70
DOI 10.1002/ejlt.200500272
Asim K. Duttaroy
Fatty acid-activated nuclear transcription factors
and their roles in human placenta
Department of Nutrition,
Institute of Basic Medical
Sciences,
Faculty of Medicine,
University of Oslo, Norway
Eur. J. Lipid Sci. Technol. 108 (2006) 70–83
Emerging evidence indicates that fatty acid-activated nuclear transcription factors
play very important and complex roles in placental biology. These fatty acid-activated
receptors are involved at a number of different levels such as differentiation, proliferation, and hormone synthesis in the feto-placental unit. Since these receptors are also
fatty acid sensors, they may be involved in placental fatty acid transport and metabolism. The present article is a review of the complex roles of peroxisome proliferatoractivated receptors, sterol regulatory element-binding proteins and liver X receptors in
placental biology.
Keywords: PPAR, fatty acid uptake, SREBP, LXR, Placenta.
Review Paper
1 Introduction
Human placental transport of long-chain polyunsaturated
fatty acids (LC-PUFA) from the maternal circulation into
the fetal circulation is essential for proper fetal growth and
development [12–14]. During this period, recruitment of
maternal LC-PUFA, mainly docosahexaenoic acid (DHA,
22:6n-3) and arachidonic acid (ARA, 20:4n-6), is critical
for rapid brain and other tissue growth [2, 13, 15, 16].
Several fatty acid-binding and transport proteins are
thought to be responsible for effective uptake of maternal
plasma fatty acids by the placental trophoblast [17].
Recent studies indicate that PPAR may be responsible for
regulating the expression of fatty acid transport or binding
proteins in tissues such as adipose, liver and skeletal
muscle [18–22]. On the other hand, fatty acids and their
oxygenated derivatives directly or indirectly regulate several cellular processes such as differentiation, development and gene expression in tissues through PPAR [23,
24]. Therefore, it is very likely that these nuclear receptors
may also be involved in placental fatty acid uptake by
modulating expression of fatty acid transport proteins
[25–27]. The main aim of this review is to discuss the
complex and diverse roles of these fatty acid-activated
transcription receptors [i.e. PPAR, sterol regulatory element-binding proteins (SREBP) and liver X receptors
(LXR)] in feto-placental growth, development and fatty
acid transport function.
The human placenta performs several important functions essential for the maintenance of pregnancy and
development of the fetus [1]. The human placenta is a
hemochorial placenta and therefore provides direct
access to the maternal blood for nutrients like glucose,
fatty acids, and amino acids [1, 2]. Placental trophoblast
cell invasion of uterine tissues and remodeling of uterine
spiral arterial walls ensure that the developing feto-placental unit receives the necessary supply of blood and
that efficient transfer of nutrients and gases and the
removal of wastes can take place. Implantation and the
formation of the placenta therefore is a highly coordinated
process involving interaction between maternal and
embryonic cells. Changes in placental development and
function have dramatic effects on the fetus and its ability
to cope with the intra-uterine environment. Insufficient
growth in utero is associated with diseases of adulthood,
such as diabetes, hypertension, and cardiovascular disease [3]. Emerging evidence suggests that peroxisome
proliferator-activated receptors (PPAR) are critical players
in growth, development and physiological functions of the
feto-placental axis [4–7]. These fatty acid-activated
nuclear transcription factors also regulate expression of
genes responsible for several placental functions including trophoblast invasion, nutrient transport, and hormone
synthesis. All PPAR subtypes are present in human placenta and their diverse biological roles have been
increasingly realized in placental biology [8–11].
2 Nuclear transcription factors in human
placenta
Correspondence: Asim K. Duttaroy, Department of Nutrition,
Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, P.O. Box 1046 Blindern, N-0316 Oslo, Norway.
Phone: 147 22851547, Fax: 147 22851341, e-mail: a.k.dutta
roy@medisin.uio.no
Nuclear receptors comprise a large family of ligand-regulated transcription factors [28]. They have been divided
into two groups: class I nuclear receptors comprising
steroid hormone receptors, and class II nuclear receptors
which are still named “orphans” because their ligands
© 2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Lipid Sci. Technol. 108 (2006) 70–83
have not yet been identified. The modular structure of
nuclear receptors is generally conserved in almost all the
members of this superfamily (Fig. 1). The structure
includes the A/B domain, containing a ligand-independent transcription activation function (AF-1) at the N terminus; the C domain containing a DNA-binding domain
(DBD), characterized by two typical zinc-fingers that are
involved in the recognition of specific DNA consensus
sequences; and the D domain which confers flexibility on
the receptor for proper dimerization and for interaction
with the DNA consensus sequences located on target
genes [29, 30]. The E domain consists of the ligand-binding domain (LBD), a hydrophobic pocket that can
accommodate the selective ligand for the receptor, and
the ligand-dependent transcription activation function
(AF-2). The F domain is present in some nuclear receptors
and seems to negatively modulate the transcription activity of the receptor [31, 32].
Upon binding of the ligand, the receptor undergoes a
conformational change that exposes a-helix 12, the surface for interaction with transcription co-activators, which
has been identified as the AF-2 of the receptor [33]. At the
same time, the structural modifications elicited by the
ligand decrease the affinity to co-repressors, which are
released from the receptors [29–32, 34]. However, nuclear
receptors can also be regulated in a ligand-independent
fashion through the AF-1. Post-translational modifications such as phosphorylation [35, 36] have been reported to modulate receptor activity. Co-activators and corepressors interacting with nuclear receptors regulate the
rate of transcription initiation not only by interacting with
proteins of the pre-initiation complex and engaging RNA
polymerase II [37], but also by recruiting histone acetyl
Fig. 1. Schematic representation of a nuclear receptor. A
typical nuclear receptor is composed of several functional
domains. The variable N-terminal region (A/B) contains
the ligand-independent AF-1 transactivation domain. The
conserved DBD is responsible for the recognition of specific DNA sequences. A variable linker region D connects
the DBD to the conserved E/F region that contains the
LBD as well as the dimerization surface. The ligand-independent transcriptional activation domain is contained
within the A/B region, and the ligand-dependent AF-2
core transactivation domain within the C-terminal portion
of the LBD.
© 2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
PPARs and their roles in human placenta
71
transferases (HAT) or histone deacetylases (HDAC). Some
of these co-regulators are also part of the HAT or HDAC
complex. HAT and HDAC have opposite effects on the
nucleosomal structure and local chromatin assembly and,
consequently, they also play a key role in the activation
and repression of gene transcription, respectively, by
affecting the accessibility of transcription factors to the
DNA and the epigenetic marking system constituting the
so-called “histone code” [38].
3 PPAR in human placental trophoblasts
PPAR are members of the nuclear receptor superfamily of
transcription factors that includes steroid receptors [28].
They bind fatty acids and their oxygenated metabolites
and so were identified as regulators of lipid homeostasis.
These receptors are involved in a wide variety of physiological processes ranging from cell differentiation, inflammatory response and regulation of vascular biology to
reproductive biology, as well as in pathological conditions
such as type II diabetes, atherosclerosis and cancers [8–
11, 39]. There are three PPAR subtypes, termed PPARa,
PPARd (also referred to as PPARb, NUC1, or FAAR) and
PPARg. Analysis of their gene sequences shows that the
three PPAR genes are probably derived from a common
ancestral gene. PPAR have a similar structural and functional organization to other nuclear receptors [40]. The
PPAR are expressed in a broad range of tissues in both
rodents and humans [41–44]. PPARa is expressed in liver,
kidney, heart, gut, brain, adipose tissue, retina and skeletal
muscle in rodents, while in humans it has been shown to be
expressed in heart, placenta, lung, liver, muscle, kidney,
pancreas and adipose tissue [42–45]. PPARd appears to
be expressed ubiquitously, with expression being similar
for both rodents and humans [41, 46, 47]. PPARg shows
much more restricted expression than PPARa or d. PPARg
is expressed in adipose tissue, intestine and immune cells,
and at much lower levels in muscle, liver, heart, kidney,
pancreas and retina [45, 47–50]. Three forms of PPARg are
known and are termed PPARg1, g2 and g3 [51]. PPARg1
has higher levels of expression than PPARg2, which is
expressed only in adipose tissue, colon and liver [52].
Expression of PPARg3 mRNA is restricted to adipose tissue and colon, similar to that of PPARg2 [53].
Binding of a ligand to the LBD leads to heterodimerization
of the PPAR to the retinoid X receptor (RXR) and, subsequently, binding of the complex to a peroxisome proliferator response element (PPRE) on the target gene,
which leads to gene transcription [54]. By analysis of the
promoters of several other peroxisome proliferatorresponsive genes, a PPRE sequence motif was defined
as two direct TG(A/T)CCT repeats, known as half-sites,
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A. K. Duttaroy
separated by a single nucleotide and thus called a direct
repeat one (DR1). PPRE located at variable distances
upstream of the transcription initiation site have been
identified in other genes known to be activated by peroxisome proliferators, including genes encoding peroxisomal, microsomal, mitochondrial, nuclear, and cytosolic
or extracellular proteins [55–57]. Comparison of PPRE
sequences with the DNA-binding motifs of other nuclear
receptors, including the thyroid hormone receptor (TR),
the retinoic acid receptor (RAR), RXR, and the vitamin D3
receptor (VDR), revealed that these receptors all recognize the same half-site sequence motifs (TGACCT). Like
PPAR, these receptors bind to direct repeats as heterodimers with a common partner, RXR. The relative spacing
and orientation of the half-site motifs determine which
nuclear receptor-RXR heterodimer binds to the response
element. The RXR heterodimers with RAR, TR, VDR, RAR,
and PPAR recognize direct repeats separated by five,
four, three, two, or one nucleotide, respectively. A number
of studies point to the importance of the sequences
flanking the PPRE for maintaining the optimal conformation of the PPAR-RXR heterodimer on the PPRE [58]. Not
all of the PPRE in responsive genes act to mediate
increases in transcription. A growing number of genes,
including transthyretin, some apolipoprotein genes,
transferrin, and hepatocyte nuclear factor-4, possess
DR1-like motifs but are negatively regulated by peroxisome proliferators through PPAR. PPAR may negatively
regulate some genes through DR1-like elements by competing for binding to the DR1 with other nuclear receptors
that constitutively activate expression [58].
In addition to PPAR, gene targeting studies in mice have
demonstrated a critical role for RXRa also in feto-placental development [59]; however, this review will concentrate only on the roles of the PPAR, LXR, and SREBP.
3.1 PPARÆ
The importance of PPARa in placental biology is relatively
small compared with that of the other two PPAR [5].
PPARa mRNA has been detected in amnion, choriodecidua, placental syncytial and cytotrophoblast cells
at term, as well as in placental choriocarcinoma (BeWo)
cell lines [5, 60, 61]. PPARa, however, may not be essential for feto-placental biology [62]. Unlike the situation in
PPARg and PPARd knockout mice, normal fertility was
observed in PPARa knockout mice. The few available
data suggest the existence of metabolic roles of PPARa in
placenta. A PPARa agonist, clofibric acid, was reported to
suppress proliferation of the trophoblast cell line JEG-3
by stimulating p53 expression [63]. Hashimoto et al.
studied the effect of PPARa agonists on cell growth and
© 2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Lipid Sci. Technol. 108 (2006) 70–83
function of the immortalized human extravillous trophoblast cell line TCL.1 [64]. Both gemfibrozil and clofibrate
inhibited proliferation of these cells and secretion of human chorionic gonadotrophin (hCG). Moreover, PPARa
was suggested to be involved in the development of the
fetal epidermal barrier [65, 66]. PPARa agonists accelerated epidermal barrier development in skin explants from
fetal rats in vitro [65]. However, further studies are warranted in order to understand the importance of PPARa in
the feto-placental unit.
3.2 PPARª
The critical importance of PPARg in the regulation of fetoplacental development was first demonstrated in the
knockout mouse [4]. PPARg-deficient embryos had
abnormal trophoblast differentiation as well as defective
placental vasculature. Barak et al. reported a robust
expression of PPARgd mRNA in the placenta from
embryonic day 8.5 (E8.5) onwards [4]. This is lethal by E10,
at the point when the primary responsibility for the maintenance of fetal metabolism is transferred from the yolk
sac to the placenta [4, 67]. In addition, a complete absence
of all types of adipose tissue in the mutant pups and severe
defects of the heart were observed. Disruption of either
PPAR-binding protein or PPAR-interacting protein also
results in defective placental development and embryonic
lethality due to defects in multiple organ systems [67–69].
In order to overcome the problem of embryonic lethality in
PPARg null mice, cell-specific deletion of the gene using
the Cre-loxP recombination system has been performed.
While some cell types did not appear to be dependent on
functional PPARg, the loss of the PPARg gene in oocytes
and granulosa cells resulted in impaired fertility, featuring
reduced progesterone levels and implantation rates [70].
PPARg is expressed in human placental tissues at various
stages of gestation. PPARg mRNA was also present in all
choriodecidual and villous human placental samples, and
its level remained unaltered with the onset of labor [48].
PPARg protein was localized in the nuclei of the syncytiotrophoblast, cytotrophoblast and endothelial cells of the
term human placenta. The placental choriocarcinoma
cells (BeWo and JEG-3 cells) express PPARg, which is
functionally responsive to 15-deoxy-D12,14-prostaglandin J2 (15d-PGJ2) [27, 48, 71, 72].
Implantation of the human conceptus involves invasion of
the uterine epithelium and the underlying stroma by trophoblastic cells, which undergo a complex process involving proliferation, migration and differentiation. Trophoblast differentiation is modulated by PPARg, and its
effects are reported to be ligand specific [73]. Troglitazone
(a synthetic agonist of PPARg) stimulates PPARg activity
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Eur. J. Lipid Sci. Technol. 108 (2006) 70–83
in BeWo cells and enhances the biochemical and morphological differentiation of primary trophoblasts. In contrast, 15d-PGJ2 (endogenous agonist of PPARg) stimulates PPARg activity in BeWo cells, but reduces differentiation and increases apoptosis of human trophoblasts
in culture [73]. A similar induction of apoptosis by 15dPGJ2 was observed in many carcinoma cell lines [74–76].
The mechanism of 15d-PGJ2-induced apoptosis is not
clearly understood; however, an increased expression of
apoptotic proteins (caspase 3, caspase 9, and Bax) and
decreased expression of the anti-apoptotic protein Bcl-2
and the transcription factor NF-kB were observed in
these cases [75, 77]. In vivo production of diverse PPARg
ligands in the feto-placental unit may result in differential
and perhaps opposing effects on trophoblast differentiation and apoptosis.
PPARg ligands also inhibit extravillous cytotrophoblast
invasion in vitro [26, 27, 78]. Both 15d-PGJ2 and rosiglitazone inhibited extravillous cytotrophoblast invasion in a
concentration-dependent manner and in synergy with
pan-RXR agonists. Both PPARg and pan-RXR antagonists were found to promote cytotrophoblast invasion in
this model system [26, 27]. Subsequently, it was shown
that other putative natural ligands for PPARg, such as
oxidized low-density lipoproteins (oxLDL), also inhibited
cytotrophoblast invasion [78]. These data indicate that
PPARg may also play a role in human trophoblastic invasion, which, unlike tumor invasion, is precisely regulated.
A defective invasion of the uterine spiral arteries is directly
involved in preeclampsia.
PPARg protein expression and activation are dramatically
increased in a trophoblast cell line (JEG-3 cells) when
incubated in the presence of serum lipids isolated from
pregnant women [79]. In addition, PPARg-RXRa heterodimers have been shown to be important modulators of
hormone synthesis in the human trophoblast [27, 73].
Activation of PPARg in these cells by rosiglitazone
increased the levels of hCG, leptin, human placental lactogen and human growth hormone [27]. PPARg and RXRa
ligands increase the hCGb transcript level; the hCGb
promoter was suggested to contain binding sites for
PPARg-RXRa heterodimers [27]. Several other endogenous PPARg ligands, such as 9S-hydroxy-10E,12S-octadecadienoic acid (9-HODE), 13S-hydroxy-9Z,11E-octadecadienoic acid (13-HODE), and 15S-hydroxy5Z,8Z,11Z,13E-eicosatetraenoic acid (15-HETE), stimulated hCG production in primary human trophoblasts [80].
This indicates a role for these oxygenated fatty acids and
lipids in placental differentiation and function. Interestingly, no effect of these ligands on the expression of
markers for syncytium formation (syncytin) or cell cycle
progression was observed [80]. All these data warrant
further research into the feto-placental synthesis of
© 2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
PPARs and their roles in human placenta
73
diverse ligands in relation to PPARg activity, as this may
affect pregnancies via cell differentiation and hormone
synthesis in the feto-placental unit.
The current hypothesis regarding the etiology of preeclampsia is focused on maladaptation of immune
responses and defective trophoblast invasion. An excessive maternal inflammatory response perhaps results in a
chain of events including shallow trophoblast invasion,
defective spiral artery remodeling, placental infarction
and release of pro-inflammatory cytokines and placental
fragments into the systemic circulation. Several cytokines, produced at the maternal-fetal interface, have an
impact on trophoblast invasion. Inflammation is associated with oxidative stress and enhanced expression of
adhesion molecules and cytokines in the vasculature,
resulting in the infiltration of neutrophils and monocytes/
macrophages [81]. PPARg ligands inhibit the activation of
inflammatory gene expression and can negatively interfere with pro-inflammatory transcription factor signaling
pathways in vascular and inflammatory cells [81]. Apart
from trans-activating genes, a major role of PPARg is in
the trans-suppression of inflammatory gene activation, by
negatively interfering with the NF-kB, STAT-1, and AP-1
signaling pathways in a DNA binding-independent manner [82]. Several lines of evidence suggest that PPARg
exerts anti-inflammatory effects by negatively regulating
the expression of pro-inflammatory genes induced in response to macrophage differentiation and activation. An
increased oxLDL uptake leads to the formation of foam
cells in macrophages, a critical step for the development
of atherosclerosis lesions; however, very little information
is available with respect to placental trophoblast uptake
of oxLDL and subsequent development of pathological
states such as preeclampsia. The macrophage scavenger
receptor CD36 (FAT) plays a key role in the initiation of
atherosclerosis through its ability to bind to and internalize oxLDL. FAT/CD36 is also expressed on the cell
surface trophoblasts [12], and therefore it may be
involved in the uptake of oxLDL and can thus supply the
necessary agonist for activation of PPARg and LXR in
trophoblast cells (please see the LXR section). The multifunctional activities of CD36 in trophoblasts suggest that
modulation of CD36 expression might lead to a series of
potential beneficial or harmful effects in pregnancy.
3.3 PPAR
PPARd, mRNA and protein, is expressed in human trophoblast cells [47, 83], but its function is still not fully
known. Like PPARg, disruption of the PPARd gene in mice
results in placental defects, and for more than 90% of
fetuses it is lethal early in gestation (E10.5) [84]. Homozygous loss of PPARd resulted in frequent embryonic
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A. K. Duttaroy
lethality and revealed an abnormal gap in the placentaldecidual interface by E9.5, 1 day before onset of lethality.
Three out of four PPARd null embryos that survived
beyond E10.5 exhibited extensive maternal hemorrhages
into the labyrinthine zone [84]. PPARd is therefore essential for feto-placental growth and development, but its
roles appear to be quite different from PPARg in feto-placental growth and development. While PPARg appears to
be required for differentiation of the placental labyrinth,
PPARd seems to be more important for the normal development of the placental-decidual interface [4, 84].
A recent study indicates that the prostacyclin (PGI2) analogue carbaprostacyclin (cPGI2), a ligand of PPARd, reduced
11b-hydroxysteroid dehydrogenase type 2 (11b-HSD2) activity as well as expression at both protein and mRNA levels
in cultured human placental trophoblasts [85]. Placental
11b-HSD2 plays a pivotal role in controlling the precise
levels of fetal exposure to maternal glucocorticoids and its
modulation within the placenta [86]. An appropriate level of
11b-HSD2 in the human placenta appears to be critical for
normal fetal development, because the reduced expression
of this enzyme is associated with complicated pregnancies
(such as IUGR). PPARd therefore may be involved in the
regulation of placental function via 11b-HSD2.
PPARd may also be involved in embryo implantation and
decidualization [87]. Scherle et al. [88] have shown that
activation of the p38 signaling cascade is required for the
induction of cyclooxygenase (COX)-2 and PPARd expression during decidualization in the mouse. PPARd is markedly induced in the stroma surrounding the implanting
blastocyst from the time when the attachment reaction
occurs [89]. cPGI2 enhanced the heterodimerization of
PPARd and RXRa within the decidual cell nucleus and
induced transcription of a PPRE-containing reporter gene in
a human endometrial cell line [87]. The maintenance of early
pregnancy requires an intracrine prostanoid signaling pathway involving COX-2, PGI2 and PPARd [89]. Taken together,
these results provide evidence that COX-2-derived PGI2 is
involved in implantation and decidualization via activation of
PPARd. All these data indicate that PPARd is a regulating
factor for feto-placental growth and development. An
abnormal activity of PPARd in the human placenta may lead
to an altered expression of its target genes and thus may
contribute to pathological pregnancies. Further research is
required at the molecular level for definitive conclusions.
Eur. J. Lipid Sci. Technol. 108 (2006) 70–83
to their target DNA sequences as heterodimers with the
RXR to direct repeat four (DR-4)-type sequence motifs
termed LXR-responsive elements. There are two known
types: LXRa (NR1H3) and LXRb (NR1H2) [90]. LXRa and
LXRb play a key role in regulating the transcription of multiple genes involved in bile acid and fatty acid synthesis,
glucose metabolism, and sterol efflux [90]. LXRb is ubiquitously expressed in all tissues, whereas the expression of
LXRa is predominantly restricted to tissues known to play
important roles in lipid metabolism, such as liver, kidney,
macrophages, small intestine, and adipose tissue [91]. Although sterol loading induces LXR target genes, neither
cholesteryl esters nor free cholesterol can act as ligands
for LXR and conversion to oxysterols is required for transcriptional activity. The endogenous ligands for both LXR
are likely to be intermediates or end products of sterol
metabolic pathways, such as 22(R)-hydroxycholesterol,
24(S),25-epoxycholesterol, 24(S)-hydroxycholesterol and
27-hydroxycholesterol [92]. ABCA1 and ABCG1 induction
in macrophages, liver, intestine, neuronal cells, and Sertoli
cells synergistically occurs with 9-cis retinoic acid as RXR
agonist and the natural oxysterols 20-hydroxycholesterol,
22-hydroxycholesterol, 24-hydroxycholesterol, 24,25epoxycholesterol, and 27-hydroxycholesterol. 24-Hydroxycholesterol is very abundant in the brain and the liver,
which also produces significant amounts of 22-hydroxycholesterol and 27-hydroxycholesterol. The oxysterols
20-hydroxycholesterol,
22-hydroxycholesterol,
and
24,25-epoxycholesterol are not present in cholesterolloaded macrophages, rendering them unlikely to be natural ligands of LXR. In contrast, 27-hydroxycholesterol is
the predominant oxysterol in the circulation, as well as in
macrophage-derived foam cells from atherosclerotic
lesions, directly linking this cholesterol metabolite to processes in atherogenesis.
The LXR belong to a subclass of nuclear hormone receptors that form obligate heterodimers with RXR and are
bound and activated by oxidized cholesterol [90]. LXR bind
The LXR control the expression of several genes required
for cholesterol metabolism, such as members of the ATPbinding cassette (ABC) transporters, and apolipoprotein E, CYP7A1 [93]. LXR also influence lipoprotein metabolism through the control of modifying enzymes such
as lipoprotein lipase, cholesteryl ester transfer protein
and phospholipids transfer protein. [94]. LXRa-deficient
mice were devoid of the expression of a number of lipogenic genes, e.g. SREBP-1c, fatty acid synthase (FAS),
stearoyl-CoA desaturase-1 (SCD-1) and acetyl-CoA carboxylase-a (ACC-a). FAS, SCD-1 and ACC-a are directly
regulated by SREBP-1 [93]. Therefore, LXR are not only
involved in sterol metabolism, but also in the general lipid
metabolism. Recently, we demonstrated the presence of
both LXRa and b in human primary trophoblasts and
BeWo cells [95]. The LXR agonist tularic (T0901317)
increased the lipid synthesis associated with an
increased synthesis of lipogenic target genes, SREBP-1
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3.4 LXR and SREBP in human placental
trophoblasts
Eur. J. Lipid Sci. Technol. 108 (2006) 70–83
and FAS, in BeWo cells [95]. SREBP-1 and -2 are separate gene products of approximately 125 kDa located in
the membranes of the endoplasmic reticulum and the
nuclear envelope [96]. The gene for SREBP-1 has two
different transcription start sites that generate two mRNA
and proteins: SREBP-1a and -1c. SREBP-1 and -2 are
both detected in the placenta. Insulin is also known to act
via SREBP-1c via augmenting the nuclear content of
SREBP-1c, while LC-PUFA suppress the nuclear content
through a post-transcriptional mechanism. The roles of
SREBP-1c in placenta are still not elucidated. Although
PUFA evidently decrease lipogenesis in adipose tissue, in
an SREBP-dependent manner, one cannot yet determine
the importance of this effect in relation to the effect of the
maternal PUFA transport across the placenta.
PPARs and their roles in human placenta
75
effect of PPARg-induced increase of hCG production [27]
and thereby contributing to balancing the production of
hCG during pregnancy.
4 Fatty acid uptake by the placenta: Roles
of PPAR
Like PPARa [64], activation of LXR reduced secretion of
hCG in trophoblasts [95]. Although the mechanisms of
LXR-mediated inhibition of hCG secretion in BeWo cells is
not known at present, we can speculate that LXRa may
have a regulatory role in trophoblasts, countervailing the
Human fetal growth and development have a unique
requirement for the supply of dietary lipids. Fetal brain
and retina are very rich in ARA and DHA, and a sufficient
supply of these LC-PUFA from the maternal plasma by
the placenta during the last trimester of pregnancy is of
great importance [16, 98]. Free fatty acid (FFA) is the
mode of transport of fatty acids across the placenta [17,
99]. The presence of several membrane fatty acid transport proteins [fatty acid binding protein (FABP)pm, fatty
acid translocase (FAT), fatty acid transport protein (FATP)]
and cytoplasmic fatty acid-binding proteins [liver-type (LFABP) and heart-type (H-FABP)] in human placenta was
demonstrated [17]. FAT and FATP are present in placental
membranes, microvillous and basal membranes whereas
p-FABPpm is only present in microvillous membranes [17]
of trophoblasts [100]. Studies in different tissues suggested that these membrane proteins alone or in tandem
might be involved in effective uptake of FFA [12, 99, 101].
Unlike p-FABPpm, other fatty acid transporters such as
FAT/CD36 and FATP do not have any preference for LCPUFA [102]. Therefore, location of FAT and FATP on both
sides of the bipolar placental cells may allow bi-directional flow of all types of FFA across the placenta,
whereas the exclusive location of p-FABPpm on the
maternal side may favor the unidirectional flow of maternal plasma LC-PUFA to the fetus (Fig. 2). In addition to
these membrane transporters, cytoplasmic fatty acidbinding proteins (L-FABP and H-FABP) were also identified in human placenta [17]. As there are differences in
binding affinity and capacity of these two FABP, their
expression in the placental trophoblasts may indicate
differential fatty acid transport and metabolism. The COX
metabolites of ARA, such as prostaglandin (PG)E2, TxB2
and LTB4 do not bind L-FABP, whereas cyclopentenone
PG, PGA1, PGA2, PGJ2, and D12-PGJ2, bind more avidly
than oleic acid to L-FABP. PGD2, PGE2 and PGF2a are
poor competitors, whereas PGE1 is intermediate [103–
106]. It has been demonstrated that L-FABP transports
these ligands to PPAR through protein-protein interaction
and thus may play an important role in gene expression
[107, 108]. In addition, differential effects of FABP on fatty
acid uptake and esterification were demonstrated using
transfected mouse L-cell fibroblasts [109]. It is possible
that these proteins have different roles in terms of intracellular trafficking of fatty acids in the placenta. Daoud et
al. reported an increased expression of L-FABP and H-
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Expression of LXRa was at higher levels in undifferentiated than in differentiated trophoblasts, while this was
opposite in the case of LXRb expression [95]. In addition,
LXRa but not LXRb mRNA expression was increased by
T0901317 treatment in BeWo cells [95]. LXRb is involved
in inhibitory effects of oxLDL on trophoblast invasion in
vitro [97]; however, underlying mechanisms are not known
yet. LXR may therefore play an important role in preeclampsia, a condition in which lipid peroxidation is
increased and invasion of trophoblasts is reduced.
The receptors (FAT/CD36) for oxLDL in trophoblasts may
supply oxysterols through uptake of oxLDL for activation
of LXR and thus may increase fatty acid synthesis. Fatty
acid synthesized in the trophoblasts may then contribute
to fetal or maternal plasma lipids. Hyperlipidemia is the
most common complication of pregnancy and remains a
source of maternal-child morbidity; however, the etiology
of this disorder is still not understood. Maternal hyperlipidemia is a characteristic feature during pregnancy and
corresponds to an accumulation of triglycerides not only
in very-low-density lipoproteins (VLDL) but also in LDL
and high-density lipoproteins (HDL). In preeclampsia,
there is a further increase in plasma lipids compared with
normal pregnancy. Maternal liver may play an important
role in lipid homeostasis; however, a placental role in the
development of hyperlipidemia has been increasingly
evident. It is therefore highly likely that LXR-SREBP interaction may work in tandem in regulating lipid metabolism
in the placenta. In fact, the simultaneous regulation of
enzymes in both cholesterol and fatty acid synthesis
pathways by LXR may allow coordinate regulation of
overall lipid metabolism in the placenta.
76
A. K. Duttaroy
Eur. J. Lipid Sci. Technol. 108 (2006) 70–83
Fig. 2. Schematic diagram of the putative roles of fatty acid binding/transporter proteins
in human placental fatty acid uptake and metabolism. The presence of FAT and FATP on
both sides of bipolar placental cell membranes allows transport of all sorts of fatty acids in
both directions (from the mother to the fetus and vice versa). However, by virtue of its
exclusive location on the maternal-facing placental membrane, p-FABPpm sequesters
maternal plasma LC-PUFA to the placenta for fetal supply. Cytoplasmic FABP may be
responsible for transcytoplasmic movement of FFA to their sites of esterification, b-oxidation, or induce gene expression by interacting with PPAR. FAT, fatty acid translocase;
FATP, fatty acid transport protein; L-FABP, liver-type fatty acid-binding protein; H-FABP,
heart-type fatty acid-binding protein.
The tissue-specific regulation of FAT/CD36 and FATP
expression by PPAR has been demonstrated, with hepatic
expression of FAT, and FATP under the control of PPARa,
whereas in adipose tissue these proteins are controlled by
PPARg [11, 71, 110–113]. In contrast, it appears that
FABPpm expression is not under control of PPARa and
PPARg. Several naturally occurring ligands for PPARg have
been identified, including fatty acids, oxLDL derivatives,
and PG metabolites (15d-PGJ2). The potential natural
ligands involved in activating PPAR/RXR heterodimers in
the placenta are not yet known; however, it is possible that
these ligands may activate expression of fatty acid binding/transport proteins in human placenta. Expression of p-
FABPpm permits the placenta to recruit ARA and DHA
which may also act as ligands for PPAR and RXR. The
presence of FAT, FATP, L-FABP, and H-FABP in placental
trophoblasts may help to deliver the ligands (fatty acid and
eicosanoids) to PPARg for gene expression. Therefore, it is
conceivable that natural ligands for PPAR are either synthesized or taken up by the trophoblast, enabling PPARRXR heterodimer activation, and this may lead to an
increased fatty acid uptake. Schaiff et al. have reported
recently that PPARg and RXR regulate fatty acid transport
and storage in human placental trophoblasts [114]. They
found that stimulation of trophoblast fatty acid uptake by
ligand-activated PPARg and/or RXR was associated with
enhanced expression of adipophilin and FATP-4 [114,
115]. Their data also suggested that RXR, most possibly in
collaboration with other nuclear receptors, may predominantly regulate fatty acid transport in these cells. In fact, we
have also observed similar increased fatty acid uptake
© 2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.ejlst.com
FABP in placental trophoblasts during differentiation, although the increased expression of these proteins was
not associated with increased fatty acid uptake by these
cells [71].
Eur. J. Lipid Sci. Technol. 108 (2006) 70–83
after incubating placental trophoblasts with DHA, which is
a known ligand for RXR or PPAR (Tobin et al., unpublished
observation). Further systematic studies are required
using selective knockdown of these nuclear transcription
factors as well as fatty acid transport/binding proteins, in
order to determine the relative importance of these transcription factors and their relationships with the fatty acid
transport system in the placenta.
5 Placental synthesis of ligands for PPAR
Fatty acids have been involved in the proliferation and
differentiation of numerous cells mediated via PPAR or
their metabolites. The PPAR are a family of nuclear
receptors activated by selected long-chain fatty acids
and their oxygenated derivatives. In fact, PPARa was
identified first as a transcription factor activated by a
diverse class of compounds that cause proliferation of
peroxisomes, including fatty acids and their metabolites
[116]. In general, numerous naturally occurring fatty acids
and ARA metabolites have been shown to be putative
endogenous ligands for PPAR [87, 117, 118].
PPARs and their roles in human placenta
77
ligand to date, several other eicosanoids have been identified. Ferry et al. [126] identified PGH1 and PGH2 as ligands for
PPARg, each having similar affinity to 15d-PGJ2 in both
binding and subsequent transactivation assays. The role of a
PG endoperoxide-PPAR signaling pathway in pregnancy is a
strong possibility, although it is completely unknown. PGF2a
is also produced by human placenta and is a known inhibitor
of PPARg [127]. Implication of the interaction between
PPARg and PGF2a in placental biology is not known. PGI2
and its synthetic analogues (cPGI2 and iloprost), which activate cell surface PGI2 receptors [128], have also been shown
to bind and activate PPARd. Therefore, PGI2 can act via two
different receptor signaling pathways to control cell metabolism, apparently depending on whether it is produced
intracellularly or extracellularly [129].
The feto-placental unit synthesizes diverse eicosanoids and
these may serve as putative ligands for PPAR and LXR in the
placenta. In fact, PG concentrations in maternal plasma,
amniotic fluid, and intra-uterine tissues increase in late human pregnancy [119]. PG are synthesized from ARA by the
action of COX-1 or -2 and specific PG isomerases/synthases in human placenta [120, 121]. Once outside the cell,
PG may bind to specific plasma membrane receptors to elicit a diverse range of biological responses [122, 123]. High
concentrations of PGD2 have been reported in the human
placenta, extra-placental membranes and amniotic fluid,
with increased amniotic fluid levels at term compared to
preterm [120, 121]. Detection and measurement of this PG
has been complicated by the fact that PGD2 spontaneously
converts into J-series PG, including PGJ2, D12-PGJ2 and
15d-PGJ2, in vitro. It has been speculated that 15d-PGJ2 and
other PGJ2 derivatives may contribute to the mechanisms
that underlie the rupture of gestational membranes at term or
preterm [60, 124]. The pro-apoptotic effect of PGJ2 and its
derivatives D12-PGJ2 and 15d-PGJ2 have previously been
demonstrated in JEG-3 cells and amnion-like WISH cells,
where apoptosis was shown to be caspase dependent and
mimicked by the synthetic PPARg ligand, ciglitazone. However, there is increasing evidence that 15d-PGJ2 has nonPPARg-mediated effects in several cell systems. Despite
intense investigation of the actions of 15d-PGJ2 in a variety
of cell systems, conclusive evidence for its endogenous
production and in vivo activity has been lacking until recently.
Shibata et al. [125] have now demonstrated in vivo production of 15d-PGJ2 during inflammatory processes. Although
15d-PGJ2 is perhaps the most studied putative natural PPAR
Lipoxygenase products of ARA and linoleate, the
hydroxyeicosatetraenoic acids (HETE) and hydroxyoctadecadienoic acids (HODE), respectively, have been
shown to activate PPAR. LTB4 is a downstream product of
the 5-lipoxygenase (5-LO) pathway of ARA. 5-LO translocates to the nucleus where it associates with FLAP, and
has the potential to generate a nuclear pool of leukotrienes
[130, 131]. LTB4 has been reported to bind and activate
PPARa with nanomolar affinity [132, 133]. Interestingly,
several lipoxygenase metabolites of ARA (LTB4 and LTC4;
5-, 12-, and 15-HETE) are produced by gestational tissues
and placental trophoblasts [121, 134–138] and may have a
role in the onset of labor [134–139]. Amniotic fluid concentration of LTB4 was suggested as a possible marker for
women with preterm labor [140]. A mixture of (S)-enantiomer HETE was shown to activate PPARa but had no effect
on the other PPAR subtypes. Most of this activity was
shown to be due to 8(S)-HETE and was stereoselective
[141, 142], although less is known about the biological role
of 8(S)-HETE compared to the more frequently studied 5-,
12-, and 15-HETE [140]. Several other oxidized fatty acids,
including 9-HODE and 13-HODE, can activate PPARg and
there is evidence to suggest that these endogenous
PPARg ligands may be important regulators of gene
expression in the feto-placental unit. All these diverse
ligands for PPAR produced in the feto-placental unit can
modulate the feto-placental unit through both PPAR and
non-PPAR pathways and can affect the course of pregnancy. Although the nature of true endogenous PPAR
ligands is still not known, PPAR can be activated by a wide
variety of ‘endogenous’ or pharmacological ligands. Although fatty acids are generally considered as PPAR agonists, there have been considerable variations among
published reports regarding the potency of different types
of fatty acids and their oxygenated metabolites on the
ligand-binding activity of PPAR and transactivation of
PPRE. Tab. 1 summarizes the major endogenous ligands
for PPAR. PPARá activators include a variety of endogen-
© 2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.ejlst.com
78
A. K. Duttaroy
Eur. J. Lipid Sci. Technol. 108 (2006) 70–83
ously present fatty acids, LTB4 and HETE, and clinically
used drugs such as the fibrates, a class of first-line drugs in
the treatment of dyslipidemia. Similarly, PPARg can be
activated by a number of ligands, including DHA, linoleic
acid, the anti-diabetic glitazones used as insulin sensitizers, and a number of lipids including oxLDL, azoyle-PAF,
and eicosanoids such as 5,8,11,14-eicosatetraynoic acid
and the prostanoids PGA1, PGA2, PGD2, and their dehydration products of the PGJ series of cyclopentanones.
6 Conclusions
Emerging evidence indicates that PPAR, LXR, and
SREBP-1c play very important and complex roles in
placental biology. The biological responses initiated by
these receptors depend on their activation by liganddependent or -independent pathways as well as the
cross-talk with each other and their response elements,
as well as several transcription factors. It is therefore
possible that these nuclear transcription factors (PPAR,
SREBP, and LXR), either alone or in tandem, control fetoplacental growth and development. Tab. 2 shows the
interaction and function of these transcription factors in
human placenta. Since these receptors are fatty acid
sensors, their expression in the placenta may also be
regulated by the flux of fatty acids in the feto-placental
unit. It is important to note that placental uptake of fatty
acids and their metabolism (b-oxidation) are not regulated by insulin or leptin as in the case of adipose or
other tissues [143].
Tab. 1. Fatty acids and their oxygenated derivative ligands of PPAR.
Major endogenous ligands
PPARÆ
PPAR
PPARª
Palmitic acid, 16:0
Stearic acid, 18:0
Palmitoleic acid, 16:1n-7
Oleic acid, 18:1n-9
Linoleic acid, 18:2n-6
Arachidonic acid, 20:4n-6
Eicosapentaenoic acid, 20:5n-3
Docosahexanenoic acid, 22:6n-3
LTB4
Fatty acids
Prostacyclin
Arachidonic acid, 20:4n-6
15d-PGJ2
9-HODE
13-HODE
15-HETE
Linoleic acid
Arachidonic acid, 20:4n-6
Docosahexaenoic acid, 22:6n-3
Docosahexaenoic acid, 22:6n-3
Tab. 2. Role of nuclear transcription factors in placental trophoblasts.
PPARÆ
PPAR
PPARª
LXR
SREBP–1c
Cell growth
Inhibits cell
growth
Stimulates cell
growth
Depends on
ligands
Stimulates cell
growth
Not known
Apoptosis/
differentiation
Not known
Increases
differentiation
Depends on
ligands
Increases
differentiation
Not known
Critical for fetoplacental
growth and
development
Not essential
Critically
essential
Critically
essential
Not essential
Not known
hCG secretion
Decreases hCG
secretion
Not known
Increases hCG
secretion
Decreases hCG
secretion
Not known
Trophoblast
invasion
Not known
Not known
Inhibits invasion
Inhibits invasion
Not known
Lipid metabolism
Not known
Increases fatty
acid uptake
Increases fatty
acid uptake
Increases fatty
acid synthesis
via FAS and
SREBP-1
expression
Increases fatty
acid synthesis
© 2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.ejlst.com
Eur. J. Lipid Sci. Technol. 108 (2006) 70–83
Maternal LC-PUFA taken up by the placenta may also act as
ligands for these receptors and modulate the placental biology. A recent study by Waite et al. reported that circulating
activators of PPAR are reduced in preeclamptic pregnant
women’s sera [144]. The reduction was much more prominent for PPARg than for PPARa activation. The endogenous
factors in the maternal plasma may play a role in lipid metabolism and immune function in the feto-placental unit as
seen in preeclampsia. LTB4, saturated and monounsaturated fatty acids are ligands for PPARa, whereas oxygenated fatty acids (9-HODE, 13-HODE, and 15-HETE) and
15d-PGJ2 are PPARg ligands. Identification of circulating
ligands and their interactions with the nuclear transcription
factors in the feto-placental unit may be an important aspect
of future research in this area. Better understanding of these
transcription factors and their ligands in the feto-placental
unit possibly gives us clues to prevent maternal, fetal and
adult diseases associated with placental dysfunction.
Acknowledgment
This work has been supported by the grant Throne Holst
Foundation, Norway.
References
[1] N. M. Gude, C. T. Roberts, B. Kalionis, R. G. King: Growth and
function of the normal human placenta. Thromb Res. 2004,
114, 397–407.
[2] A. K. Duttaroy: Fatty acid transport and metabolism in the
feto-placental unit and the role of fatty acid-binding proteins.
J Nutr Biochem. 1997, 8, 548–557.
[3] K. K. Ong, D. B. Dunger: Perinatal growth failure: The road to
obesity, insulin resistance and cardiovascular disease in
adults. Best Pract Res Clin Endocrinol Metab. 2002, 16, 191–
207.
[4] Y. Barak, M. C. Nelson, E. S. Ong, Y. Z. Jones, P. Ruiz-Lozano,
K. R. Chien, A. Koder, R. M. Evans: PPAR gamma is required
for placental, cardiac, and adipose tissue development. Mol
Cell. 1999, 4, 585–595.
[5] E. B. Berry, R. Eykholt, R. J. Helliwell, R. S. Gilmour, M. D.
Mitchell, K. W. Marvin: Peroxisome proliferator-activated
receptor isoform expression changes in human gestational
tissues with labor at term. Mol Pharmacol. 2003, 64, 1586–
1590.
[6] N. Z. Ding, C. B. Teng, H. Ma, H. Ni, X. H. Ma, L. B. Xu, Z. M.
Yang: Peroxisome proliferator-activated receptor delta
expression and regulation in mouse uterus during embryo
implantation and decidualization. Mol Reprod Dev. 2003, 66,
218–224.
[7] Y. Xu, T. J. Cook, G. T. Knipp: Effects of di-(2-ethylhexyl)phthalate (DEHP) and its metabolites on fatty acid homeostasis regulating proteins in rat placental HRP-1 trophoblast
cells. Toxicol Sci. 2005, 84, 287–300.
[8] M. V. Chakravarthy, Z. J. Pan, Y. M. Zhu, K. Tordjman, J. G.
Schneider, T. Coleman, J. Turk, C. F. Semenkovich: “New”
hepatic fat activates PPAR alpha to maintain glucose, lipid,
and cholesterol homeostasis. Cell Metab. 2005 1, 309–322.
© 2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
PPARs and their roles in human placenta
79
[9] H. Glosli, O. A. Gudbrandsen, A. J. Mullen, B. Halvorsen, T.
H. Rost, H. Wergedahl, H. Prydz, P. Aukrust, R. K. Berge:
Down-regulated expression of PPAR alpha target genes,
reduced fatty acid oxidation and altered fatty acid composition in the liver of mice transgenic for hTNF alpha. Biochim
Biophys Acta. 2005, 1734, 235–246.
[10] C. Hohberg, G. Lubben, T. Forst, N. Marx, M. M. Weber, M.
Lobig, A. Pfutzner: PPAR gamma stimulation improves cardiovascular risk profile independent from its glucose lowering effects. Diabetes. 2005, 54, A149–A150.
[11] S. Luquet, C. Gaudel, D. Holst, J. Lopez-Soriano, C. JehlPietri, A. Fredenrich, P. A. Grimaldi: Roles of PPAR delta in
lipid absorption and metabolism: A new target for the treatment of type 2 diabetes. Biochim Biophys Acta. 2005, 1740,
313–317.
[12] A. K. Duttaroy: Transport mechanisms for long-chain polyunsaturated fatty acids in the human placenta. Am J Clin
Nutr. 2000, 71, 315S–322S.
[13] P. Haggarty: Effect of placental function on fatty acid
requirements during pregnancy. Eur J Clin Nutr. 2004, 58,
1559–1570.
[14] S. M. Innis: Essential fatty acids in growth and development.
Prog Lipid Res. 1991, 30, 39–103.
[15] S. M. Innis: The role of dietary n-6 and n-3 fatty acids in the
developing brain. Dev Neurosci. 2000, 22, 474–480.
[16] S. M. Innis: Essential fatty acid transfer and fetal development. Placenta. 2005, 26 SupplA, S70–S75.
[17] F. M. Campbell, P. G. Bush, J. H. Veerkamp, A. K. Duttaroy:
Detection and cellular localization of plasma membraneassociated and cytoplasmic fatty acid-binding proteins in
human placenta. Placenta. 1998, 19, 409–415.
[18] B. I. Frohnert, T. Y. Hui, D. A. Bernlohr: Identification of a
functional peroxisome proliferator-responsive element in the
murine fatty acid transport protein gene. J Biol Chem. 1999,
274, 3970–3977.
[19] N. M. Lapsys, A. D. Kriketos, M. Lim-Fraser, A. M. Poynten,
A. Lowy, S. M. Furler, D. J. Chisholm, G. J. Cooney:
Expression of genes involved in lipid metabolism correlate
with peroxisome proliferator-activated receptor gamma
expression in human skeletal muscle. J Clin Endocrinol
Metab. 2000, 85, 4293–4297.
[20] G. Martin, K. Schoonjans, A. M. Lefebvre, B. Staels, J.
Auwerx: Coordinate regulation of the expression of the fatty
acid transport protein and acyl-CoA synthetase genes by
PPAR alpha and PPAR gamma activators. J Biol Chem.
1997, 272, 28210–28217.
[21] K. Motojima, P. Passilly, J. M. Peters, F. J. Gonzalez, N.
Latruffe: Expression of putative fatty acid transporter genes
are regulated by peroxisome proliferator-activated receptor
alpha and gamma activators in a tissue- and inducer-specific manner. J Biol Chem. 1998, 273, 16710–16714.
[22] K. Schoonjans, B. Staels, J. Auwerx: The peroxisome proliferator activated receptors (PPARs) and their effects on
lipid metabolism and adipocyte differentiation. Biochim
Biophys Acta. 1996, 1302, 93–109.
[23] S. D. Clarke: Polyunsaturated fatty acid regulation of gene
transcription: A molecular mechanism to improve the metabolic syndrome. J Nutr. 2001, 131, 1129–1132.
[24] D. B. Jump: Fatty acid regulation of gene transcription. Crit
Rev Clin Lab Sci. 2004, 41, 41–78.
[25] A. K. Duttaroy: Fetal growth and development: Roles of fatty
acid transport proteins and nuclear transcription factors in
human placenta. Indian J Exp Biol. 2004, 42, 747–757.
[26] T. Fournier, L. Pavan, A. Tarrade, K. Schoonjans, J. Auwerx,
C. Rochette-Egly, D. Evain-Brion: The role of PPAR-gamma/
www.ejlst.com
80
A. K. Duttaroy
RXR-alpha heterodimers in the regulation of human trophoblast invasion. Ann N Y Acad Sci. 2002, 973, 26–30.
[27] A. Tarrade, K. Schoonjans, J. Guibourdenche, J. M. Bidart,
M. Vidaud, J. Auwerx, C. Rochette-Egly, D. Evain-Brion:
PPAR gamma/RXR alpha heterodimers are involved in human CG beta synthesis and human trophoblast differentiation. Endocrinology. 2001, 142, 4504–4514.
[28 A. Chawla, J. J. Repa, R. M. Evans, D. J. Mangelsdor:
Nuclear receptors and lipid physiology: Opening the X-files.
Science. 2001, 294, 1866–1870.
[29] J. D. Chen, R. M. Evans: A transcriptional co-repressor that
interacts with nuclear hormone receptors. Nature. 1995,
377, 454–457.
[30] A. J. Horlein, A. M. Naar, T. Heinzel, J. Torchia, B. Gloss, R.
Kurokawa, A. Ryan, Y. Kamei, M. Soderstrom, C. K. Glass:
Ligand-independent repression by the thyroid hormone
receptor mediated by a nuclear receptor co-repressor. Nature 1995, 377, 397–404.
[31] M. Hadzopoulou-Cladaras, E. Kistanova, C. Evagelopoulou,
S. Zeng, C. Cladaras, J. A. Ladias: Functional domains of
the nuclear receptor hepatocyte nuclear factor 4. J Biol
Chem. 1997, 272, 539–550.
[32] M. D. Ruse, Jr., M. L. Privalsky, F. M. Sladek: Competitive
cofactor recruitment by orphan receptor hepatocyte nuclear
factor 4alpha1: Modulation by the F domain. Mol Cell Biol.
2002, 22, 1626–1638.
[33] B. D. Darimont, R. L. Wagner, J. W. Apriletti, M. R. Stallcup,
P. J. Kushner, J. D. Baxter, R. J. Fletterick, K. R. Yamamoto:
Structure and specificity of nuclear receptor-coactivator
interactions. Genes Dev. 1998, 12, 3343–3356.
[34] R. Kurokawa, M. Soderstrom, A. Horlein, S. Halachmi, M.
Brown, M. G. Rosenfeld, C. K. Glass: Polarity-specific activities of retinoic acid receptors determined by a corepressor. Nature. 1995, 377, 451–454.
[35] E. Hu, J. B. Kim, P. Sarraf, B. M. Spiegelman: Inhibition of
adipogenesis through MAP kinase-mediated phosphorylation of PPARgamma. Science. 1996, 274, 2100–2103.
[36] E. Soutoglou, N. Katrakili, I. Talianidis: Acetylation regulates
transcription factor activity at multiple levels. Mol Cell. 2000,
5, 745–751.
[37] M. G. Rosenfeld, C. K. Glass: Coregulator codes of transcriptional regulation by nuclear receptors. J Biol Chem.
2001, 276, 36865–36868.
[38] T. Jenuwein, C. D. Allis: Translating the histone code. Science. 2001, 293, 1074–1080.
[39] F. M. Gregoire, V. Rakhmanova, F. Zhang, Y. Zhu, J. Y. Ma, P.
Cheng, S. Zhao, B. Lavan, T. A. Gustafson: Effects of novel
PPAR delta, PPAR dual delta/gamma and PPAR delta/
gamma/alpha (pan (TM)) agonists on PPAR-responsive
genes in human adipocytes and macrophages. Diabetes.
2005, 54, A140.
[40] T. Lemberger, R. Saladin, M. Vazquez, F. Assimacopoulos,
B. Staels, B. Desvergne, W. Wahli, J. Auwerx: Expression of
the peroxisome proliferator-activated receptor alpha gene is
stimulated by stress and follows a diurnal rhythm. J Biol
Chem. 1996, 271, 1764–1769.
[41] O. Braissant, F. Foufelle, C. Scotto, M. Dauca, W. Wahli:
Differential expression of peroxisome proliferator-activated
receptors (PPARs): Tissue distribution of PPAR-alpha, -beta,
and -gamma in the adult rat. Endocrinology. 1996, 137, 354–
366.
[42] T. E. Cullingford, K. Bhakoo, S. Peuchen, C. T. Dolphin, R.
Patel, J. B. Clark: Distribution of mRNAs encoding the peroxisome proliferator-activated receptor alpha, beta, and
gamma and the retinoid X receptor alpha, beta, and gamma
in rat central nervous system. J Neurochem. 1998, 70,
1366–1375.
© 2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Lipid Sci. Technol. 108 (2006) 70–83
[43] S. A. Kliewer, B. M. Forman, B. Blumberg, E. S. Ong, U.
Borgmeyer, D. J. Mangelsdorf, K. Umesono, R. M. Evans:
Differential expression and activation of a family of murine
peroxisome proliferator-activated receptors. Proc Natl Acad
Sci USA. 1994, 91, 7355–7359.
[44] T. Lemberger, O. Braissant, C. Juge-Aubry, H. Keller, R. Saladin, B. Staels, J. Auwerx, A. G. Burger, C. A. Meier, W.
Wahli: PPAR tissue distribution and interactions with other
hormone-signaling pathways. Ann N Y Acad Sci. 1996, 804,
231–251.
[45] A. V. Ershov, N. G. Bazan: Photoreceptor phagocytosis
selectively activates PPARgamma expression in retinal pigment epithelial cells. J Neurosci Res. 2000, 60, 328–337.
[46] D. Auboeuf, J. Rieusset, L. Fajas, P. Vallier, V. Frering, J. P.
Riou, B. Staels, J. Auwerx, M. Laville, H. Vidal: Tissue distribution and quantification of the expression of mRNAs of
peroxisome proliferator-activated receptors and liver X
receptor-alpha in humans: No alteration in adipose tissue of
obese and NIDDM patients. Diabetes. 1997, 46, 1319–1327.
[47] R. Mukherjee, L. Jow, G. E. Croston and J. R. Paterniti, Jr.:
Identification, characterization, and tissue distribution of
human peroxisome proliferator-activated receptor (PPAR)
isoforms PPARgamma2 versus PPARgamma1 and activation with retinoid X receptor agonists and antagonists. J Biol
Chem. 1997, 272, 8071–8076.
[48] K. W. Marvin, R. L. Eykholt, J. A. Keelan, T. A. Sato, M. D.
Mitchell:
The
15-deoxy-delta(12,14)-prostaglandin
J(2)receptor, peroxisome proliferator activated receptorgamma (PPARgamma) is expressed in human gestational
tissues and is functionally active in JEG3 choriocarcinoma
cells. Placenta. 2000, 21, 436–440.
[49] P. Tontonoz, E. Hu, B. M. Spiegelman: Stimulation of adipogenesis in fibroblasts by PPAR gamma 2, a lipid-activated
transcription factor. Cell 1994, 79, 1147–1156.
[50] P. Tontonoz, E. Hu, R. A. Graves, A. I. Budavari, B. M. Spiegelman: PPAR gamma 2: Tissue-specific regulator of an
adipocyte enhancer. Genes Dev. 1994, 8, 1224–1234.
[51] P. Escher, W. Wahli: Peroxisome proliferator-activated
receptors: Insight into multiple cellular functions. Mutat Res.
2000, 448, 121–138.
[52] L. Fajas, D. Auboeuf, E. Raspe, K. Schoonjans, A. M.
Lefebvre, R. Saladin, J. Najib, M. Laville, J. C. Fruchart, S.
Deeb, A. Vidal-Puig, J. Flier, M. R. Briggs, B. Staels, H. Vidal,
J. Auwerx: The organization, promoter analysis, and
expression of the human PPARgamma gene. J Biol Chem.
1997, 272, 18779–18789.
[53] L. Fajas, J. C. Fruchart, J. Auwerx: PPARgamma3 mRNA: A
distinct PPARgamma mRNA subtype transcribed from an
independent promoter. FEBS Lett. 1998, 438, 55–60.
[54] J. Vamecq, N. Latruffe: Medical significance of peroxisome
proliferator-activated receptors. Lancet. 1999, 354, 141–
148.
[55] C. N. Palmer, M. H. Hsu, A. S. Muerhoff, K. J. Griffin, E. F.
Johnson: Interaction of the peroxisome proliferator-activated receptor alpha with the retinoid X receptor alpha
unmasks a cryptic peroxisome proliferator response element that overlaps an ARP-1-binding site in the CYP4A6
promoter. J Biol Chem. 1994, 269, 18083–18089.
[56] C. N. Palmer, M. H. Hsu, H. J. Griffin, E. F. Johnson: Novel
sequence determinants in peroxisome proliferator signaling.
J Biol Chem. 1995, 270, 16114–16121.
[57] P. Targett-Adams, M. J. McElwee, E. Ehrenborg, M. C. Gustafsson, C. N. Palmer, J. McLauchlan: A PPAR response
element regulates transcription of the gene for human adipose differentiation-related protein. Biochim Biophys Acta.
2005, 1728, 95–104.
www.ejlst.com
Eur. J. Lipid Sci. Technol. 108 (2006) 70–83
[58] J. C. Corton, S. P. Anderson, A. Stauber: Central role of
peroxisome proliferator-activated receptors in the actions of
peroxisome proliferators. Annu Rev Pharmacol Toxicol.
2000, 40, 491–518.
[59] O. Wendling, P. Chambon, M. Mark: Retinoid X receptors are
essential for early mouse development and placentogenesis. Proc Natl Acad Sci USA. 1999, 96, 547–551.
[60] J. Keelan, R. Helliwell, B. Nijmeijer, E. Berry, T. Sato, K.
Marvin, M. Mitchell, R. Gilmour: 15-Deoxy-delta12,14-prostaglandin J2-induced apoptosis in amnion-like WISH cells.
Prostaglandins Lipid Mediat. 2001, 66, 265–282.
[61] Q. Wang, D. Herrera-Ruiz, A. S. Mathis, T. J. Cook, R. K.
Bhardwaj, G. T. Knipp: Expression of PPAR, RXR isoforms
and fatty acid transporting proteins in the rat and human
gastrointestinal tracts. J Pharm Sci. 2005, 94, 363–372.
[62] S. S. Lee, T. Pineau, J. Drago, E. J. Lee, J. W. Owens, D. L.
Kroetz, P. M. Fernandez-Salguero, H. Westphal, F. J. Gonzalez: Targeted disruption of the alpha isoform of the peroxisome proliferator-activated receptor gene in mice results
in abolishment of the pleiotropic effects of peroxisome proliferators. Mol Cell Biol. 1995, 15, 3012–3022.
[63] H. Matsuo, J. F. Strauss, III: Peroxisome proliferators and
retinoids affect JEG-3 choriocarcinoma cell function. Endocrinology. 1994, 135, 1135–1145.
[64] F. Hashimoto, Y. Oguchi, M. Morita, K. Matsuoka, S. Takeda,
M. Kimura, H. Hayashi: PPARalpha agonists clofibrate and
gemfibrozil inhibit cell growth, down-regulate hCG and upregulate progesterone secretions in immortalized human
trophoblast cells. Biochem Pharmacol. 2004, 68, 313–321.
[65] K. Hanley, Y. Jiang, D. Crumrine, N. M. Bass, R. Appel, P. M.
Elias, M. L. Williams, K. R. Feingold: Activators of the
nuclear hormone receptors PPARalpha and FXR accelerate
the development of the fetal epidermal permeability barrier.
J Clin Invest. 1997, 100, 705–712.
[66] M. Schmuth, K. Schoonjans, Q. C. Yu, J. W. Fluhr, D.
Crumrine, J. P. Hachem, P. Lau, J. Auwerx, P. M. Elias, K. R.
Feingold: Role of peroxisome proliferator-activated receptor
alpha in epidermal development in utero. J Invest Dermatol.
2002, 119, 1298–1303.
[67] N. Kubota, Y. Terauchi, H. Miki, H. Tamemoto, T. Yamauchi,
K. Komeda, S. Satoh, R. Nakano, C. Ishii, T. Sugiyama, K.
Eto, Y. Tsubamoto, A. Okuno, K. Murakami, H. Sekihara, G.
Hasegawa, M. Naito, Y. Toyoshima, S. Tanaka, K. Shiota, T.
Kitamura, T. Fujita, O. Ezaki, S. Aizawa, T. Kadowaki: PPAR
gamma mediates high-fat diet-induced adipocyte hypertrophy and insulin resistance. Mol Cell. 1999, 4, 597–609.
[68] S. E. Crawford, C. Qi, P. Misra, V. Stellmach, M. S. Rao, J. D.
Engel, Y. Zhu, K. Reddy: Defects of the heart, eye, and
megakaryocytes in peroxisome proliferator activator receptor-binding protein (PBP) null embryos implicate GATA family
of transcription factors. J Biol Chem. 2002, 277, 3585–3592.
[69] Y. J. Zhu, S. E. Crawford, V. Stellmach, R. S. Dwivedi, M. S.
Rao, F. J. Gonzalez, C. Qi, J. K. Reddy: Coactivator PRIP, the
peroxisome proliferator-activated receptor-interacting protein, is a modulator of placental, cardiac, hepatic, and
embryonic development. J Biol Chem. 2003, 278, 1986–
1990.
[70] Y. Cui, K. Miyoshi, E. Claudio, U. K. Siebenlist, F. J. Gonzalez, J. Flaws, K. U. Wagner, L. Hennighausen: Loss of the
peroxisome proliferation-activated receptor gamma (PPARgamma) does not affect mammary development and propensity for tumor formation but leads to reduced fertility. J
Biol Chem. 2002, 277, 17830–17835.
[71] G. G. Daoud, L. Simoneau, A. Masse, E. Rassart, J. Lafond:
Expression of cFABP and PPAR in trophoblast cells: Effect
of PPAR ligands on linoleic acid uptake and differentiation.
Biochim Biophys Acta. 2005, 1687, 181–194.
© 2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
PPARs and their roles in human placenta
81
[72] A. K. Duttaroy, D. Crozet, J. Taylor, M. J. Gordon: Acyl-CoA
thioesterase activity in human placental choriocarcinoma
(BeWo) cells: Effects of fatty acids. Prostaglandins Leukot
Essent Fatty Acids. 2003, 68, 43–48.
[73] W. T. Schaiff, M. G. Carlson, S. D. Smith, R. Levy, D. M.
Nelson, Y. Sadovsky: Peroxisome proliferator-activated
receptor-gamma modulates differentiation of human trophoblast in a ligand-specific manner. J Clin Endocrinol
Metab. 2000, 85, 3874–3881.
[74] J. H. Lee, H. S. Kim, S. Y. Jeong, I. K. Kim: Induction of p53
and apoptosis by delta 12-PGJ2 in human hepatocarcinoma SK-HEP-1 cells. FEBS Lett. 1995, 368, 348–352.
[75] G. Eibl, M. N. Wente, H. A. Reber, O. J. Hines: Peroxisome
proliferator-activated receptor gamma induces pancreatic
cancer cell apoptosis. Biochem Biophys Res Commun.
2001, 287, 522–529.
[76] Y. Tsubouchi, H. Sano, Y. Kawahito, S. Mukai, R. Yamada, M.
Kohno, K. Inoue, T. Hla, M. Kondo: Inhibition of human lung
cancer cell growth by the peroxisome proliferator-activated
receptor-gamma agonists through induction of apoptosis.
Biochem Biophys Res Commun. 2000, 270, 400–405.
[77] E. J. Kim, K. S. Park, S. Y. Chung, Y. Y. Sheen, D. C. Moon, Y.
S. Song, K. S. Kim, S. Song, Y. P. Yun, M. K. Lee, K. W. Oh, D.
Y. Yoon, J. T. Hong: Peroxisome proliferator-activated
receptor-gamma activator 15-deoxy-Delta12,14-prostaglandin J2 inhibits neuroblastoma cell growth through
induction of apoptosis: Association with extracellular signalregulated kinase signal pathway. J Pharmacol Exp Ther.
2003, 307, 505–517.
[78] D. Evain-Brion, T. Fournier, P. Therond, A. Tarrade, L. Pavan:
Pathogenesis of pre-eclampsia: Role of gamma PPAR in
trophoblast invasion. Bull Acad Natl Med. 2002, 186, 409–
418.
[79] L. L. Waite, E. C. Person, Y. Zhou, K. H. Lim, T. S. Scanlan, R.
N. Taylor: Placental peroxisome proliferator-activated
receptor-gamma is up-regulated by pregnancy serum. J Clin
Endocrinol Metab. 2000, 85, 3808–3814.
[80] R. L. Schild, W. T. Schaiff, M. G. Carlson, E. J. Cronbach, D.
M. Nelson, Y. Sadovsky: The activity of PPAR gamma in primary human trophoblasts is enhanced by oxidized lipids. J
Clin Endocrinol Metab. 2002, 87, 1105–1110.
[81] L. A. Moraes, L. Piqueras, D. Bishop-Bailey: Peroxisome
proliferator-activated receptors and inflammation. Pharmacol Ther. 2005 (epub).
[82] B. Staels, W. Koenig, A. Habib, R. Merval, M. Lebret, I. P.
Torra, P. Delerive, A. Fadel, G. Chinetti, J. C. Fruchart, J.
Najib, J. Maclouf, A. Tedgui: Activation of human aortic
smooth-muscle cells is inhibited by PPARalpha but not by
PPARgamma activators. Nature. 1998, 393, 790–793.
[83] Q. Wang, H. Fujii, G. T. Knipp: Expression of PPAR and RXR
isoforms in the developing rat and human term placentas.
Placenta. 2002, 23, 661–671.
[84] Y. Barak, D. Liao, W. He, E. S. Ong, M. C. Nelson, J. M.
Olefsky, R. Boland, R. M. Evans: Effects of peroxisome proliferator-activated receptor delta on placentation, adiposity,
and colorectal cancer. Proc Natl Acad Sci USA. 2002, 99,
303–308.
[85] L. Julan, H. Guan, J. P. van Beek, K. Yang: Peroxisome proliferator-activated receptor delta suppresses 11beta-hydroxysteroid dehydrogenase type 2 gene expression in human
placental trophoblast cells. Endocrinology. 2005, 146, 1482–
1490.
[86] K. Yang: Placental 11 beta-hydroxysteroid dehydrogenase:
Barrier to maternal glucocorticoids. Rev Reprod. 1997, 2,
129–132.
www.ejlst.com
82
A. K. Duttaroy
[87] H. Lim, S. K. Dey: PPAR delta functions as a prostacyclin
receptor in blastocyst implantation. Trends Endocrinol
Metab. 2000, 11, 137–142.
[88] P. A. Scherle, W. Ma, H. Lim, S. K. Dey, J. M. Trzaskos:
Regulation of cyclooxygenase-2 induction in the mouse
uterus during decidualization. An event of early pregnancy.
J Biol Chem. 2000, 275, 37086–37092.
[89] R. J. Helliwell, E. B. Berry, S. J. O’Carroll, M. D. Mitchell:
Nuclear prostaglandin receptors: Role in pregnancy and
parturition? Prostaglandins Leukot Essent Fatty Acids.
2004, 70, 149–165.
[90] C. C. Song, R. A. Hiipakka, S. Liao: Selective activation of
liver X receptor alpha by 6alpha-hydroxy bile acids and
analogs. Steroids. 2000, 65, 423–427.
[91] P. J. Willy, K. Umesono, E. S. Ong, R. M. Evans, R. A. Heyman, D. J. Mangelsdorf: LXR, a nuclear receptor that
defines a distinct retinoid response pathway. Genes Dev.
1995, 9, 1033–1045.
[92] J. M. Lehmann, S. A. Kliewer, L. B. Moore, T. A. Smith-Oliver, B. B. Oliver, J. L. Su, S. S. Sundseth, D. A. Winegar, D.
E. Blanchard, T. A. Spencer, T. M. Willson: Activation of the
nuclear receptor LXR by oxysterols defines a new hormone
response pathway. J Biol Chem. 1997, 272, 3137–3140.
[93] S. M. Ulven, H. I. Nebb: Liver X receptors (LXRs): Important
regulators of lipid homeostasis. In: Cellular Proteins and
Their Fatty Acids in Health and Disease. Eds. A. K. Duttaroy,
F. Spener, VCH-Wiley, Weinheim (Germany) 2003, pp. 209–
220.
[94] A. Venkateswaran, B. A. Laffitte, S. B. Joseph, P. A. Mak, D.
C. Wilpitz, P. A. Edwards, P. Tontonoz: Control of cellular
cholesterol efflux by the nuclear oxysterol receptor LXR
alpha. Proc Natl Acad Sci USA. 2000, 97, 12097–12102.
[95] M. S. Weedon-Fekjaer, A. K. Duttaroy, H. I. Nebb: Liver X
receptors mediate inhibition of hCG secretion in a human
placental trophoblast cell line. Placenta. 2005, 26, 721–
728.
[96] H. Shimano: Sterol regulatory element-binding proteins
(SREBPs): Transcriptional regulators of lipid synthetic
genes. Prog Lipid Res. 2001, 40, 439–452.
[97] L. Pavan, A. Hermouet, V. Tsatsaris, P. Therond, T. Sawamura, D. Evain-Brion, T. Fournier: Lipids from oxidized lowdensity lipoprotein modulate human trophoblast invasion:
Involvement of nuclear liver X receptors. Endocrinology.
2004, 145, 4583–4591.
[98] P. Haggarty: Placental regulation of fatty acid delivery and
its effect on fetal growth – a review. Placenta. 2002, 23
Suppl A, S28–S38.
[99] A. K. Duttaroy: Cellular uptake of long-chain fatty acids:
Role of membrane-associated fatty-acid-binding/transport
proteins. Cell Mol Life Sci. 2000, 57, 1360–1372.
[100] F. M. Campbell, A. K. Duttaroy: Plasma-membrane fattyacid-binding protein (FABPpm)) is exclusively located in
the maternal facing membranes of the human placenta.
FEBS Lett. 1995, 375, 227–230.
[101] J. F. C. Glatz, J. J. F. P. Luiken, A. Bonen: Involvement of
membrane-associated proteins in the acute regulation of
cellular fatty acid uptake. J Mol Neurosci. 2001, 16, 123–
132.
[102] F. M. Campbell, M. J. Gordon, A. K. Duttaroy, Preferential
uptake of long chain polyunsaturated fatty acids by isolated human placental membranes. Mol Cell Biochem.
1996, 155, 77–83.
[103] A. K. Duttaroy, N. Gopalswamy, D. V. Trulzsch: Prostaglandin-E1 binds to Z-protein of rat liver. Eur J Biochem.
1987, 162, 615–619.
© 2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Lipid Sci. Technol. 108 (2006) 70–83
[104] R. A. Peeters, M. A. in ’t Groen, M. P. de Moel, H. T. van
Moerkerk, J. H. Veerkamp: The binding affinity of fatty acidbinding proteins from human, pig and rat liver for different
fluorescent fatty acids and other ligands. Int J Biochem.
1989, 21, 407–418.
[105] J. H. Veerkamp, H. T. van Moerkerk, C. F. Prinsen, T. H. van
Kuppevelt: Structural and functional studies on different
human FABP types. Mol Cell Biochem. 1999, 192, 137–
142.
[106] A. W. Zimmerman, H. T. van Moerkerk, J. H. Veerkamp:
Ligand specificity and conformational stability of human
fatty acid-binding proteins. Int J Biochem Cell Biol. 2001,
33, 865–876.
[107] C. Wolfrum, T. Borchers, J. C. Sacchettini, F. Spener:
Binding of fatty acids and peroxisome proliferators to
orthologous fatty acid binding proteins from human, murine, and bovine liver. Biochemistry. 2000, 39, 14363–
14370.
[108] C. Wolfrum, C. M. Borrmann, T. Borchers, F. Spener: Fatty
acids and hypolipidemic drugs regulate peroxisome proliferator-activated receptors alpha – and gamma-mediated
gene expression via liver fatty acid binding protein: A signaling path to the nucleus. Proc Natl Acad Sci USA. 2001,
98, 2323–2328.
[109] E. J. Murphy, D. R. Prows, J. R. Jefferson, F. Schroeder:
Liver fatty acid-binding protein expression in transfected
fibroblasts stimulates fatty acid uptake and metabolism.
Biochim Biophys Acta. 1996, 1301, 191–198.
[110] J. C. Fruchart, P. Duriez, B. Staels: Peroxisome proliferatoractivated receptor-alpha activators regulate genes governing lipoprotein metabolism, vascular inflammation and
atherosclerosis. Curr Opin Lipidol. 1999, 10, 245–257.
[111] B. D. Hegarty, S. M. Furler, N. D. Oakes, E. W. Kraegen, G.
J. Cooney: Peroxisome proliferator-activated receptor
(PPAR) activation induces tissue-specific effects on fatty
acid uptake and metabolism in vivo – a study using the
novel PPARalpha/gamma agonist tesaglitazar. Endocrinology. 2004, 145, 3158–3164.
[112] B. Staels, J. Dallongeville, J. Auwerx, K. Schoonjans, E.
Leitersdorf, J. C. Fruchart: Mechanism of action of fibrates
on lipid and lipoprotein metabolism. Circulation. 1998, 98,
2088–2093.
[113] Y. Tamori, J. Masugi, N. Nishino, M. Kasuga: Role of peroxisome proliferator-activated receptor-gamma in maintenance of the characteristics of mature 3T3-L1 adipocytes. Diabetes. 2002, 51, 2045–2055.
[114] W. T. Schaiff, I. Bildirici, M. Cheong, P. L. Chern, D. M. Nelson, Y. Sadovsky: Peroxisome proliferator-activated
receptor-gamma and retinoid X receptor signaling regulate
fatty acid uptake by primary human placental trophoblasts.
J Clin Endocrinol Metab. 2005, 90, 4267–4275.
[115] I. Bildirici, C. R. Roh, W. T. Schaiff, B. M. Lewkowski, D. M.
Nelson, Y. Sadovsky: The lipid droplet-associated protein
adipophilin is expressed in human trophoblasts and is
regulated by peroxisomal proliferator-activated receptorgamma/retinoid X receptor. J Clin Endocrinol Metab. 2003,
88, 6056–6062.
[116] I. Issemann, S. Green: Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators. Nature. 1990, 347, 645–650.
[117] K. Ohta, T. Endo, K. Haraguchi, J. M. Hershman, T. Onaya:
Ligands for peroxisome proliferator-activated receptor
gamma inhibit growth and induce apoptosis of human
papillary thyroid carcinoma cells. J Clin Endocrinol Metab.
2001, 86, 2170–2177.
[118] B. H. Rovin, W. A. Wilmer, L. Lu, A. I. Doseff, C. Dixon, M.
Kotur, T. Hilbelink: 15-Deoxy-Delta12,14–prostaglandin J2
www.ejlst.com
Eur. J. Lipid Sci. Technol. 108 (2006) 70–83
regulates mesangial cell proliferation and death. Kidney Int.
2002, 61, 1293–1302.
[119] J. R. G. Challis, S. J. Lye: Parturition. In: The Physiology of
Reproduction. Eds. E. Knobill, J. D. Neill, Raven Press,
New York (USA) 1994, pp. 985–1031.
[120] M. D. Mitchell, D. L. Kraemer, D. M. Strickland: The human
placenta: A major source of prostaglandin D2. Prostaglandins Leukot Med. 1982, 8, 383–387.
[121] M. D. Mitchell, C. F. Grzyboski: Arachidonic acid metabolism by lipoxygenase pathways in intrauterine tissues of
women at term of pregnancy. Prostaglandins Leukot Med.
1987, 28, 303–312.
[122] A. K. Duttaroy, N. N. Kahn, A. K. Sinha: Interaction of
receptors for prostaglandin-E1, prostacyclin and insulin in
human erythrocytes and platelets. Life Sci. 1991, 49, 1129–
1139.
[123] A. K. Duttaroy: Insulin-mediated processes in platelets,
erythrocytes and monocytes macrophages – effects of
essential fatty-acid metabolism. Prostaglandins Leukot
Essent Fatty Acids. 1994, 51, 385–399.
[124] J. A. Keelan, T. A. Sato, K. W. Marvin, J. Lander, R. S. Gilmour, M. D. Mitchell: 15-Deoxy-Delta(12,14)–prostaglandin
J(2), a ligand for peroxisome proliferator-activated receptor-gamma, induces apoptosis in JEG3 choriocarcinoma
cells. Biochem Biophys Res Commun. 1999, 262, 579–
585.
[125] T. Shibata, M. Kondo, T. Osawa, N. Shibata, M. Kobayashi,
K. Uchida: 15-Deoxy-delta 12,14-prostaglandin J2. A
prostaglandin 14;D2 metabolite generated during inflammatory processes. J Biol Chem. 2002, 277, 10459–10466.
[126] G. Ferry, V. Bruneau, P. Beauverger, M. Goussard, M.
Rodriguez, V. Lamamy, S. Dromaint, E. Canet, J. P. Galizzi,
J. A. Boutin: Binding of prostaglandins to human PPARgamma: Tool assessment and new natural ligands. Eur J
Pharmacol. 2001, 417, 77–89.
[127] K. J. Lee, H. A. Kim, P. H. Kim, H. S. Lee, K. R. Ma, J. H.
Park, D. J. Kim, J. H. Hahn: Ox-LDL suppresses PMAinduced MMP-9 expression and activity through CD36mediated activation of PPARg. Exp Mol Med. 2004, 36,
534–544.
[128] A. K. Duttaroy, A. K. Sinha: Purification and properties of
prostaglandin-E1/prostacyclin receptor of human-blood
platelets. J Biol Chem. 1987, 262, 12685–12691.
[129] T. Hatae, M. Wada, C. Yokoyama, M. Shimonishi, T.
Tanabe: Prostacyclin-dependent apoptosis mediated by
PPAR delta. J Biol Chem. 2001, 276, 46260–46267.
[130] F. R. Homaidan, I. Chakroun, H. A. Haidar, M. E. El Sabban:
Protein regulators of eicosanoid synthesis: Role in inflammation. Curr Protein Pept Sci. 2002, 3, 467–484.
[131] T. G. Brock, E. Maydanski, R. W. McNish, M. PetersGolden: Co-localization of leukotriene a4 hydrolase with 5lipoxygenase in nuclei of alveolar macrophages and rat
basophilic leukemia cells but not neutrophils. J Biol Chem.
2001, 276, 35071–35077.
© 2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
PPARs and their roles in human placenta
83
[132] P. R. Devchand, H. Keller, J. M. Peters, M. Vazquez, F. J.
Gonzalez, W. Wahli: The PPARalpha-leukotriene B4 pathway to inflammation control. Nature. 1996, 384, 39–43.
[133] P. R. Devchand, A. K. Hihi, M. Perroud, W. D. Schleuning,
B. M. Spiegelman, W. Wahli: Chemical probes that differentially modulate peroxisome proliferator-activated receptor alpha and BLTR, nuclear and cell surface receptors for
leukotriene B(4). J Biol Chem. 1999, 274, 23341–23348.
[134] S. S. Edwin, S. L. LaMarche, D. Thai, D. W. Branch, M. D.
Mitchell: 5-Hydroxyeicosatetraenoic acid biosynthesis by
gestational tissues: Effects of inflammatory cytokines. Am
J Obstet Gynecol.1993, 169, 1467–1471.
[135] S. S. Edwin, M. D. Mitchell: Arachidonate lipoxygenase
metabolite formation in gestational tissues. J Lipid Mediat
Cell Signal. 1994, 9, 291–300.
[136] S. S. Edwin, D. Thai, S. LaMarche, D. W. Branch, M. D.
Mitchell: The regulation of arachidonate lipoxygenase
metabolite formation in cells derived from intrauterine tissues. Prostaglandins Leukot Essent Fatty Acids. 1995, 52,
229–233.
[137] S. S. Edwin, R. J. Romero, H. Munoz, D. W. Branch, M. D.
Mitchell: 5-Hydroxyeicosatetraenoic acid and human parturition. Prostaglandins. 1996, 51, 403–412.
[138] S. S. Edwin, M. D. Mitchell, D. J. Dudley: Action of immunoregulatory agents on 5-HETE production by cultured
human amnion cells. J Reprod Immunol. 1997, 36, 111–
121.
[139] B. A. Lopez, D. J. Hansell, T. Y. Khong, J. W. Keeling, A. C.
Turnbull: Placental leukotriene B4 release in early pregnancy and in term and preterm labour. Early Hum Dev.
1990, 23, 93–99.
[140] R. Romero, Y. K. Wu, M. Mazor, J. C. Hobbins, M. D.
Mitchell: Amniotic fluid concentration of 5-hydroxyeicosatetraenoic acid is increased in human parturition at
term. Prostaglandins Leukot Essent Fatty Acids. 1989, 35,
81–83.
[141] B. M. Forman, J. Chen, R. M. Evans: Hypolipidemic drugs,
polyunsaturated fatty acids, and eicosanoids are ligands
for peroxisome proliferator-activated receptors alpha and
delta. Proc Natl Acad Sci USA. 1997, 94, 4312–4317.
[142] K. Yu, W. Bayona, C. B. Kallen, H. P. Harding, C. P. Ravera,
G. McMahon, M. Brown, M. A. Lazar: Differential activation
of peroxisome proliferator-activated receptors by eicosanoids. J Biol Chem. 1995, 270, 23975–23983.
[143] A. K. Duttaroy, A. Jørgensen: Insulin and leptin do not affect
fatty acid uptake and metabolism in human placental
choriocarcinoma (BeWo) cells. Prostaglandins Leukot
Essent Fatty Acids. 2005, 72, 403–408.
[144] L. L. Waite, R. E. Louie, R. N. Taylor: Circulating activators
of peroxisome proliferator-activated receptors are reduced
in preeclamptic pregnancy. J Clin Endocrinol Metab. 2005,
90, 620–626.
[Received: September 23, 2005; accepted: December 13, 2005]
www.ejlst.com