Oxidized phospholipids: emerging lipid mediators
in pathophysiology
Hans-Peter Deignera and Albin Hermetterb
a
Department of Chemical Sciences and Pharmacy,
University of East Anglia, Norwich, Norfolk, UK and
Institute of Biochemistry, Graz University of
Technology, Graz, Austria
b
Correspondence to Dr Albin Hermetter, Institute of
Biochemistry, Graz University of Technology,
Petersgasse 12/2, A-8010 Graz, Austria
Tel: +43 316 873 6457; fax: +43 316 873 6952;
e-mail: [email protected]
Current Opinion in Lipidology 2008, 19:289–294
Purpose of review
Oxidized phospholipids are biologically active agents that are generated by lipid
peroxidation. They are associated with inflammation, oxidative stress and several
diseased states as described by an increasing number of reports. In addition,
information about the interaction partners, the binding sites, the intracellular signalling
and the metabolizing enzymes of these compounds is rapidly increasing. This review will
briefly summarize recent findings and focus on mechanisms with potential
pathophysiological relevance.
Recent findings
Reports reviewed here provide interesting insights into the involvement of oxidized
phospholipids in interleukin transcription, phenotype switching of smooth muscle cells
and apoptotic mechanisms of the modified phospholipids as well as the identification of
metabolizing enzymes.
Summary
Recent studies shed some light on oxidized phospholipid-induced signalling with regard
to apoptosis, gene expression and receptor-mediated events. They support the notion
that the bioactivities of these natural agents detrimentally contribute to the pathological
alteration of basic mechanisms to states recognized in numerous medical conditions.
Advances in the knowledge of signalling pathways and interaction partners of oxidized
phospholipids will increase our understanding of inflammatory processes and molecular
mechanisms of various diseases including atherosclerosis and may play an important
role in the development of future therapeutic options or diagnostics.
Keywords
cellular signalling, inflammation, oxidized phospholipids, receptors
Curr Opin Lipidol 19:289–294
ß 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins
0957-9672
Introduction
Phospholipids containing polyunsaturated fatty acids are
highly prone to modification by reactive oxygen species.
They readily undergo peroxidation under various conditions and various states of diseases to afford oxidized
phospholipids (oxPls), which induce cytotoxicity and
apoptosis and may have a significant role in inflammation.
Bioactive species comprise phospholipids with extensively modified or truncated fatty acid chains in the
sn-2 position typically carrying polar terminal carboxylic
or aldehydic groups required for certain biological activities of the agents (Fig. 1) [1].
Peroxidation thus greatly alters the physicochemical properties of membrane lipid bilayers and as a consequence
induces signalling dependent on the formation or
reorganization of membrane domains or specific molecular
binding. OxPl may also affect the pharmacokinetics of
0957-9672 ß 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins
drugs. Kinnunen and colleagues [2] found that oxidized
phospholipids with aldehydic or carboxylic functions in the
sn-2 position react with haloperidol, doxorubicin and
chlorpromazine. Last but not least, distinct oxPl species
may interact with specific binding sites and receptors
leading to activation of individual signalling pathways.
We intend here to highlight selected novel aspects in this
field that have been published during the last year rather
than present an exhaustive review of all findings in the
area, which was published by our group last year [3].
Role in atherogenesis and inflammation
The role of oxPl and inflammation has not only gained
much attention with regard to atherosclerosis but has also
moved beyond this chronic disease. Leitinger, Bochkov
and colleagues previously demonstrated that oxPls
counteract the lipopolysaccharide (LPS) pathway [4,5].
In agreement with an anti-inflammatory role of oxPls,
290 Lipid metabolism
Figure 1 Chemical structures of oxidized phospholipids
Shown are three typical oxidation products of
1-palmitoyl-2-arachidonoylphosphatidylcholine (PAPC). Long-chain
phospholipid: 1-palmitoyl-2epoxyisoprostanoyl-phosphatidylcholine
(PEIPC); truncated phospholipids: 1-palmitoyl2-glutaroyl-phosphatidylcholine (PGPC) and
1-palmitoyl-2-oxovaleroyl-phosphatidylcholine
(POVPC). PC, phosphorylcholine.
PAPC
POVPC
PC
O
O
PGPC
PC
O
O
O
Oxidation
O
PC
O
O
O
PEIPC
PC
O
O
O
O
O
O
O
O
O
HO
O
O
they reported that oxidized 1-palmitoyl-2-arachidonoylsn-glycero-3-phosphocholine (oxPAPC) interfered with
the ability of LPS to bind to the LPS-binding protein
(LBP) and to CD14, thus suppressing LPS-induced
nuclear factor-kB (NF-kB)-mediated upregulation of
inflammatory genes. Administration of this phospholipid
to LPS-challenged mice alleviated tissue damage, protected mice from lethal endotoxin shock, and reduced
the mortality rate. Similarly, in rodent models of acute
necrotizing pancreatitis (ANP) oxPAPC exhibited a
therapeutic effect and reduced the severity of the symptoms [6]. This effect was also attributed to an inhibition
of LPS-induced signalling.
In line with these observations, Knapp et al. [7] found that
oxPAPC inhibits the interaction of LPS with LPS-binding
protein and CD14. It also reduces the phagocytotic activity
of neutrophils and macrophages by a CD14-independent
mechanism. In these experiments, however, administration of oxPAPC rendered mice highly susceptible to
Escherichia coli peritonitis, which may contribute to
mortality during Gram-negative sepsis in vivo. Thus,
impairment of the host response to bacterial infections
is likely to contribute to the overall harmful profile of
phospholipid oxidation products in this case. The apparent
discrepancy in the reported consequences of oxPl interactions with LPS may be associated with the dual role of
LPS. It influences the status and development of the
immune system on the one hand and is detrimental in
(Gram negative) sepsis on the other hand.
Recent findings of Gharavi and colleagues [8] implicate a
role for JAK2/STAT3 in atherogenesis. These authors
report the activation of this pathway by oxidized phospholipids. 1-Palmitoyl-2-epoxyisoprostane-sn-glycero-3phosphocholine, an oxidation product of 1-palmitoyl-2arachidonoyl-sn-glycero-3-phosphocholine, induces c-Src
kinase-dependent activation of JAK2 in endothelial cells
OH
and synthesis of chemotactic factors, such as interleukin
(IL)-8. In turn, STAT3 activation and regulation of IL-8
transcription is dependent on JAK2 leading to enhanced
levels of STAT3 activity in inflammatory regions of
human atherosclerotic lesions. Since STAT3 activation
is obviously involved in other chronic inflammatory diseases as well (such as rheumatoid arthritis, psoriasis, and
systemic lupus erythematosus), the authors suggest that
STAT3 activation by oxidized phospholipids could be an
important interventional target for atherosclerosis and
other diseases with inflammatory components.
Determination of oxPls might be useful in an assessment
of cardiovascular risks. In blood, oxPls are found to be
associated with apolipoprotein B-100-containing particles,
especially lipoprotein (a) [Lp(a)]. Studies on interactions
of lipoproteins with oxPl as well as on the biological effects
of these complexes still reveal interesting novel aspects. In
the Bruneck study [9], plasma levels of oxPls (oxPl/apoB)
and Lp(a) were measured in 765 subjects in 1995 and the
incidence of cardiovascular disease (cardiovascular death,
myocardial infarction, stroke, transient ischaemic attack)
was assessed. High levels of oxPl were found to be associated with an increased risk of cardiovascular events, which
was further enhanced by elevated lipoprotein-associated
phospholipase activity. The atherogenicity of oxLDL/
apoB levels was similar to the effect of Lp(a). The similar
power of both values as independent predictors could be
partially explained by the ability of Lp(a) to preferentially
bind oxidized phospholipids. It is noteworthy in this context, however, that Lp(a) carries both elevated levels of
oxPls and platelet activating factor (PAF)-acetylhydrolase,
an enzyme capable of hydrolysing oxPl [10].
Oxidized phospholipid-induced signalling
Phospholipid oxidation products such as 1-palmitoyl-2(5-oxovaleroyl)-sn-glycero-3-phosphocholine (POVPC)
Oxidized phospholipids Deigner and Hermetter 291
and 1-palmitoyl-2-glutaroyl-sn-glycero-3-phosphocholine
(PGPC) are found in atherosclerotic lesions. POVPC is
one of the most bioactive oxPl components. Pidkovka
and colleagues [11] published a very important study
demonstrating how oxPls contribute to the pathobiochemistry of atherosclerosis. They found that oxPls such
as POVPC and oxPAPC switch the phenotype of smooth
muscle cells (SMCs) in vivo to an inflammatory state. The
respective lipids lead to changes in gene expression that
are regulated by the transcription factor KLF4. The
suppressed transcription of SMC differentiation marker
genes induces expression of proinflammatory genes,
enhances the rate of cellular proliferation and increases
the synthesis of extracellular matrix proteins. POVPC
and PGPC cause suppression of smooth muscle actin
and myosin heavy chain expression while increasing
expression of MCP-1, MCP-3, and cytolysin; siRNA
targeting of transcription factor KLF4 reduced
POVPC-induced suppression of SMC marker genes,
which is also observed in KLF4 knockout cells.
In line with a pro-apototic activity of oxPl and with
inhibition of this effect by enzymatic hydrolysis, we have
found that POVPC and PGPC induce apoptosis and
growth inhibition in vascular smooth muscle cells [12].
The phospholipids induce apoptosis under low serum
conditions whereas under high serum conditions the resultant mixture is no longer apoptotic but antiproliferative
[13]. An acid sphingomyelinase, which generates the
second messenger ceramide, has been identified as a
key upstream component of apoptotic signalling. It is
activated within minutes, very likely on the protein level.
Specific inhibition of acid sphingomyelinase gene expression abolishes activation of the signalling components
downstream of this enzyme and as a consequence the
apoptotic effect [12]. The initial molecular processes
leading to acid sphingomyelinase activation and the
contribution of the complex enzymatic network contributing to the apparent ceramide levels are still unknown
(Fig. 2).
McIntyre’s group [14] reports that LDL-associated
phosphatidylcholine esterified with sn-2-azelaic acid at
the sn-2 position is readily taken up by cells. This
compound, one of the main phospholipid oxidation
products in LDL, induces apoptosis of HL60 cells at
low micromolar concentrations. Obviously, the intact
phospholipid is required for signalling since this effect
can be prevented by overexpression of PAF acetylhydrolase known for hydrolysing oxidized phospholipids
with polar residues at the sn-2 position. sn-2-Azelaoyl
phospholipids seem to exert a direct effect on mitochondria since they cause rapid swelling of these organelles
and cytochrome c release leading to apoptosome formation followed by caspase 3 and caspase 9 activation.
The apoptotic cells also serve as sources for oxPls [15],
Figure 2 Apoptotic signalling of truncated phospholipids
PGPC
POVPC
A. Primary targets
acSMse
1. Membrane, biophysical
2. Membrane, biochemical
proteins, lipids
3. Other targets
=>protein and lipid trafficking?
B. Sphingolipid network
Ceramide
1. Ceramide modification
2. Ceramide de-novo synthesis
=>sphingolipid rheostat
responsible for cell survival,
proliferation and apoptosis
MAPK
APOPTOSIS
Yet uncharacterized effects of the oxidized phospholipids 1-palmitoyl-2glutaroyl-phosphatidylcholine (PGPC) and 1-palmitoyl-2-oxovaleroylphosphatidylcholine (POVPC) on their supramolecular or molecular
targets and the ceramide rheostat are essential features of their cellular
activities.
which may contribute to an amplification of cell death
in atherosclerosis.
Lipoproteins transport oxPl and deliver these compounds
to cells. In addition, the lipoprotein particles influence the
signalling of oxidized phospholipids in terms of pro-inflammatory and anti-inflammatory criteria [16]. It was shown
that 1-palmitoyl-2-(5,6 epoxyisoprostanoyl)-sn-glycero-3phosphocholine (PEIPC), an oxidation product of 1-palmitoyl-2-arachidonyl-sn-3-glycero-phosphorylcholine,
induces an inflammatory response in endothelial cells,
which is due to induction of specific genes. This effect was
suppressed after preincubation with HDL. The same
lipoprotein fraction also reduced the oxPl-dependent
chemotactic activity and monocyte binding. In addition
to its cholesterol-lowering effect, these phenomena may
add to the list of protective properties of HDL.
Truncated phospholipids on the one hand and epoxyisoprostane phospholipids on the other hand specifically
modulate the transcription of several genes. Berliner’s
group [17] reported that the levels of OKL38 mRNA (also
named bone marrow-derived growth factor), a tumour
growth inhibitor, were increased by oxPAPC and 1-palmitoyl-2-epoxyisoprostanoyl-sn-glycero-3-phosphocholine
(PEIPC). This effect appears to be limited to distinct
oxidized phospholipids since PEIPC, but neither POVPC
nor PGPC, induced Nrf2 translocation and OKL38 expression. We analysed the effects of POVPC and PGPCs on
monocyte transcription using microarrays and found that
292 Lipid metabolism
these phospholipids enhanced transcription of CCl11,
MMP1 and several other genes. Most remarkably, many
of these changes matched the effects mediated by ceramide (M. Blaess, A. Hermetter, H.P. Deigner, unpublished data).
Receptors for oxidized phospholipids
Specific receptor binding of oxPl is the subject of an
ongoing debate [3]. Evidence that oxidized phospholipids
may act by binding to a G protein-coupled receptor
(GPCR) has previously been provided by Parhami et al.
[18,19]. These authors demonstrated that minimally
modified LDL stimulated a putative Gs-coupled receptor,
thus increasing cyclic AMP (cAMP) levels in endothelial
cells.
More recently, the prostaglandin E2 (PGE2) receptor
EP2, a Gs-linked GPCR, has been added to the list of
binding sites for oxidized phospholipids. Activation
of endothelial cells by the oxidized phospholipid
PEIPC may occur via this receptor and provide a
mechanism by which monocytes/macrophages are
recruited to the subendothelial space: Li et al. [20]
found that PEIPC induced monocyte adhesion to
endothelial cells by activating EP2, leading to increased
cAMP levels and activation of protein kinase A. Further
signalling may proceed via activation of R-Ras and
1-integrins, enhancing surface expression of CS-1
fibronectin capable of interacting with VLA-4 on monocytes.
the phospholipid and is not affected by the structure of
the polar head group.
Aldehydo-phospholipids are capable of reacting with NH2
groups of proteins and phospholipids to form new epitopes
and to cause immune reactions [23,24]. An unspecific
occupation of receptors and partial antagonisms with
natural or specific synthetic ligands may be due to an
aldehyde amino reaction and Schiff base formation. The
identification of the modified targets and their relevance to
signalling are the subjects of intense research in our
laboratory. Along these lines, investigations are currently
being performed to characterize the oxPl-associated proteome of vascular cells. For this purpose, we have developed specific molecular tools to study uptake, distribution,
cellular localization and reactivity of oxPl [25] (Fig. 3).
Metabolism of oxidized phospholipids
It has previously been shown that POVPC binds to
human macrophages via the PAF receptor (PAF-R).
Occupation of the PAF-R by the oxidized phospholipids
modifies the transcription levels of pro-inflammatory
genes [21] such as IL-8. Other genes, however, including
those encoding for matrix metalloproteinase-13 and 15lipoxygenase, that are stimulated by binding of PAF to its
receptor were not affected by the phospholipids. Thus, it
was suggested that POVPC signalling in macrophages
occurs only partially via the PAF-R.
It has been known for years that oxidized fatty acyl chains
can be released from the sn-2 position of membrane
phospholipids by PAF-acetylhydrolase (PAF-AH) in
plasma and an intracellular type II PAF acetylhydrolase.
The substrate preferences of plasma PAF-AH and the
intracellular enzyme which is found in the cytosol as well
as in membrane-associated form are very similar. Overexpression of the type II enzyme, which shows elevated
expression levels in epithelial cells, was previously shown
to suppress oxidative stress-induced apoptosis. Arai’s
group [26] very recently reported on the effect of
PAF-AH (II) deficiency in mice (Pafah2 / mice). While
Pafah2 / mice apparently developed normally and were
phenotypically indistinguishable from wild-type mice,
mouse embryonic fibroblasts derived from Pafah2 /
mice were more sensitive to tert-butylhydroperoxide
treatment than those derived from wild-type animals.
This effect was attributed to the activity of oxPl. Interestingly, Pafah2 / mice displayed impaired recovery
from CCl4-induced hepatic injury. These data support
a protective role of PAF-AH against the overt effects of
oxPl in vivo and it would be interesting to test the oxPl
effects on lifespan in animal models.
A very interesting study reporting on the molecular
mechanisms of macrophage interaction with oxidized cell
membranes has been published very recently. According
to the ‘lipid whisker model’ of Greenberg et al. [22],
macrophage binding to cell surfaces is mediated by the
interaction of CD36 with the oxidized phospholipid acyl
chains protruding from the plasma membrane. Recognition of the phospholipids head group is not involved.
From studies performed with oxidized phosphatidylcholine and ethanolamine, Berliner’s group [1] arrived
at a similar conclusion. They found that binding of
monocytes to endothelial cells is solely dependent on
the type of the oxidized fatty acid in the sn-2 position of
As tools for systems biology approaches are becoming
increasingly available, it will be possible to analyse
complex scenarios such as formation, metabolism and
partitioning of oxPl and its metabolites together with the
associated signal transduction phenomena. Oxidative
stress may be reflected by enhanced concentrations of
oxPl and their oxidized fatty acid components as well as
their conjugates with proteins and other lipids. Efforts are
already being made to apply metabolomics aiming at a
comprehensive characterization of virtually all relevant
lipid species. In addition to lipidome analyses, an extensive mapping of cell components on the levels of the
transcriptome, the proteome and the apparent enzyme
Oxidized phospholipids Deigner and Hermetter 293
Figure 3 Import of fluorescent oxidized phospholipids into vascular smooth muscle cells
The fluorescent 1-palmitoyl-2-glutaroyl-phosphatidylcholine (PGPC) analogue localizes to the lysosomes (left). 1-Palmitoyl-2-oxovaleroylphosphatidylcholine (POVPC), which forms Schiff bases with the amino groups of proteins and phospholipids, is retained in the plasma membrane
(right).
activities will ultimately lead to a picture of the signalling
networks that mediate the biological effects of oxPl.
So far it has not been known whether or to what extent
the aldehyde function in phospholipids such as POVPC
[1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphocholine] is enzymatically processed further. The aldehyde
function, however, is a prerequisite for certain biological
properties of this molecule. Phospholipid aldehydes
such as POVPC activate binding of monocytes by endothelial cells [27] and increase the production of monocyte
chemotactic factors. It has previously been shown that
reduction of the aldehyde group to the corresponding
alcohol abolished oxPl-induced stimulation of monocyte
binding [1]. Spite and colleagues [28] recently reported
that POVPC is reduced efficiently by mammalian aldoketo reductases (AKRs; AKR1A and B families). Among
these enzymes, which may catalyse tissue-specific metabolism of phospholipid aldehydes, the human aldose
reductase AKR1B1, but not AKR6 or ARK7, shows the
highest catalytic activity.
defined synthetic and labelled oxPl species and the modern omics techniques of systems biology. They will
undoubtedly help establish a molecular network of the
cellular signalling components that are involved in the
mediation of the pathophysiological effects of oxPl and
thus represent potential pharmaceutical targets.
Acknowledgements
Financial support from the Austrian Science Fund FWF is gratefully
acknowledged (project F30-B05 of the special research programme
SFB LIPOTOX ).
References and recommended reading
Papers of particular interest, published within the annual period of review, have
been highlighted as:
of special interest
of outstanding interest
Additional references related to this topic can also be found in the Current
World Literature section in this issue (p. 319).
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Conclusion
OxPls may show detrimental as well as beneficial cellular
effects. Key components of their intracellular signal
transduction have been identified that mediate the
observed cellular effects including inflammation, apoptosis and phenotype switching; however, the fundamental
molecular mechanisms underlying signal initiation and
propagation, such as lipid mediators and complex enzyme
networks, are still far from clear. An advancement in this
field can be expected from studies that are based on well
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8
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