Mutation Research 690 (2010) 57–63

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Mutation Research/Fundamental and Molecular
Mechanisms of Mutagenesis
journal homepage: www.elsevier.com/locate/molmut
Community address: www.elsevier.com/locate/mutres

Role of PPAR-gamma in inflammation. Prospects for therapeutic intervention by

food components夽
Harry Martin ∗
The New Zealand Institute for Plant & Food Research Limited, Palmerston North 4474, New Zealand

a r t i c l e i n f o a b s t r a c t

Article history: Peroxisome proliferator activated receptor gamma (PPAR␥) is a ligand-dependent transcription factor
and a member of the nuclear receptor superfamily. Acting as sensors of hormones, vitamins, endoge-
nous metabolites and xenobiotic compounds, the nuclear receptors control the expression of a very
Keywords: large number of genes. PPAR␥ has been known for some time to regulate adipocyte differentiation, fatty
Peroxisome proliferator activated receptor acid storage and glucose metabolism, and is a target of anti-diabetic drugs. More recently, PPAR␥ has
gamma (PPAR␥)
been recognized as playing a fundamentally important role in the immune response through its abil-
Inflammatory disease
ity to inhibit the expression of inflammatory cytokines and to direct the differentiation of immune cells
Diet
towards anti-inflammatory phenotypes. A feature of PPAR␥ is the structural diversity of its ligands, which
encompass endogenous metabolites, dietary compounds and synthetic drugs. The high and increasing
incidence of inflammatory and allergic disease, coupled with encouraging results from recent clinical
trials, suggest that natural PPAR␥ agonists found in foods may be beneficial to human health by acting
as anti-inflammatory molecules. PPAR␥ is therefore not only a target of the pharmaceutical industry,
but also of great potential interest to the food industry, since it is activated by several natural dietary
constituents. The prospects for dietary intervention in inflammatory disease have improved somewhat
over the last few years, and are reviewed here.
© 2009 Elsevier B.V. All rights reserved.

1. Introduction—PPAR␥ and its role in inflammation
Inflammatory disease is a broad term encompassing a wide
range of pathological conditions affecting many organs and tis-
sues. Inflammatory diseases include inflammatory bowel disease,
atherosclerosis, rheumatoid arthritis, multiple sclerosis, asthma
and psoriasis. The incidence of atopic illness including asthma has
increased considerably over recent decades [1]. Ulcerative Colitis
and the less prevalent, but more severe, Crohn’s disease, were both
considered to be the diseases of Western societies but the incidence
DOI of original article:10.1016/j.mrfmmm.2009.06.009.
Abbreviations: 15d-PGJ2 , 15-deoxy-12,14 prostaglandin J2; 5-ASA, 5-
aminosalicylic acid; c9, t11, cis-9 trans-11; CLA, conjugated linoleic acid; DHA,
docosahexaenoic acid; EPA, eicosapentaenoic acid; IgA, immunoglobulin A; IL,
interleukin; PPAR␥, peroxisome proliferator activated receptor gamma; PUFA,
polyunsaturated fatty acid; t10, c12, trans-10, cis-12; TNF-␣, tumour necrosis factor
alpha.
夽 An error resulted in this article appearing in a previous volume of this journal.
The article is reprinted here for the reader’s convenience and for the continuity of
this special issue. The details of the original publication are as follows [Martin, 2009.
Role of PPAR-gamma in inflammation. Prospects for therapeutic intervention by
food components. Mutation Research 669, 1–7. 10.1016/j.mrfmmm.2009.06.009].
∗ Tel.: +64 6 953 7747; fax: +64 6 953 7701.
E-mail address: hmartin@hortresearch.co.nz.
and prevalence of these illnesses in Asia are increasing [2–4]. The
risk of developing colorectal carcinoma is increased for individu-
als with inflammatory bowel disease [5]. In geographical regions
where diets are high in n-3 polyunsaturated fatty acids (PUFAs)
cancer incidence is low [6]. It has been suggested that some of the
protective effect of dietary n-3 PUFAs may be due to their anti-
inflammatory, PPAR␥ activating properties [7].
The peroxisome proliferator activated receptors (PPARs) are
a subset of the nuclear receptor superfamily. Unlike the classi-
cal hormone-activated receptors such as the estrogen receptor,
which is located in the cytoplasm and translocates to the nucleus
after binding of the activating ligand, the PPAR receptors reside
in the nucleus bound to DNA response elements [8]. The nuclear
location of the PPAR receptor is typical of metabolite-activated
nuclear receptors. There are three forms of PPAR receptor: alpha,
beta/delta and gamma [9], all of which form obligate heterodimers
with the retinoid-X-receptor (RXR-receptor). PPAR␣ is the tar-
get for hypolipidaemic drugs known as fibrates. PPAR␤/␦ is
now emerging as an important regulator of bowel cell prolifera-
tion/differentiation. The tissue expression of the three PPAR forms
is different but overlapping. The functions of PPAR␥ and PPAR␣ also
overlap somewhat. PPAR␥ is expressed in a range of tissues includ-
ing adipocytes, skeletal muscle cells, osteoclasts, osteoblasts and
several immune-type cells. Unsurprisingly, germ-line knockout of

0027-5107/$ – see front matter © 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.mrfmmm.2009.09.009
58 H. Martin / Mutation Research 690 (2010) 57–63
PPAR␥ is lethal. Four transcripts of the PPAR␥ gene are found in
human tissue as a result of tissue specific variations in promoters
and splicing [10–12]. However in normal cells only two proteins,
PPARG-1 and PPARG-2 are expressed. PPARG-1 protein can be pro-
duced from transcripts PPARG-1, PPARG-3 and PPARG-4. PPARG-1
protein is widely expressed whereas PPARG-2 is mainly restricted
to adipocytes [13].
PPAR␥ is activated, not only by ligand (agonist) binding, but
also by phosphorylation, which increases the ligand-independent
transcriptional activity [14]. Apart from its role as a transcrip-
tion factor, PPAR␥ also acts as a trans-repressor of macrophage
inflammatory genes [15]. In this mechanism the ligand-dependent
sumoylation of PPAR␥ represses inflammatory gene expression.
Binding of sumoylated PPAR␥ to a DNA-bound repressor complex
blocks the expression of inflammatory gene products by prevent-
ing the 19S proteasome-mediated degradation of the repressor
complex. Ligand-independent activation of PPAR␤/␦ can suppress
bowel disease by down regulation of inflammatory signalling [16].
Evidence of the role of PPAR␥ in inflammatory disease is appar-
ent from genetic screening of patients suffering from multiple
sclerosis (MS), an autoimmune disease of the central nervous
system. Various genetic linkages to immune genes have been rec-
ognized for MS, notably the receptors for interleukin (IL) 2 and
IL7. Very recently a PPAR␥ polymorphism has been added to
the list of MS-linked genes. In a study of 116 patients and 211
healthy age-matched controls, the Ala/Ala genotype of the PPAR␥
Pro12Ala polymorphism was associated with a 10-year, statisti-
cally significantly delayed onset of disease in patients with MS
[17]. The anti-inflammatory effects of the Pro12Ala polymorphism
are corroborated by a recent study of atherosclerosis, a chronic,
macrophage-mediated, inflammatory disease of the arterial blood
vessels. This 10-year follow-up study of men with coronary artery
disease showed that carriers of the Pro12Ala allele of PPAR␥ have
less widespread atherosclerosis and are considerably protected
against 10-year vascular morbidity and mortality [18].
The use of PPAR␥ knockout mice has provided strong evidence
for the role of natural PPAR␥ ligands in controlling inflammation.
In a seminal study, colitis was induced in mice deficient in colonic
PPAR␥ by two unrelated mechanisms, either by treatment with oral
dextran sodium sulfate or by transfer of CD4+ CD45RBhi T-cells. In
the former approach colitis is induced by chemical irritation of the
mucosa and is dependent on macrophage activation and epithelial
cell apoptosis whereas in the latter method, colitis is mediated by
antigen driven TH1-cell activation. In both of these models, wild
type mice responded to dietary conjugated linoleic acid (CLA) by
clinical amelioration of colitis while the colonic PPAR␥ knockout
mice were unresponsive [19].
The anti-inflammatory effects of PPAR␥ are closely linked with
its anti-diabetic effects. Mice with a macrophage-specific dele-
tion of PPAR␥ were tested for their ability to resist a challenge
with Leishmania major, a parasitic infection which requires an
M1 (cell-mediated) type response from the host for immunity to
occur. Mice lacking macrophage PPAR␥ were not only less sus-
ceptible to Leishmania spp. infection, as expected, but the same
animals were also prone to diabetic illness [20]. Selective knockout
of macrophage PPAR␥ resulted in a reduced capacity for skele-
tal muscle to metabolise fatty acids and sugars. The expression of
transcription factors and co-activator proteins necessary for mito-
chondrial biogenesis were also greatly reduced. Thus macrophage
PPAR␥ activation not only induces differentiation of macrophages
into the non-inflammatory, M2 type but also has profound effects
on the metabolic status of the whole mouse.
A similar demonstration of the profound physiological effect of
selective knockout (KO) of the PPAR␥ gene, this time selectively
removing the gene from endothelial cells, resulted in the whole-
trunk hair loss in the offspring of the KO mice. The mechanism
underlying these bizarre symptoms was traced to the default syn-
thesis of toxic, highly inflammatory oxidised lipids in the milk of
mice lacking the endothelial PPAR␥ gene. These oxidised lipids
were generated due to a huge excess of lipoxygenase activity, nor-
mally repressed by the endothelial PPAR␥ gene. Accumulation of
the inflammatory lipid mediators in the skin of the suckling mice
caused inflammation and subsequent alopecia. Skin inflammation
was confirmed as the cause of alopecia when topical aspirin cured
the inflammation and prevented the hair loss [21]. These exam-
ples suggest that systemic inflammation is the default physiological
condition, held in check by PPAR␥ under normal circumstances.
Animal studies and human trials of PPAR␥ activating drugs, nor-
mally used to treat diabetes, have shown these compounds to have
great potential as anti-inflammatory drugs. In a mouse model of
asthma, pioglitazone, a PPAR␥ activator, was found to be as effec-
tive as dexamethasone, a corticosteroid commonly used in asthma
treatment [22]. In a rat model of rheumatoid arthritis known as
adjuvant induced arthritis, the PPAR␥ activating drugs pioglita-
zone and rosiglitazone, were found to reduce bone erosion and
inflammatory bone loss [23]. Using Type II diabetic rats as a model
of inflammatory renal disease, pioglitazone reduced nephropathy
by an anti-inflammatory mechanism [24]. The successes of PPAR␥
activators in animal models of the autoimmune disease multi-
ple sclerosis (MS) have given strong support to the use of PPAR␥
agonists in human trials [25]. The use of rosiglitazone in human
inflammatory bowel disease gave beneficial results in an Ulcera-
tive Colitis clinical trial [26]. The US National Institutes of Health
are currently recruiting participants for a trial of pioglitazone in
the inflammatory diseases rheumatoid arthritis and atherosclero-
sis (clinical trial identifier NCT00554853). A trial of pioglitazone in
asthma (clinical trial identifier NCT00787644) is currently in the
planning phase.
PPAR␥ is of particular interest to the food industry because
PPAR␥ activators and their precursors e.g. linolenic and linoleic
acid are abundant in several foods. In addition, certain isoforms
of linoleic acid, notably the trans-10, cis-12 isoform are normally
rare in the diet but present in higher concentration in certain syn-
thetic food supplements used for weight loss [27]. The t10, c12
isoform of CLA is effective at inducing weight loss in mice, but it
does this by antagonising PPAR␥ and inducing the stress response
in adipocytes [28,29]. On the other hand, the cis-9, trans-11 iso-
form of linoleic acid, which is commonly found in natural food
products, inhibits allergic airway sensitization and inflammation
in mice [30] via a PPAR␥ dependent mechanism. The mechanisms
by which dietary PPAR␥ activators may ameliorate inflammatory
disease are discussed.
2. Anti-inflammatory effects of PPAR␥ ligands—synthetic
and natural
PPAR␥ ligands can be divided into various categories: nat-
ural/synthetic, endogenous/exogenous or covalent/reversible. To
demonstrate the variety of PPAR␥ ligands, the structures of the
ligands discussed in this article are shown in Fig. 1.
PPAR␥ agonists known as thiazolidinediones are commonly pre-
scribed for the treatment of diabetes but have been investigated
for their anti-inflammatory effects. PPAR␥ protein was identified
in the antigen presenting cells, monocytes and macrophages and
synthetic PPAR␥ agonists including pioglitazone, troglitazone and
rosiglitazone were shown to suppress production of inflammatory
cytokines by these cells [31,32]. Subsequently, PPAR␥ was identi-
fied in dendritic cells which are potent and highly differentiated,
professional antigen presenting cells. The same thiazolidinedione
compounds were demonstrated to decrease dendritic cell secre-
tion of IL12, a potent TH1-type inflammatory cytokine [33,34].
 H. Martin / Mutation Research 690 (2010) 57–63 59

Fig. 1. The diversity of PPAR␥ ligands.

In addition, the synthesis of TH1-cell but not TH2-cell recruiting
chemokines was also suppressed by thiazolidinediones [33]. An
mRNA profiling study using mouse macrophages demonstrated
that rosiglitazone acted via PPAR␥ as a general repressor of a
broad range of lipopolysaccharide and interferon-␥ target genes.
Taken together, these studies provide strong evidence of the anti-
inflammatory function of PPAR␥ through its ability to suppress
TH1-type cytokine production in macrophages and dendritic cells
[35].
Beneficial effects of the PPAR␥ activator, rosiglitazone, were
reported in two recent clinical trials for the treatment of Ulcerative
Colitis [36,37].
Animal models of inflammation are now being used to explore
the utility of PPAR␥ agonists in other inflammatory diseases. In
a mouse model of systemic lupus erthythematosus, rosiglitazone
reduced autoantibody production, renal disease, and atheroscle-
rosis [38]. The PPAR␥ agonist troglitazone, a thiazolidinedione,
reduced renal scarring and inflammation in a mouse model of renal
fibrosis [39]. In a rat model of post-operative brain inflammation,
rosiglitazone attenuated myeloperoxidase activity and qualita-
tively decreased expression of the cytokine markers of inflamma-
tion, IL1␤ and tumour necrosis factor ␣ (TNF-␣) [40]. The beneficial
effects of rosiglitazone in brain inflammation are tempered by the
fact that it has poor penetrance through the blood–brain barrier.
Conceivably its effects are mediated outside the brain, perhaps in
the brain vasculature. In a mouse model of gastro-intestinal can-
didiasis, rosiglitazone prevented gut colonization by activation of
PPAR␥ [41]. This effect was mediated by increased expression of
the mannose-receptor on mucosal macrophages. Using a rat model
of pancreatitis, it was shown that the PPAR␥ agonists 15-deoxy-
12,14 prostaglandin J2 (15d-PGJ2 ) and troglitazone both suppress
pancreatic inflammation which was measured by reduced pancre-
atic weight and lowered levels of the inflammatory cytokines IL6
and Transforming-Growth-Factor-1␤ [42].
60 H. Martin / Mutation Research 690 (2010) 57–63
5-Aminosalicylic acid (5-ASA) is widely used in the treatment
of inflammatory bowel disease. The anti-inflammatory mechanism
of 5-ASA has been shown to be dependent on PPAR␥ activation
in a PPAR␥ +/− mouse model of colitis [43]. These data were also
confirmed by culture of human colonic biopsies.
These human clinical trials and animal studies show that PPAR␥
agonists can have systemic anti-inflammatory effects. Similar stud-
ies using natural dietary PPAR␥ ligands corroborate the drug-based
evidence. The dietary PUFAs and PPAR␥ ligands, docosahexaenoic
acid (DHA), eicosapentaenoic acid (EPA) and ␥-linolenic acid were
used to treat the human enterocyte cell line, Caco-2 and human
dendritic cells, during exposure of the cells to IL1␤ and lipopolysac-
charide. Not only was secretion of the pro-inflammatory cytokines,
IL6 and IL8, reduced by these PUFAs, but the expression of PPAR␥
was itself enhanced [44]. The central role of PPAR␥ in these cellu-
lar responses to PUFAs was confirmed by the use of GW 9662, a
synthetic PPAR␥ antagonist, which blocked the anti-inflammatory
actions of the PUFAs. In a recent animal feeding trial in pigs,
linseed oil significantly reduced the expression of TNF-␣, a pro-
inflammatory cytokine and marker of inflammation, and increased
muscle mass [45]. Linseed oil’s main components are the PPAR␥
agonists linoleic and linolenic acid. In this study, PPAR␥ concentra-
tion in the spleen and muscle negatively correlated with TNF-␣ in
the serum.
X-ray crystallographic studies of PPAR␥ with bound ligands has
provided great insight into the mechanism of PPAR␥ activation.
The crystal structures showed that the ligand binding pocket can
accommodate two fatty acids simultaneously. More remarkable
was the finding that oxo-fatty acid metabolites [46] and the anti-
inflammatory 15-deoxy-12,14 prostaglandin J2 (15d-PGJ2 ) [47]
bind covalently to the sulfhydryl group of at Cys285 in the ligand
binding domain by a Michael addition mechanism. The covalently
bound ligands were shown to be particularly effective PPAR␥ acti-
vators.
The variety and apparent lack of selectivity of the PPAR␥ ligand
binding pocket has led to concern about which ligands should be
considered physiologically relevant. The discovery of the covalent-
binding nature of certain ligands strongly supports the credibility
of these ligands as being physiologically important since reversibly
binding ligands are much more dependant on concentration for
activity than covalent binders. This is because a reversible ligand
relies on a having either a high affinity or a high concentration
to achieve appreciable binding to its receptor i.e. to establish a
dynamic equilibrium in which the receptor function is affected. By
contrast, a covalent binder with only moderate affinity is more able
to influence receptor function since, once covalently bound, it does
not dissociate from the receptor. Penicillin and aspirin, are classic
examples of covalently binding drugs.
3. Dietary PPAR␥ activators, their sources and
bioavailability
Linoleic acid is a well known component of many foods and
is present in vegetables, fruits, nuts, grains and seeds among
other dietary sources. Linoleic and linolenic acids are highly orally
bioavailable to the plasma and the brain. Indeed the exceptional
bioavailability characteristics of these fatty acids have lead to their
design as drug-delivery vehicles in emulsions with anti-HIV pro-
tease treatments to enhance drug delivery to plasma and brain
[48], demonstrated using a mouse model. The conjugated form of
linoleic acid cis-9, trans-11, a well researched PPAR␥ ligand, was
shown to be produced naturally from linoleic acid by the action
of gut flora, especially probiotic bacteria [49]. In the same study
using human HT-29 colonic carcinoma cells, CLA was also shown
to enhance expression of PPAR␥. CLA is sold as a dietary supplement
to induce weight loss. The safety of this treatment is controversial
due to the high-content of t10, c12 linoleic acid in some synthetic
preparations. Recently, the probiotic bacterium Lactobacillus crispa-
tus M247, was shown to induce increased PPAR␥ expression and
activity in the intestinal epithelial cells of mice [50]. The medi-
ator of the PPAR␥ inducing activity was identified as bacterially
derived hydrogen peroxide. Bacterial strains unable to produce
H2 O2 were also unable to induce PPAR␥ expression while antioxi-
dants and H2 O2 scavengers blocked the effect. These data illustrate
the important point that probiotic bacteria can increase PPAR␥
activity either by the metabolism of precursors into PPAR␥ ago-
nists or by the synthesis of compounds which enhance PPAR␥ gene
expression.
The dependence of PPAR␥ function on the colonizing microbiota
of the gut was demonstrated when Enterococcus faecalis isolated
from newborn babies was shown to induce phosphorylation of
PPAR␥ in primary colonic cells and colonic cell lines. Phospho-
rylation of PPAR␥ activated transcription of anti-inflammatory
target genes, notably including the anti-inflammatory IL10 [51].
The PPAR␥ antagonist GW9662 specifically blocked these effects.
The authors did not identify which product of Enterococcus faecalis
was responsible for the PPAR␥ phosphorylation but suggested CLA
as a likely mediator.
A meta-analysis of several studies concluded that CLA is mod-
erately beneficial for human health [52]. As discussed earlier,
macrophage PPAR␥ has both anti-inflammatory and anti-diabetic
actions. It is therefore feasible that the dietary benefits of CLA, seen
in the meta-analysis, derive from the transformation of unconju-
gated linoleic acid to CLA by gut bacteria. In an in vitro study of 30
strains of gram-positive intestinal bacteria, certain species, notably
Roseburia, were capable of converting the unconjugated form of
linoleic acid (cis-9, cis-12, 18:2) to the immediate precursors of
the health promoting cis-9, trans-11 form. An in vitro, biochemical
study showed that the variability among bacterial strains was sub-
stantial, some strains having almost none of the required linoleate
isomerase activity necessary to perform this metabolic step [53].
The implications from this work are that variations in the gut flora
among individuals may well influence their inflammatory and dia-
betic status.
CLA isoforms differ in terms of health benefit and PPAR␥ activa-
tion. In primary cultures of human adipocytes the t10–c12 isoform
caused adipocyte delipidation, insulin resistance and inflammation
by acting as a PPAR␥ antagonist. These activities were not associ-
ated with the more common and natural cis-9, trans-11 (c9, t11)
isoform of CLA [54]. The pro-inflammatory effects of the trans-10,
cis-12 (t10, c12) CLA isoform in human adipocytes were subse-
quently shown to be reversible by resveratrol [55] in an in vitro,
cell-based study. A 16-week dietary trial comparing c9, t11 CLA
with the synthetic form t10, c12 CLA in a group of 75 healthy post-
menopausal women, found that the t10, c12 isoform increased
levels of inflammatory markers including C-reactive protein and
fibrinogen [56].
A study of the effects of long term feeding of c9, t11 CLA to
rats gave two compelling examples of beneficial immune modu-
lation from an analysis of their immune response to ovalbumin
[57]. Firstly, the ovalbumin-specific response of the splenocytes
was enhanced 50%, while at the same time, the polyclonal spleno-
cyte response to mitogen stimulation was reduced by up to
20%. Secondly, the intestinal anti-ovalbumin immunoglobulin A
(IgA) response was increased by 75%. Although these effects may
be mediated, in part, by PPAR␥, no evidence was presented in
this particular study to test PPAR␥ involvement in the immuno-
logically beneficial effects of dietary c9, t11 CLA. However the
anti-lymphoproliferative effects of the dietary PUFAs and PPAR␥
ligands, linoleic acid and DHA have been demonstrated on human
dendritic cells [58]. In this cell-based, in vitro study, specific block-
 H. Martin / Mutation Research 690 (2010) 57–63
ing of PPAR␥ activity with the antagonist GW9662, also blocked the
anti-inflammatory effects of the PUFAs.
Although the evidence for PPAR␥ mediated anti-inflammatory
effects is convincing, interpretation of the data from CLA feed-
ing trial is complicated by the fact that CLA is also an activator
of PPAR␣ and PPAR␤/␦ [59,60]. Likewise, in the mRNA profiling
study using rosiglitazone to stimulate PPAR␥ receptors in mouse
macrophages, it was apparent, using PPAR␥ deficient macrophages,
that PPAR␦ was activated at higher concentrations of rosiglitazone
[35]. Similarly, in a study using normal and PPAR␣ deficient mice,
the PPAR␥ ligand, pioglitazone was shown to suppress inflamma-
tion through a PPAR␣ dependent mechanism [61]. Thus the human
health benefits of PPAR␥ agonists, in the diet and from pharmaceu-
tical sources, are probably not restricted to their PPAR␥ activating
properties. Furthermore the metabolic fate of CLA in humans is not
fully understood but it is apparent that the conversion of CLA to
conjugated arachidonic acid is substantially more efficient in rats
than in humans [62]. Differences in CLA metabolism may therefore
explain the apparent disagreement between animal trials which
suggest CLA induces weight loss and human trials which are equiv-
ocal on this issue [62].
Dietary phytochemicals with quite different structures and
properties from the unsaturated fatty acids discussed so far,
have been characterised from oregano by activity-based frac-
tionation. Various flavonoids and other phytochemicals from
oregano were characterised for their agonist and antagonist PPAR␥
activities. Compounds were first identified as ligands using a
PPAR␥ fluorescence-polarization assay and subsequently classi-
fied as agonist or antagonist, based on their ability to inhibit
rosiglitazone-induced cellular responses. The dietary flavonoids
quercetin, luteolin, rosmarinic acid and diosmetin were found
to be PPAR␥ antagonists, naringenin and apigenin were modu-
lators and biochanin A was found to be a PPAR␥ agonist [63].
Although the bioavailability of these phytochemicals needs to
be addressed, the approach demonstrates that many common
phytochemicals have the potential to influence PPAR␥ activity,
due to the promiscuous nature of the binding site. The notion
of potentially harmful over-activation of PPAR␥ by dietary con-
stituents was raised by Adapala, who suggested that prolonged
consumption of curcumin, a polyphenol and principal compo-
nent of the spice turmeric, suppressed the immune response and
exacerbated Leishmania donovani infection in mice [64]. However,
curcumin is not itself a PPAR␥ ligand and probably exerts its
anti-inflammatory effects by other mechanisms such as upregu-
lated expression of PPAR␥ [65,66]. Zingerone, the active ingredient
in ginger, which is structurally similar to curcumin, is also anti-
inflammatory through its ability to increase PPAR␥ expression
[67].
Apoptosis delivers anti-inflammatory signals to macrophages
while necrosis is pro-inflammatory [68]. The sumoylation of PPAR␥
in mouse macrophages exposed, in vitro, to apoptotic cells results
in a phenotype shift in the macrophages from pro-inflammatory to
anti-inflammatory [69]. Diets which contain pro-apoptotic com-
pounds may not only protect against cancer, but also reduce
inflammation [70–72]. The dietary PUFA and PPAR␥ ligand EPA has
a PPAR␥ mediated apoptotic effect in HT-29 colon cancer cells [7] in
vitro and CLA has been reported to induce apoptosis in the human
breast cancer cell line SKBr3 [73]. A synergistic effect may therefore
occur when cells are exposed to compounds such as these, which
are both pro-apoptotic and also anti-inflammatory.
4. Conclusion
The tissue-specific knockout of the PPAR␥ gene has revealed the
pivotal role of PPAR␥ in regulating inflammation and metabolism
61
in mice. The importance of PPAR␥ in inflammatory disease is
evident from the success of PPAR␥ activating drugs in animal dis-
ease models and human Ulcerative Colitis trials. Furthermore, the
genetic association between PPAR␥ polymorphisms and diseases
such as multiple sclerosis and atherosclerosis confirms the role
of PPAR␥ in human inflammatory disease. These data support the
hypothesis that PPAR␥ activation in healthy individuals suppresses
systemic inflammation. The prospects that dietary factors may have
beneficial effects in inflammatory disease are good, since various
dietary ligands such as conjugated (c9, t11) linoleic acid or DHA,
are present in certain foods. Pre-biotic foods and probiotic bacte-
ria play an important role in influencing the immune phenotype
through their ability to convert food components into PPAR␥ ago-
nists and to synthesise compounds de novo which stimulate PPAR␥
gene expression. The discovery of new dietary PPAR␥ activators
coupled with understanding of the subtle mechanisms by which
these compounds influence PPAR␥ activity promises to be an excit-
ing field in the immediate future—with enormous implications for
human health.
Role of funding source
Internal funding from Plant and Food Research.
Conflict of interest
None.
References
[1] S.F. Bloomfield, R. Stanwell-Smith, R.W.R. Crevel, J. Pickup, Too clean, or not too
clean: the hygiene hypothesis and home hygiene, Clinical and Experimental
Allergy 36 (2006) 402–425.
[2] K.L. Goh, S.D. Xiao, Inflammatory bowel disease: a survey of the epidemiology
in Asia, Journal of Digestive Diseases 10 (2009) 1–6.
[3] E.V. Loftus, Clinical epidemiology of inflammatory bowel disease: inci-
dence, prevalence, and environmental influences, Gastroenterology 126 (2004)
1504–1517.
[4] B.A. Jacobsen, J. Fallingborg, H.H. Rasmussen, K.R. Nielsen, A.M. Drewes, E.
Puho, G.L. Nielsen, H.T. Sorensen, Increase in incidence and prevalence of
inflammatory bowel disease in northern Denmark: a population-based study,
1978–2002, European Journal of Gastroenterology & Hepatology 18 (2006)
601–606.
[5] A.B. Carter, S.A. Misyak, R. Hontecillas, J. Bassaganya-Riera, Dietary modula-
tion of inflammation-induced colorectal cancer through PPAR␥, PPAR Research
2009 (2009), Article ID 498352.
[6] C.P.J. Caygill, M.J. Hill, Fish, N-3 fatty-acids and human colorectal and breast-
cancer mortality, European Journal of Cancer Prevention 4 (1995) 329–332.
[7] C.D. Allred, D.R. Talbert, R.C. Southard, X. Wang, M.W. Kilgore, PPAR gamma 1
as a molecular target of eicosapentaenoic acid in human colon cancer (HT-29)
cells, Journal of Nutrition 138 (2008) 250–256.
[8] C.K. Glass, M.G. Rosenfeld, The coregulator exchange in transcriptional func-
tions of nuclear receptors, Genes & Development 14 (2000) 121–141.
[9] C.K. Glass, S. Ogawa, Combinatorial roles of nuclear receptors in inflammation
and immunity, Nature Reviews Immunology 6 (2006) 44–55.
[10] T.T. Wang, J. Xu, X.F. Yu, R.C. Yang, Z.C. Han, Peroxisome proliferator-activated
receptor gamma in malignant diseases, Critical Reviews in Oncology Hematol-
ogy 58 (2006) 1–14.
[11] L. Michalik, J. Auwerx, J.P. Berger, V.K. Chatterjee, C.K. Glass, F.J. Gonzalez,
P.A. Grimaldi, T. Kadowaki, M.A. Lazar, S. O’Rahilly, C.N.A. Palmer, J. Plutzky,
J.K. Reddy, B.M. Spiegelman, B. Staels, W. Wahli, International Union of Phar-
macology. LXI. Peroxisome proliferator-activated receptors, Pharmacological
Reviews 58 (2006) 726–741.
[12] C. Bruedigam, M. Koedam, H. Chiba, M. Eijken, J. van Leeuwen, Evidence for mul-
tiple peroxisome proliferator-activated receptor gamma transcripts in bone:
fine-tuning by hormonal regulation and mRNA stability, FEBS Letters 582
(2008) 1618–1624.
[13] P. Escher, O. Braissant, S. Basu-Modak, L. Michalik, W. Wahli, B. Desvergne, Rat
PPARs: quantitative analysis in adult rat tissues and regulation in fasting and
refeeding, Endocrinology 142 (2001) 4195–4202.
[14] C. Diradourian, J. Girard, J.P. Pegorier, Phosphorylation of PPARs: from molec-
ular characterization to physiological relevance, Biochimie 87 (2005) 33–38.
[15] G. Pascual, A.L. Fong, S. Ogawa, A. Gamliel, A.C. Li, V. Perissi, D.W. Rose, T.M.
Willson, M.G. Rosenfeld, C.K. Glass, A SUMOylation-dependent pathway medi-
ates transrepression of inflammatory response genes by PPAR-gamma, Nature
437 (2005) 759–763.
62 H. Martin / Mutation Research 690 (2010) 57–63
[16] J.M. Peters, H.E. Hollingshead, F.J. Gonzalez, Role of peroxisome-proliferator-
activated receptor beta/delta (PPAR beta/delta) in gastrointestinal tract
function and disease, Clinical Science 115 (2008) 107–127.
[17] L. Klotz, S. Schmidt, R. Heun, T. Klockgether, H. Kolsch, Association of the PPAR
gamma gene polymorphism Pro12Ala with delayed onset of multiple sclerosis,
Neuroscience Letters 449 (2009) 81–83.
[18] J.J. Regieli, J.W. Jukema, P.A. Doevendans, A.H. Zwinderman, Y. van der Graaf, J.J.
Kastelein, D.E. Grobbee, PPAR gamma variant influences angiographic outcome
and 10-year cardiovascular risk in male symptomatic coronary artery disease
patients, Diabetes Care 32 (2009) 839–844.
[19] J. Bassaganya-Riera, K. Reynolds, S. Martino-Catt, Y.Z. Cui, L. Hennighausen, F.
Gonzalez, J. Rohrer, A.U. Benninghoff, R. Hontecillas, Activation of PPAR gamma
and delta by conjugated linoleic acid mediates protection from experimental
inflammatory bowel disease, Gastroenterology 127 (2004) 777–791.
[20] J.I. Odegaard, R.R. Ricardo-Gonzalez, M.H. Goforth, C.R. Morel, V. Subrama-
nian, L. Mukundan, A.R. Eagle, D. Vats, F. Brombacher, A.W. Ferrante, A.
Chawla, Macrophage-specific PPAR gamma controls alternative activation and
improves insulin resistance, Nature 447 (2007), pp. 1116-U1112.
[21] Y.H. Wan, A. Saghatelian, L.W. Chong, C.L. Zhang, B.F. Cravatt, R.M. Evans, Mater-
nal PPAR gamma protects nursing neonates by suppressing the production of
inflammatory milk, Genes & Development 21 (2007) 1895–1908.
[22] V.R. Narala, R. Ranga, M.R. Smith, A.A. Berlin, T.J. Standiford, N.W. Lukacs, R.C.
Reddy, Pioglitazone is as effective as dexamethasone in a cockroach allergen-
induced murine model of asthma, Respiratory Research 8 (2007).
[23] M. Koufany, D. Moulin, A. Bianchi, M. Muresan, S. Sebillaud, P. Netter, G.
Weryha, J.Y. Jouzeau, Anti-inflammatory effect of antidiabetic thiazolidine-
diones prevents bone resorption rather than cartilage changes in experimental
polyarthritis, Arthritis Research & Therapy 10 (2008).
[24] G.J. Ko, Y.S. Kang, S.Y. Han, M.H. Lee, H.K. Song, K.H. Han, H.K. Kim, J.Y.
Han, D.R. Cha, Pioglitazone attenuates diabetic nephropathy through an
anti-inflammatory mechanism in type 2 diabetic rats, Nephrology Dialysis
Transplantation 23 (2008) 2750–2760.
[25] J.J. Brightt, C.C. Walline, S. Kanakasabai, S. Chakraborty, Targeting PPAR as a
therapy to treat multiple sclerosis, Expert Opinion on Therapeutic Targets 12
(2008) 1565–1575.
[26] J.D. Lewis, G.R. Lichtenstein, J.J. Deren, B.E. Sands, S.B. Hanauer, J.A. Katz, B. Lash-
ner, D.H. Present, S. Chuai, J.H. Ellenberg, L. Nessel, G.D. Wu, Rosiglitazone for
active ulcerative colitis: a randomized placebo-controlled trial, Gastroenterol-
ogy 134 (2008) 688–695.
[27] X.R. Zhou, C.H. Sun, J.R. Liu, D. Zhao, Dietary conjugated linoleic acid increases
PPAR gamma gene expression in adipose tissue of obese rat, and improves
insulin resistance, Growth Hormone & Igf Research 18 (2008) 361–368.
[28] P.C. LaRosa, J.J.M. Riethoven, H. Chen, Y. Xia, Y. Zhou, M. Chen, J. Miner, M.E.
Fromm, Trans-10, cis-12 conjugated linoleic acid activates the integrated stress
response pathway in adipocytes, Physiological Genomics 31 (2007) 544–553.
[29] H. Poirier, J.S. Shapiro, R.J. Kim, M.A. Lazar, Nutiritional supplementation with
trans-10, cis-12-conjugated linoleic acid induces inflammation of white adi-
pose tissue, Diabetes 55 (2006) 1634–1641.
[30] A. Jaudszus, M. Krokowski, P. Mockel, Y. Darcan, A. Avagyan, P. Matricardi, G.
Jahreis, E. Hamelmann, Cis-9, trans-11-conjugated linoleic acid inhibits allergic
sensitization and airway inflammation via a PPAR gamma-related mechanism
in mice, Journal of Nutrition 138 (2008) 1336–1342.
[31] M. Ricote, A.C. Li, T.M. Willson, C.J. Kelly, C.K. Glass, The peroxisome proliferator-
activated receptor-gamma is a negative regulator of macrophage activation,
Nature 391 (1998) 79–82.
[32] C.Y. Jiang, A.T. Ting, B. Seed, PPAR-gamma agonists inhibit production of mono-
cyte inflammatory cytokines, Nature 391 (1998) 82–86.
[33] P. Gosset, A.S. Charbonnier, P. Delerive, J. Fontaine, B. Staels, J. Pestel, A.B. Tonnel,
F. Trottein, Peroxisome proliferator-activated receptor gamma activators affect
the maturation of human monocyte-derived dendritic cells, European Journal
of Immunology 31 (2001) 2857–2865.
[34] C. Faveeuw, S. Fougeray, V. Angeli, J. Fontaine, G. Chinetti, P. Gosset, P.
Delerive, C. Maliszewski, M. Capron, B. Staels, M. Moser, F. Trottein, Peroxi-
some proliferator-activated receptor gamma activators inhibit interleukin-12
production in murine dendritic cells, FEBS Letters 486 (2000) 261–266.
[35] J.S. Welch, M. Ricote, T.E. Akiyama, F.J. Gonzalez, C.K. Glass, PPAR gamma and
PPAR delta negatively regulate specific subsets of lipopolysaccharide and IFN-
gamma target genes in macrophages, in: Proceedings of the National Academy
of Sciences of the United States of America 100, 2003, pp. 6712–6717.
[36] J.D. Lewis, G.R. Lichtenstein, J.J. Deren, B.E. Sands, S.B. Hanauer, J.A. Katz, B. Lash-
ner, D.H. Present, S. Chuai, J.H. Ellenbergr, L. Nessel, G.D. Wu, Rosiglitazone for
active ulcerative colitis: a randomized placebo-controlled trial, Gastroenterol-
ogy 134 (2008) 688–695.
[37] H.L. Liang, Q. Ouyang, A clinical trial of combined use of rosiglitazone and 5-
aminosalicylate for ulcerative colitis, World Journal of Gastroenterology 14
(2008) 114–119.
[38] T. Aprahamian, R.G. Bonegio, C. Richez, K. Yasuda, L.K. Chiang, K. Sato, K. Walsh,
I.R. Rifkin, The peroxisome proliferator-activated receptor gamma agonist
rosiglitazone ameliorates murine lupus by induction of adiponectin, Journal
of Immunology 182 (2009) 340–346.
[39] T. Kawai, T. Masaki, S. Doi, T. Arakawa, Y. Yokoyama, T. Doi, N. Kohno, N. Yorioka,
PPAR-gamma agonist attenuates renal interstitial fibrosis and inflammation
through reduction of TGF-beta, Laboratory Investigation 89 (2009) 47–58.
[40] A. Hyong, V. Jadhav, S. Lee, W. Tong, J. Rowe, J.H. Zhang, J.P. Tang, Rosiglitazone,
a PPAR gamma agonist, attenuates inflammation after surgical brain injury in
rodents, Brain Research 1215 (2008) 218–224.
[41] A. Coste, C. Lagane, C. Filipe, H. Authier, A. Gales, J. Bernad, V. Douin-Echinard,
J.C. Lepert, P. Balard, M.D. Linas, J.F. Arnal, J. Auwerx, B. Pipy, IL-13 attenuates
gastrointestinal candidiasis in normal and immunodeficient RAG-2(−/−) mice
via peroxisome proliferator-activated receptor-gamma activation, Journal of
Immunology 180 (2008) 4939–4947.
[42] J.H. Yu, K.H. Kim, H. Kim, SOCS 3 and PPAR-gamma ligands inhibit the expres-
sion of IL-6 and TGF-beta 1 by regulating JAK2/STAT3 signaling in pancreas,
International Journal of Biochemistry & Cell Biology 40 (2008) 677–688.
[43] C. Rousseaux, B. Lefebvre, L. Dubuquoy, P. Lefebvre, O. Romano, J. Auwerx, D.
Metzger, W. Wahli, B. Desvergne, G.C. Naccari, P. Chavatte, A. Farce, P. Bulois,
A. Cortot, J.F. Colombel, P. Desreumaux, Intestinal antiinflammatory effect
of 5-aminosalicylic acid is dependent on peroxisome proliferator-activated
receptor-gamma, Journal of Experimental Medicine 201 (2005) 1205–
1215.
[44] R. Marion-Letellier, M. Butler, P. Dechelotte, R.J. Playford, S. Ghosh, Comparison
of cytokine modulation by natural peroxisome proliferator-activated receptor
gamma ligands with synthetic ligands in intestinal-like Caco-2 cells and human
dendritic cells-potential for dietary modulation of peroxisome proliferator-
activated receptor gamma in intestinal inflammation, American Journal of
Clinical Nutrition 87 (2008) 939–948.
[45] F.R. Huang, Z.P. Zhan, J. Luo, S.W. Jiang, J. Peng, Duration of feeding linseed
diet influences peroxisome proliferator-activated receptor gamma and tumor
necrosis factor gene expression, and muscle mass of growing-finishing bar-
rows, Livestock Science 119 (2008) 194–201.
[46] T. Itoh, L. Fairall, K. Amin, Y. Inaba, A. Szanto, B.L. Balint, L. Nagy, K. Yamamoto,
J.W.R. Schwabe, Structural basis for the activation of PPAR gamma by oxidized
fatty acids, Nature Structural & Molecular Biology 15 (2008) 924–931.
[47] T. Waku, T. Shiraki, T. Oyama, Y. Fujimoto, K. Maebara, N. Kamiya, H. Jingami, K.
Morikawa, Structural insight into PPAR[gamma] activation through covalent
modification with endogenous fatty acids, Journal of Molecular Biology 385
(2009) 188–199.
[48] T.K. Vyas, A. Shahiwala, M.M. Amiji, Improved oral bioavailability and brain
transport of Saquinavir upon administration in novel nanoemulsion formula-
tions, International Journal of Pharmaceutics 347 (2008) 93–101.
[49] J.B. Ewaschuk, J.W. Walker, H. Diaz, K.L. Madsen, Bioproduction of conjugated
linoleic acid by probiotic bacteria occurs in vitro and in vivo in mice, Journal of
Nutrition 136 (2006) 1483–1487.
[50] S. Voltan, D. Martines, M. Elli, P. Brun, S. Longo, A. Porzionato, V. Macchi, R.
D’Inca, M. Scarpa, G. Palu, G.C. Sturniolo, L. Morelli, I. Castagliuolo, Lactobacillus
crispatus M247-derived H2 O2 acts as a signal transducing molecule activating
peroxisome proliferator activated receptor-gamma in the intestinal mucosa,
Gastroenterology 135 (2008) 1216–1227.
[51] A. Are, L. Aronsson, S.G. Wang, G. Greicius, Y.K. Lee, J.A. Gustafsson, S. Pet-
tersson, V. Arulampalam, Enterococcus faecalis from newborn babies regulate
endogenous PPAR gamma activity and IL-10 levels in colonic epithelial cells,
in: Proceedings of the National Academy of Sciences of the United States of
America 105, 2008, pp. 1943–1948.
[52] L.D. Whigham, A.C. Watras, D.A. Schoeller, Efficacy of conjugated linoleic acid
for reducing fat mass: a meta-analysis in humans, American Journal of Clinical
Nutrition 85 (2007) 1203–1211.
[53] E. Devillard, F.M. McIntosh, S.H. Duncan, R.J. Wallace, Metabolism of linoleic
acid by human gut bacteria: different routes for biosynthesis of conjugated
linoleic acid, Journal of Bacteriology 189 (2007) 2566–2570.
[54] A. Kennedy, S. Chung, K. LaPoint, O. Fabiyi, M.K. McIntosh, Trans-10, cis-12
conjugated linoleic acid antagonizes ligand-dependent PPAR gamma activ-
ity in primary cultures of human adipocytes, Journal of Nutrition 138 (2008)
455–461.
[55] A. Kennedy, A. Overman, K. LaPoint, R. Hopkins, T. West, C.C. Chuang, K. Mar-
tinez, D. Bell, M. McIntosh, Conjugated linoleic acid-mediated inflammation
and insulin resistance in human adipocytes are attenuated by resveratrol, Jour-
nal of Lipid Research 50 (2009) 225–232.
[56] T. Tholstrup, M. Raff, E.M. Straarup, P. Lund, S. Basu, J.M. Bruun, An oil mixture
with trans-10, cis-12 conjugated linoleic acid increases markers of inflamma-
tion and in vivo lipid peroxidation compared with cis-9, trans-11 conjugated
linoleic acid in postmenopausal women, Journal of Nutrition 138 (2008)
1445–1451.
[57] C. Ramirez-Santana, C. Castellote, M. Castell, M. Rivero, M. Rodriguez-Palmero,
A. Franch, F.J. Perez-Cano, Long-term feeding of the cis-9,trans-11 isomer of
conjugated linoleic acid reinforces the specific immune response in rats, Journal
of Nutrition 139 (2009) 76–81.
[58] F. Zapata-Gonzalez, F. Rueda, J. Petriz, P. Domingo, F. Villarroya, J. Diaz-Delfin,
M.A. de Madariaga, J.C. Domingo, Human dendritic cell activities are modulated
by the omega-3 fatty acid, docosahexaenoic acid, mainly through PPAR gamma:
RXR heterodimers: comparison with other polyunsaturated fatty acids, Journal
of Leukocyte Biology 84 (2008) 1172–1182.
[59] S.Y. Moya-Camarena, J.P. Vanden Heuvel, S.G. Blanchard, L.A. Leesnitzer, M.A.
Belury, Conjugated linoleic acid is a potent naturally occurring ligand and acti-
vator of PPAR alpha, Journal of Lipid Research 40 (1999) 1426–1433.
[60] S.Y. Moya-Camarena, J.P. Vanden Heuvel, M.A. Belury, Conjugated linoleic acid
activates peroxisome proliferator-activated receptor a and B subtypes but
does not induce hepatic peroxisome proliferation in Sprague–Dawley rats,
Biochimica Et Biophysica Acta: Molecular and Cell Biology of Lipids 1436 (1999)
331–342.
[61] G. Orasanu, O. Ziouzenkova, P.R. Devchand, V. Nehra, O. Hamdy, E.S. Hor-
ton, J. Plutzky, The peroxisome proliferator-activated receptor-gamma agonist
pioglitazone represses inflammation in a peroxisome proliferator-activated
 H. Martin / Mutation Research 690 (2010) 57–63
receptor-alpha-dependent manner in vitro and in vivo in mice, Journal of the
American College of Cardiology 52 (2008) 869–881.
[62] M. Plourde, S. Jew, S.C. Cunnane, P.J.H. Jones, Conjugated linoleic acids: why the
discrepancy between animal and human studies? Nutrition Reviews 66 (2008)
415–421.
[63] M. Mueller, B. Lukas, J. Novak, T. Simoncini, A.R. Genazzani, A. Jung-
bauert, Oregano: a source for peroxisome proliferator-activated receptor
gamma antagonists, Journal of Agricultural and Food Chemistry 56 (2008)
11621–11630.
[64] N. Adapala, M.M. Chan, Long-term use of an antiinflammatory, curcumin, sup-
pressed type 1 immunity and exacerbated visceral leishmaniasis in a chronic
experimental model, Laboratory Investigation 88 (2008) 1329–1339.
[65] A.M. Siddiqui, X.X. Cui, R.Q. Wu, W.F. Dong, M. Zhou, M.W. Hu, H.H.
Simms, P. Wang, The anti-inflammatory effect of curcumin in an exper-
imental model of sepsis is mediated by up-regulation of peroxisome
proliferator-activated receptor-gamma, Critical Care Medicine 34 (2006) 1874–
1882.
[66] V.R. Narala, M.R. Smith, R.K. Adapala, R. Ranga, K. Panati, B.B. Moore, T. Leff,
V.D. Reddy, A.K. Kondapi, R.C. Reddy, Curcumin is not a ligand for peroxisome
proliferator-activated receptor-␥, Gene Therapy & Molecular Biology 13 (2009)
20–25.
[67] S.W. Chung, M.K. Kim, J.H. Chung, D.H. Kim, J.S. Choi, S. Anton, A.Y. Seo, K.Y. Park,
T. Yokozawa, S.H. Rhee, B.P. Yu, H.Y. Chung, Peroxisome proliferator-activated
63
receptor activation by a short-term feeding of zingerone in aged rats, Journal
of Medicinal Food 12 (2009) 345–350.
[68] R.E. Cocco, D.S. Ucker, Distinct modes of macrophage recognition for apoptotic
and necrotic cells are not specified exclusively by phosphatidylserine exposure,
Molecular Biology of the Cell 12 (2001) 919–930.
[69] C. Jennewein, A.M. Kuhn, M.V. Schmidt, V. Meilladec-Jullig, A. von Knethen, F.J.
Gonzalez, B. Brune, Sumoylation of peroxisome proliferator-activated receptor
gamma by apoptotic cells prevents lipopolysaccharide-induced NCoR removal
from kappa B binding sites proinflammatory cytokines, Journal of Immunology
181 (2008) 5646–5652.
[70] J. Ju, X.P. Hao, M.J. Lee, J.D. Lambert, G. Lu, H. Xiao, H.L. Newmark, C.S. Yang,
A gamma-tocopherol-rich mixture of tocopherols inhibits colon inflammation
and carcinogenesis in azoxymethane and dextran sulfate sodium-treated mice,
Cancer Prevention Research 2 (2009) 143–152.
[71] E.H. Jeffery, M. Araya, Physiological effects of broccoli consumption, Phyto-
chemistry Reviews 8 (2009) 283–298.
[72] T. Tanaka, Y. Yasui, R. Ishigamori-Suzuki, T. Oyama, Citrus compounds inhibit
inflammation- and obesity-related colon carcinogenesis in mice, Nutrition and
Cancer: An International Journal 60 (2008) 70–80.
[73] X.L. Yuan, F. He, Q. Chen, X.L. Yang, D.P. Yang, D.M. Wang, L. Zhong, Studies
on PPAR gamma signal pathway of conjugated linoleic acid isomers induce
apoptosis of human breast cancer cell line SKBr3, Progress in Biochemistry and
Biophysics 36 (2009) 491–499.