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Department of Veterinary Science and Center for Molecular Toxicology, The Pennsylvania State University, University Park, PA 16802
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ABSTRACT |
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 TOP ABSTRACT PEROXISOME...PEROXISOME PROLIFERATORS AS...PEROXISOME PROLIFERATORS AS...PPAR-REGULATED GENESEFFECTS OF GROWTH FACTOR...SUMMARYREFERENCES |
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KEY WORDS: • peroxisome proliferator-activated receptor • conjugated linoleic acid • (n-3) fatty acids • peroxisome proliferators • cancer
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PEROXISOME PROLIFERATOR–ACTIVATED RECEPTORS |
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TOPABSTRACTPEROXISOME...PEROXISOME PROLIFERATORS AS...PEROXISOME PROLIFERATORS AS...PPAR-REGULATED GENESEFFECTS OF GROWTH FACTOR...SUMMARYREFERENCES |
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) has added yet another
signaling molecule to the arsenal utilized by fatty acids and their
metabolites. Due to the initial characterization of activation by
xenobiotics, these receptors were named peroxisome
proliferator–activated receptors (PPAR). PPAR could have easily been
labeled as fatty acid receptors because these proteins are activated by
PP as well as endogenous fatty acids (reviewed in Latruffe and Vamecq 1997
). Similar to other steroid hormone receptors, PPAR
are ligand-activated transcription factors that control gene expression
by interacting with specific DNA response elements (PPRE) located
upstream of responsive genes (Tugwood et al. 1992
).
Genes containing PPRE motifs include acyl-CoA oxidase (ACO),
peroxisomal bifunctional enzyme, liver fatty acid-binding protein
(L-FABP), and microsomal CYP4A, a cytochrome P450
fatty acid 
-hydroxylase (reviewed in Belury et al. 1998
). In addition to these lipid metabolism enzymes,
peroxisome proliferators regulate the expression of several growth
regulatory genes (Ledwith et al. 1993
), as will be
discussed in more detail below. The battery of genes regulated by fatty
acids and PP is critical to their effects on lipid metabolism, cellular
differentiation and ultimately cancer (see Fig. 1).
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), led to the realization that a subfamily of these
receptors existed. Currently, the subfamily has been defined as
PPAR
, PPARß (also called PPAR
and NUC1) and PPAR
. The
potency of various chemicals to activate PPAR is subtype specific, and
the expression of PPAR, ß and varies widely from tissue to
tissue. In numerous cell types of ectodermal, mesodermal or endodermal
origin, PPAR are coexpressed, although their concentration relative to
each other varies widely (Braissant et al. 1996
).
PPAR is highly expressed in hepatocytes, cardiomyocytes, enterocytes
and the proximal tubule cells of kidney. PPARß is expressed
ubiquitously and often at higher levels than PPAR and . PPAR
is expressed predominantly in adipose tissue and the immune system and
exists as two distinct forms 1 and 2, which arise by differential
transcription start sites and alternative splicing (Fajas et al. 1997
). The distinct tissue distribution suggests that the PPAR
subtypes play different biological roles. In fact, it is widely
believed that of the different subtypes, PPAR predominates in
hepatic lipid metabolism and PPAR plays a pivotal role in
adipogenesis and immune responses. There is also evidence to support
the role of PPAR in cell growth and differentiation, which will be
discussed subsequently. |
PEROXISOME PROLIFERATORS AS "MODEL" FATTY ACIDS |
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TOPABSTRACTPEROXISOME...PEROXISOME PROLIFERATORS AS...PEROXISOME PROLIFERATORS AS...PPAR-REGULATED GENESEFFECTS OF GROWTH FACTOR...SUMMARYREFERENCES |
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and PPAR at
physiologic concentrations (Kliewer et al. 1997
). The
eicosanoid 8(S)-hydroxyeicosatetraenoic acid is a PPAR ligand,
whereas 15-deoxy-
12,14-prostaglandin J2 specifically
associates with PPAR (Kliewer et al. 1995 and 1997
). The chemotactic agent leukotriene B4 and the
hypolipidemic drug Wy 14,643 are specific PPAR ligands (Brown et al. 1997
). It appears that the question whether PPAR should be
classified as "orphan receptors" is no longer a point of
contention.
Therefore, fatty acids and xenobiotic PP share the ability to bind to
and activate various PPAR subtypes. The genes that are regulated by PP
and fatty acids are essentially identical (Ledwith et al. 1996
). From an experimental standpoint, PP have the advantage
of undergoing fewer metabolic processes and are generally more potent
than endogenous fatty acids (Krey et al. 1997
). In the
remaining discussion, PP will be used to typify the effects of fatty
acids on gene expression and hence more complicated processes such as
cell proliferation, differentiation and apoptosis.
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PEROXISOME PROLIFERATORS AS REGULATORS OF CELLULAR GROWTH/DIFFERENTIATION |
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TOPABSTRACTPEROXISOME...PEROXISOME PROLIFERATORS AS...PEROXISOME PROLIFERATORS AS...PPAR-REGULATED GENESEFFECTS OF GROWTH FACTOR...SUMMARYREFERENCES |
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A theory that has been gaining favor over recent years is that
peroxisome proliferators, and possibly other tumor promoters and fatty
acids, cause cancer by altering the expression of a particular subset
of genes that in turn affects the rate of proliferation of cells.
Support for this theory includes the induction by PP of growth
regulatory genes such as c-myc, c-Ha-ras,
fos, jun and egr-1 (Cherkaoui Malki et al. 1990
, Ledwith et al. 1993 and 1996
). Compared with other growth regulators, the
profile of PP-induced gene expression was most similar to that induced
by arachidonic acid and eicosatetraynoic acid. Fatty acid– or
PP-induced expression of growth regulatory genes precedes entry of the
cell into S phase (Ledwith et al. 1996
). The most
convincing data regarding a PPAR-cell proliferation-tumor promotion
connection come from the PPAR-null mouse model system (Lee et al. 1995
). Remarkably, the mice that lack PPAR do not
display the typical pleiotropic response, such as hepatomegaly,
peroxisome proliferation and transcriptional-activation of target
genes, when challenged with PP (Lee et al. 1995
). These
mice display abnormal lipid homeostasis (Aoyama et al. 1998
), including fatty acid metabolism (Peters et al. 1997b
). Importantly, in PPAR null mice fed the PP Wy-14,643
in diet, there was no increase in hepatic cell proliferation
(Peters et al. 1997a
), in stark contrast to the
wild-type mice. After 11 mo of consuming Wy14,643, 100% of the
wild-type mice had multiple hepatocellular neoplasms, including
adenomas and carcinomas, whereas the PPAR-null mice were unaffected.
This work demonstrates that the effects of Wy-14,643 on replicative DNA
synthesis and hepatocarcinogenesis are mediated by PPAR
(Peters et al. 1997a
).
PPAR and apoptosis.
Consistent with role of PP as hepatic tumor promoters, these chemicals
decrease the rate of programmed cell death (Bayly et al. 1994
, Roberts 1996
), thereby altering the
balance between mitosis/apoptosis, a key mechanism in carcinogenesis
(Roberts et al. 1997
). Recently, PPAR has been shown
to be an essential component of repression by PP of cell death
(Roberts et al. 1998
). These researchers showed that
overexpression of a dominant negative PPAR (thereby abolishing
PPAR activity) increases apoptosis in guinea pig liver.
PPAR as a master regulator of differentiation.
PPAR have been clearly established to be involved in differentiation of
several cell types. The wide variety of cells that can be induced to
differentiate with PP, fatty acids, thiazolidinediones and other PPAR
ligands suggest that this subfamily of proteins can be termed "master
regulators" of differentiation. This classification is reserved for
genes that specify the fate of a particular cell, such as transcription
factors capable of activating the program of differentiation
(Granneman et al. 1998
). PPAR have been shown to induce
differentiation of adipocytes (Spiegelman et al. 1997
),
oligodendrocytes (Granneman et al. 1998
), myoblasts
(Grimaldi et al. 1997
), keratinocytes (Hanley et al. 1998
) and monocyte/macrophages (Tontonoz et al. 1998
). The role of PPAR in differentiation has been the most
widely studied and demonstrates its role as a master regulator. Ectopic
expression of PPAR in fibroblasts regulated development of the
adipose lineage in response to endogenous lipid activators
(Tontonoz et al. 1994
). That is, expression and
activation of PPAR is sufficient to result in a phenotypic change in
fibroblasts. Also, ligand activation of PPAR is sufficient to induce
growth arrest in fibroblasts (Altiok et al. 1997
), a key
step in committing a cell to differentiate.
Could PPAR-dependent differentiation be responsible for anticarcinogenicity?
The ability of PP to increase differentiation is not associated with
increased cancer risk and in most instances would be considered
beneficial. A growing number of peroxisome proliferators, fatty acids
and other PPAR ligands have anticancer effects in extrahepatic tissues.
For example, the aromatic fatty acid phenylacetate and its analogs
induce tumor cytostasis and differentiation in experimental models
(Pineau et al. 1996
). The relative potency of certain
drugs to activate human PPAR correlated with drug-induced cytostasis
in human prostate carcinoma, melanoma and glioblastoma cell lines.
Also, a dietary fatty acid with anticancer effects in skin, mammary,
colon and stomach, conjugated linoleic acid (CLA; reviewed in
Belury and Vanden Heuvel 1997
), is a potent PPAR
activator (Belury et al. 1997
).
Many fatty acids that activate PPAR (Fig. 3) have been demonstrated to be either anticancer or prodifferentiation in various animal and cellular models. Polyunsaturated fatty acids such as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) as well as dietary lipids such as CLA and lipoic acid have received the most attention. A brief summary of fatty acids with anticancer properties is shown in Table 1 .The paradoxical antitumor effects of peroxisome proliferators and these fatty acids may be attributed to their effects on differentiation at the expense of cell replication. A direct connection between the anticarcinogenicity of chemicals such as CLA, DHA and EPA with PPAR activation requires further study. However, the connection is intriguing and may help explain the isomer-, tissue- and sex-specific inhibition of tumors that has been observed.
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PPAR-REGULATED GENES |
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TOPABSTRACTPEROXISOME...PEROXISOME PROLIFERATORS AS...PEROXISOME PROLIFERATORS AS...PPAR-REGULATED GENESEFFECTS OF GROWTH FACTOR...SUMMARYREFERENCES |
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), there are several PP-responsive genes with a link to
cell cycle control. Induction of the oncogenes c-Ha-ras,
jun and c-myc by PP has been reported and the
ability to induce these genes correlates well with tumor-promoting
potential (Ledwith et al. 1993, 1996 and 1997
, Rokos and Ledwith 1997
). For
example, the tumor promoters Wy14,643, clofibrate, ciprofibrate and
DEHP were inducers of c-fos, c-jun, junB egr-1, and NUP475 whereas the
noncarcinogenic PP dehydroepiandrosterone (DHEA) was ineffective
(Ledwith et al. 1996
). In addition, an immediate early
gene (IEG) critically involved in lipid metabolism, tumor promotion and
inflammation, cyclooxygenase-2, is also regulated by PP (Ledwith et al. 1997
). IEG are key genes involved in regulating the cell
cycle and are characterized by rapid response to mitogens as well as
serum and cycloheximide (CHX) inducibility (Gashler and Sukhatme 1995
). Our laboratory has recently identified and cloned a
novel IEG involved in neuronal differentiation, rZFP-37, as a
PP-regulated gene in rodent liver (Vanden Heuvel et al. 1998
).
Because PPRE motifs have not been observed in the IEG discussed above,
how PP regulate their expression is a matter of debate. Some have
suggested that PPAR was not a major player in IEG expression because
higher doses of a peroxisome proliferator were required to induce c-jun
or c-myc than required to induce ACO or CYP4A1 (Ledwith et al. 1996
). However, the involvement of PPAR in regulating IEG
expression can be implied from effects of this receptor on
differentiation, apoptosis and carcinogenesis. In particular, the fact
that the PPAR-null mouse has abrogated PP-induced cell proliferation
and tumor formation demonstrates that this protein must be involved in
regulating key cell-cycle control genes. We have recently shown that
PPAR-null mice are no longer responsive to peroxisome
proliferator–induced c-myc mRNA (Belury et al. 1998
) or
rZFP-37 (Vanden Heuvel et al. 1998
). Certainly, the
induction of IEG by PP is much more difficult to explain than genes
involved in lipid metabolism (Belury et al. 1998
). The
convergence of PP with growth factor pathways, in particular the
mitogen-activated protein kinase (MAPK; Rokos and Ledwith 1997
) and direct interaction of PPAR with other transcription
factors (Sakai et al. 1995
) may explain the complex
regulation of IEG by PP. The role of growth factor pathways in
affecting PPAR activity is discussed subsequently.
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EFFECTS OF GROWTH FACTOR PATHWAYS ON PPAR ACTIVITY |
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TOPABSTRACTPEROXISOME...PEROXISOME PROLIFERATORS AS...PEROXISOME PROLIFERATORS AS...PPAR-REGULATED GENESEFFECTS OF GROWTH FACTOR...SUMMARYREFERENCES |
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, Khan et al. 1995
, Sumida 1995
, Tsai et al. 1989
). We can now add PPAR to this list of signaling molecules
affected by these small chemicals. A large number of growth factors
including epidermal growth factor (EGF), fibroblast growth factor,
tumor necrosis factor- (TNF), insulin, various interleukins and
cytokines regulate gene expression upon binding to membrane-bound
tyrosine kinase receptors. Each of these receptors may recruit
different signaling molecules to drive expression of IEG and hence
alter the phenotype of the target cell. The growth factor–receptor
binding results in the generation of activated kinases, which in turn
phosphorylate transcription factors involved in immediate early gene
expression. There is a growing base of literature regarding growth
factors and PPAR activity, in particular TNF, insulin and PDGF/EGF.
PDGF treatment of adipocytes in culture decreases the transcriptional
activity of PPAR1 (Camp and Tafuri 1997
). This
receptor undergoes EGF-stimulated MAPK kinase (MEK)-dependent
phosphorylation and cotransfection of adipocytes with a constitutively
active MEK decreased PPAR transcriptional activity. In vitro assays
demonstrate that extracellular signal related kinase (ERK2) and
c-jun-N-terminal kinase (JNK) are able to phosphorylate PPAR2
(Adams et al. 1997
), which may help explain the effects
of EGF and TNF, respectively, on gene expression. Insulin increases
the phosphorylation of PPAR, an effect that is associated with
increased transcriptional activity (Shalev et al. 1996
).
Insulin and a PPAR ligand (troglitazone, TZD) act synergistically to
increase the expression of an adipocyte-specific gene, aP2
(Zhang et al. 1996
). Transfection with a dominant
negative MEK resulted in a decrease in the effects of both insulin and
TZD on PPAR activity, indicating that MAPK is involved in the cross
talk between PPAR and insulin. Finally, pretreatment of ML457 cells
with PD98059, an MEK inhibitor, blocks peroxisome proliferator–induced
c-fos, egr-1 and junB expression (Rokos and Ledwith 1997
). These data show that PPAR are phosphoproteins that are
affected by MAPK and JNK activity.
Most of the studies examining growth factor/PPAR cross talk have
focused on the MAPK pathways. However, we have examined the effects of
various chemical inhibitors of signaling pathways on PPAR activity and
have found other potential cross-talk mechanisms (see Fig. 4
).For example, PI3K inhibitors wortmannin and LY294002 cause a very
dramatic enhancement of PPAR activity. We also have evidence for JNK
and CamKII, as well as MAPK, impinging upon PPAR activity. These data
are supported by work reported previously (Ledwith et al. 1996
) showing that H7, a protein kinase inhibitor, affected
peroxisome proliferator–induced IEG expression. Thapsigargin and
A23187 also affected peroxisome proliferator–induced DNA synthesis,
suggesting a role of calcium mobilization on IEG expression.
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). The
data presented above suggest that PPAR, similar to PKC, may represent a
downstream effector of both fatty acids as well as growth factors. |
SUMMARY |
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TOPABSTRACTPEROXISOME...PEROXISOME PROLIFERATORS AS...PEROXISOME PROLIFERATORS AS...PPAR-REGULATED GENESEFFECTS OF GROWTH FACTOR...SUMMARYREFERENCES |
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) and undergo less extensive
metabolism. Similar to other members of this superfamily of
transcription factors, PPAR affects the phenotype of a target cell by
regulating a battery of growth regulatory and immediate early genes.
PPAR and growth factor signaling processes are highly convergent, which
may have an effect on the immediate early gene expression and hence on
cellular phenotype. In this review article, we have shown that fatty
acids activate PPAR. We have also demonstrated that PPAR is involved in
liver carcinogenesis as well as being a "master regulator" of
differentiation in extrahepatic tissues. Whether PPAR activation
results in proliferation or differentiation may depend on the PPAR
subtype as well as other tissue-specific components. However, fatty
acids such as CLA, DHA and EPA have anticancer activity in extrahepatic
tissues and are known PPAR activators. This raises the possibility that
PPAR activation and its subsequent effect on differentiation may
explain in part why certain polyunsaturated fatty acids have a
beneficial health effect and may also point to future means of
intervention in cancer therapy.
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FOOTNOTES |
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2 Supported in part by grants from Public Health
Service-National Institutes of Health (DK49009 and ES07799)
3 Abbreviations used: ACO, fatty acyl-CoA oxidase;
CLA, conjugated linoleic acid; DHA, docosahexaenoic acid; EGF,
epidermal growth factor; EPA, eicosapentaenoic acid; ERK, extracellular
signal related kinase; IEG, immediate early gene; JNK, c-jun-N-terminal
kinase; L-FAB, liver fatty acid binding protein; MAPK, mitogen
activated protein kinase; MEK, MAPK kinase; PDGF, platelet-derived
growth factor; PP, peroxisome proliferators; PPAR, peroxisome
proliferator-activated receptor; TNF, tumor necrosis factor; TXD,
troglitazone.
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TOPABSTRACTPEROXISOME...PEROXISOME PROLIFERATORS AS...PEROXISOME PROLIFERATORS AS...PPAR-REGULATED GENESEFFECTS OF GROWTH FACTOR...SUMMARYREFERENCES |
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