the interaction of LPL with LDL.
The interaction of LPL with LDL has been shown to
involve electrostatic and hydrophobic interactions.54 Using
“sandwich” affinity chromatography, we made the unexpected observation that although the catalytically active
dimeric form of LPL efficiently interacts with triglyceriderich lipoproteins, the monomeric form of LPL preferentially
interacts with LDL.36 These results are in line with those of
Hendriks et al,55 who found that LPL in its native dimeric
form was unable to link LDL to J774 macrophages.
LDL has been suggested to undergo several types of
modification in the arterial intima, including oxidation, and
hydrolysis of apoB-100 and of lipids.56,57 Interestingly, although oxidation decreases the direct binding of LDL to
GAGs,58 even mild oxidation significantly enhances the
interaction between LDL and LPL.36,45,59 The mechanism(s)
responsible for this increased binding is not known but may
involve the shift of LDL to a more hydrophobic particle after
partial hydrolysis of the surface phospholipids or of apoB100.60 Moreover, as noted above, in addition to oxidation of
LDL, proteolytic degradation of apoB-100 alone could enhance the interaction between LDL and LPL.36 Thus, it is
Pentikäinen et al
possible that any modification that disturbs the wellorganized surface structure of LDL may generate particles
with increased affinity for LPL.
Proatherogenic Effects of LPL in the
Arterial Intima
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As discussed above, LPL that is bound to the components of
extracellular matrix of the arterial intima can lead to retention
of LDL in these structures by acting as a molecular bridge.
Retention increases the residence time of LDL in the intimal
matrix, thus allowing the particles to be modified more
extensively than they would otherwise have been. During
such modification, biologically active lipids, such as oxidized
phospholipids, oxysterols, free fatty acids, and ceramide, are
formed in the LDL particles. Free fatty acids and lysophosphatidylcholine are released from the modified particles to
some extent and, when bound to albumin, may be transported
to the intimal cells or, when the modified LDL particles are
ingested by the cells, may be taken up by them with other
modified lipids (Figure 2). The biologically active lipids may
have several effects on the intimal endothelial cells, macrophages, and smooth muscle cells: they are able to trigger
inflammatory reactions, and at high concentrations, they may
even be cytotoxic. Finally, LPL also bridges native and
modified lipoproteins to cell surface heparan sulfate proteoglycans and to various lipoprotein receptors on the cell
surfaces and thus facilitates the uptake of lipoproteins by the
intimal cells (see review1). According to a very recent
finding, LPL appears to cause selective uptake of cholesterol
from LDL, a process that requires cell surface proteoglycans
but is independent of lipoprotein receptors and LPL activity.61
During lipolysis of chylomicrons and VLDL by LPL, the
formed free fatty acids have been shown to release the
particles with LPL from the endothelial surface,62 allowing
the remnant particles to be transported to the liver or to
extrahepatic tissues. In addition to LDL, IDL particles, small
VLDL particles, and chylomicron remnants have also been
shown to enter the arterial wall, where they have even been
suggested to be preferentially retained.63,64 In an elegant
study, Rutledge et al65 showed that LPL increased the
retention of VLDL in perfused arteries and that when both the
surface and core of VLDL were followed, LPL appeared to
generate surface remnants of VLDL that accumulated in
arteries as “lakes.” Interestingly, particles that closely resemble remnants of triglyceride-rich lipoproteins hydrolyzed by
LPL in vitro have been isolated from the human arterial
intima.66 This important finding provides strong supportive
evidence for the view that LPL plays a role in the retention of
remnants of triglyceride-rich lipoproteins in the arterial intima. Hydrolysis of VLDL by LPL generates free fatty acids,
which are able to increase the permeability of the arteries to
LDL,67 so tending to further promote the entry and retention
of LDL. Finally, fatty acids resulting from lipolysis of VLDL
by LPL have been shown to fuel phagocytosis by macrophages in the presence of low concentrations of glucose,68 to
enhance the production of tumor necrosis factor-␣ by monocyte/macrophages,69 to cause proatherogenic changes in the
production of proteoglycans by smooth muscle cells,70 and to
induce synthesis of LPL by monocytes71 (Figure 2).
Lipoprotein Lipase in the Arterial Wall
215
Finally, LPL may have some actions potentially relevant to
the development of atherosclerosis that are more or less
independent of direct interaction with lipoproteins (Figure 2).
Thus, LPL can (1) enhance the adhesion of monocytes to the
endothelium, presumably as a result of the ability of the
dimeric LPL to bind heparan sulfate proteoglycans on endothelial and monocyte surfaces,72,73 (2) enhance the production
of proteoglycans by macrophages,74 and (3) have a proliferative effect on vascular smooth muscle cells that is independent of the presence of lipoproteins.75
Conclusions and Perspectives
Although the relative importance of the various effects of
LPL in the arterial intima is not known, all of the effects
studied so far appear to be proatherogenic, by interfering
either directly or indirectly with intimal lipoprotein metabolism and, ultimately, by enhancing the accumulation of
intracellular and extracellular lipids in the intima. Similarly,
the role of arterial endothelial LPL, through local production
of lipoprotein remnants capable of entering the intima, has
been suggested to be proatherogenic. In contrast to the arterial
pool of LPL, whether present on the endothelium or deeper in
the intima, the capillary endothelial LPL is clearly antiatherogenic through its antidyslipidemic actions. Because of the
contrasting actions of the 2 pools of LPL (arterial versus
capillary), attempts to decrease the mass or activity in the
body should be restricted to LPL in the arterial intima. A first
hint that this should be a therapeutic goal comes from studies
showing that targeted inhibition of macrophage LPL production is protective against atherosclerosis in mice.28 –30 Targeted LPL therapy may become feasible some day in humans
also. Then, in selected dyslipidemic subjects with low LPL
activity in the capillaries, attempts should be made to prevent
atherosclerosis by stimulating LPL activity in the capillary
bed while depressing it in the arterial wall.
Acknowledgments
This study was supported by grants from the Academy of Finland,
the Sigrid Juselius Foundation, the Federation of Finnish Insurance
Companies, and the European Commission (Macrophage Function
and Stability of the Atherosclerotic Plaque Consortium) to Petri T.
Kovanen and Markku O. Pentikäinen. We thank Dr Petri Laine for
providing human arterial samples for immunohistochemistry and
Suvi Mäkinen for technical assistance. The Wihuri Research Institute
is maintained by the Jenny and Antti Wihuri Foundation.
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Lipoprotein Lipase in the Arterial Wall: Linking LDL to the Arterial Extracellular Matrix
and Much More
Markku O. Pentikäinen, Riina Oksjoki, Katariina Öörni and Petri T. Kovanen
Arterioscler Thromb Vasc Biol. 2002;22:211-217
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