Narala et al: Curcumin is not a ligand for PPAR-?
Gene Ther Mol Biol Vol 13, 20-25, 2009
Curcumin is not a ligand for peroxisome
Venkata R. Narala1, Monica R. Smith1, Ravi K. Adapala1, Rajesh Ranga1, Kalpana
Panati2, Bethany B. Moore1, Todd Leff3, Vudem D. Reddy2, Anand K. Kondapi4,
Raju C. Reddy1,*
1Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan Medical
Center, Ann Arbor, MI 48109, USA
2Center for Plant Molecular Biology, Osmania University, Hyderabad 500 007, India
3Center for Integrative Metabolic and Endocrine Research, Wayne State University School of Medicine, Detroit, MI
4Department of Biotechnology, School of Life Sciences, University of Hyderabad, Hyderabad 500 046, India
*Correspondence: Raju C. Reddy M.D., University of Michigan, Division of Pulmonary and Critical Care Medicine, 109 Zina Pitcher
Place, 4062 BSRB, Ann Arbor, MI 48109-2200, USA; Tel: (734) 615-2871; Fax: (734) 615-2111; e-mail: firstname.lastname@example.org
Key words: PPAR-?, TGF-?, rosiglitazone, ciglitazone, PPRE, preadipocyte, fibroblast, turmeric, peroxisome, curcumin
Abbreviations: dithiothreitol, (DTT); glutathione-S-transferase, (GST); glyceraldehyde-3-phosphate dehydrogenase, (GAPDH);
isopropyl-1-?-D-galactopyranoside, (IPTG); peroxisome proliferator response element, (PPRE); peroxisome proliferator-activated
receptor-?, (PPAR-?); ?-smooth muscle actin, (?-SMA)
Received: 24 February 2009; Revised: 14 March 2009
Accepted: 16 March 2009; electronically published: April 2009
Curcumin, a compound found in the spice turmeric, has been shown to possess a number of beneficial biological
activities exerted through a variety of different mechanisms. Some curcumin effects have been reported to involve
activation of the nuclear transcription factor peroxisome proliferator-activated receptor-? (PPAR-?), but the
concept that curcumin might be a PPAR-? ligand remains controversial. Results reported here demonstrate that, in
contrast to the PPAR-? ligands ciglitazone and rosiglitazone, curcumin is inactive in five different reporter or DNA-
binding assays, does not displace [3H]rosiglitazone from the PPAR-? ligand-binding site, and does not induce
PPAR-?-dependent differentiation of preadipocytes, while its ability to inhibit fibroblast-to-myofibroblast
differentiation is not affected by any of four PPAR-? antagonists. These multiple lines of evidence conclusively
demonstrate that curcumin is not a PPAR-? ligand and indicate the need for further investigation of the
mechanisms through which the compound acts.
signaling pathways. These varied beneficial effects have
The polyphenol curcumin (diferuloylmethane; 1,7-
led to investigation of curcumin as a potential therapeutic
agent in a number of disease conditions (Reddy et al,
dione) is an orange-yellow compound with limited water
2005; Thangapazham et al, 2006; Aggarwal et al, 2007).
solubility that is obtained from the turmeric plant,
Peroxisome proliferator-activated receptor-? (PPAR-
Curcuma longa. Curcumin has been shown to exhibit a
?) is a member of the nuclear receptor family of
variety of biological effects (Maheshwari et al, 2006) such
transcription factors, a large group of proteins that mediate
as anti-oxidant, anti-inflammatory, anti-tumor and wound-
healing properties (Srivastava et al, 1995). These activities
transrepression (Issemann and Green, 1990). PPAR-? is
are exerted through an equally wide variety of signaling
highly expressed in adipose tissue and plays a crucial role
pathways, which may involve either inhibition (Chen and
in adipocyte differentiation (Lemberger et al, 1996). It is
Tan, 1998; Gaedeke et al, 2004; Zhou et al, 2007) or
also expressed in a variety of other tissue and cell types,
activation (Hu et al, 2005) of specific intracellular
where it plays key roles in the regulation of metabolism
and inflammation. Ligands for PPAR-? include a variety
Gene Therapy and Molecular Biology Vol 13, page 21
of natural and synthetic compounds. Most of the natural
C. Nuclear protein preparation and PPAR-?-
ligands are fatty acids or fatty acid derivatives. Synthetic
DNA binding assay
ligands include the thiazolidinediones, which are used as
CV-1 and IMR-90 cells were plated in 100 mm dishes at
insulin sensitizing agents for treatment of type 2 diabetes
70% confluence. The cells were treated with curcumin or
(Berger and Moller, 2002).
rosiglitazone for 3 h, after which nuclear protein was isolated
Curcumin has been reported to activate PPAR-? (Xu
(Cayman nuclear protein extraction kit). Protein concentrations
et al, 2003; Zheng and Chen, 2004; Chen and Xu, 2005;
were estimated using the Bio-Rad (Hercules, CA) DC protein
Lin and Chen, 2008). It remains unclear, however,
assay. PPAR-? DNA-binding activity in the nuclear protein was
detected by an ELISA-based PPAR-? transcription factor assay
whether this activation reflects curcumin binding to the
(Cayman) that detects PPAR-? bound to PPRE-containing
receptor, as has been suggested (Chen and Xu, 2005;
double-stranded DNA sequences.
Jacob et al, 2007), or is entirely the result of indirect
effects. The present study, utilizing multiple molecular and
D. Ligand binding by PPAR-?-GST
cellular assays, is the first to directly investigate the ability
The ligand binding domain of PPAR-? was introduced into
of curcumin to act as a PPAR-?-activating ligand.
the pGEX-2T bacterial expression vector (Amersham Pharmacia;
Buckinghamshire, UK). Expression of glutathione-S-transferase
II. Material and Methods
(GST)-tagged PPAR-? in Escherichia coli strain BL21-DE3
(Novagen; San Diego, CA) was induced by the addition of 1 mM
DMEM and DMEM/F12 were purchased from Gibco-BRL
(IPTG) to the growth
medium. Bacterial extracts were prepared using standard
Life Technologies (Grand Island, NY). High purity curcumin
methods and the fusion proteins were purified using Glutathione
was obtained from Sigma Chemical Co. (St. Louis, MO),
Sepharose 4B (GE Healthcare; Piscataway, NJ). GST-PPAR-?
Bioprex (Pune, Maharashtra, India), and Alfa Aesar (Ward Hill,
protein induction and receptor binding was assessed as described
MA); all experiments were repeated using each formulation.
(Fu et al, 2003). Briefly, 5 ?g of GST-PPAR-? protein,
Fetal bovine serum (FBS) was obtained from HyClone (Logan,
[3H]rosiglitazone (specific activity, 5 Ci/mmol), and various
UT). PPAR-? antagonists GW9662 and BADGE were purchased
concentrations of curcumin or unlabeled rosiglitazone were
from Cayman Chemical (Ann Arbor, MI), while PPAR-?
incubated for 2 h at 25°C in a buffer containing 10 mM Tris HCl
Antagonist III (G3335), and T0070907 were purchased from
(pH 8.0), 50 mM KCl, and 10 mM dithiothreitol (DTT). Bound
Calbiochem (La Jolla, CA). The PPAR-? agonists ciglitazone
[3H]rosiglitazone was separated from free [3H]rosiglitazone by
and rosiglitazone were purchased from Caym
an. Aliquots of
centrifugation at 8000 rpm for 1 min. The radioactivity of the
agonists and antagonists were dissolved in DMSO (Sigma-
bound [3H]rosiglitazone fraction was determined by liquid
Aldrich, St. Louis, MO) at 100 mM and stored at -30°C until use.
[3H]rosiglitazone was obtained from American Radiolabeled
Chemicals (St. Louis, MO). Anti-glyceraldehyde-3-phosphate
dehydrogenase (GAPDH) mouse monoclonal antibody was
E. 3T3-L1 differentiation and Oil Red O
obtained from Abcam (Cambridge, UK), while anti-?-smooth
muscle actin (?-SMA) mouse antibody, clone 1A4, was obtained
3T3-L1 pread ipocytes were grown and maintained in
from Dako Automation (Carpentaria, CA), and TGF-?1 was
DMEM containing 10% FBS. Differentiation of preadipocytes
obtained from R&D Systems (Minneapolis, MN). GAL4-PPAR-
was studied in cells 2 days following confluence (designated day
? plasmid was a kind gift from YE Chen, University of
0). T hese cells were cultured for 14 d in DMEM containing 10%
Michigan, Ann Arbor. The aP2-luc plasmid (Camp et al, 2001)
FBS and eithe r curcumin or rosigli tazone. The medium was
and the FATP-PPRE-luc plasmid (Monajemi et al, 2007) were
changed every 2 d. The differentiated adipocytes were stained by
constructed as previously described.
Oil Red O (Sigma) as described previously (Song et al, 2007).
Briefly, cells were washed with PBS and fixed in 4%
B. Cell culture and transfection
paraformaldehyde for 1 h, followed by rinsing with PBS and
CV-1 and 3T3-L1 cells were obtained from American
with water. After the rinsing, cells were stained with 0.1% Oil
Type Culture Collection (Manassas, VA). IMR-90 cells were
Red O for 1 h. Plates were rinsed with water and images of cells
obtained from the Coriell Institute for Medical Research
on the plate were taken in water.
(Camden, NJ). CV-1 cells were grown to 70% confluence in
DMEM/F12 supplemented with 10% FBS and 1% penicillin-
F. RNA isolation and real-time PCR
streptomycin. Cells were then transiently co-transfected with
Total RNA was extracted using TRI-Reagent (Sigma)
pRL-SV40 and a PPAR-dependent luciferase reporter, pFATP-
according to the manufacturer’s instructions. cDNA was
luc. In separate experiments, cells were co-transfected with pRL-
generated from 1 ?g of total RNA and real-time quantitative PCR
SV40 plus a luciferase gene under the control of four Gal4 DNA-
was performed using Sybr Green PCR Master Mix (Applied
binding elements (UASG × 4 TK-luciferase) and a plasmid
Biosystems; Foster City, CA) according to the manufacturer’s
containing the ligand-binding domain for PPAR-? fused to the
protocol. Quantitative changes were expressed relative to ?-actin.
Gal4 DNA-binding domain. All transfections were performed
Primers used were:
using Lipofectamine 2000 (Invitrogen) according to the
manufacturer’s instructions. Twenty-four h after transfection,
PPAR-?: (F) 5'-ATTCTGGCCCACCAACTTCGG-3'
cells were treated with test compounds and incubated for an
additional 24 h in medium with 10% FBS. The resulting
?-actin: (F) 5'-GTGGGGCGCCCCCAGGCACCA-3'
luciferase activity was measured with reporter luciferase assay
kits (Promega; Madison, WI) employing a Modulus 9201
luminometer (Turner Biosystems; Sunnydale, CA) and
G. Western immunoblotting
normalized by comparison to Renilla luciferase.
Cells were lysed in radioimmunoprecipitation (RIPA)
buffer and whole-cell protein was quantified. Ten ?g of protein
was subjected to 12% Tris-glycine SDS-PAGE (Invitrogen).
Narala et al: Curcumin is not a ligand for PPAR-?
After transfer to a polyvinylidene fluoride membrane (Millipore),
We then examined the ability of curcumin to
?-SMA and GAPDH were detected using appropriate dilutions
stimulate binding of PPAR-? to DNA using a
of primary mouse monoclonal antibodies followed by a
commercially available transcription factor assay that
horseradish peroxidase-conjugated anti-mouse IgG. Protein was
measures binding of PPAR-? to double stranded DNA
visualized using the ECL chemiluminescent detection system
probe containing a PPRE sequence. Cells were treated
with curcumin (10-40 ?M), rosiglitazone (10 ?M), or
H. Statistical analysis
vehicle (DMSO) for 3 h, after which nuclear extracts were
Data are represented as mean ± SE and were analyzed with
prepared and subjected to PPAR-? binding assay. In order
the Prism 5.0 statistical program (GraphPad Software Inc.; San
to investigate the possibility that curcumin up-regulates
Diego, CA). Comparisons between experimental groups were
PPAR-? expression, we employed IMR-90 as well as CV-
performed using one-way ANOVA followed by Dunnett’s post
1 cells. Curcumin gave results similar to those with
hoc test. All data shown are averages from at least 3 independent
vehicle, demonstrating no activation of PPAR-? in either
experiments. Differences were considered significant if P was
CV-1 cells (Figure 2B) or IMR-90 cells (Figure 2C).
less than .05.
Rosiglitazone (10 ?M), as expected, increased PPAR-?
A. Curcumin does not activate PPAR
Previous studies have reported that curcumin
activates PPAR-?. To test this, we transfected CV-1 cells
with FATP-PPRE-luc plasmid in which the peroxisome
proliferator response element (PPRE) from fatty acid
transport protein controls expression of firefly luciferase.
After 24 h, cells were treated with curcumin at different
concentrations (1-20 ?M) and following an additional 24-h
incubation, cells were lysed and luciferase activity was
measured. Curcumin did not increase the relative
transcriptional activity of PPAR-? in CV-1 cells at any
dose tested (Figure 1A). By contrast, the positive control
ciglitazone (10 ?M) increased transcriptional activity ~7-
To increase the robustness of the reporter assay, CV-
1 cells were co-transfected with a PPAR-? expression
plasmid (TR100-PPAR-?) in addition to FATP-PPRE-luc.
Curcumin (1-20 ?M) did not induce detectable PPAR-?
activation even in the presence of elevated amounts of
receptor, whereas transcriptional activity induced by
ciglitazone (10 ?M) was greater than that observed in the
absence of the expression plasmid (Figure 1B). Similar
results were obtained with curcumin and rosiglitazone in
NIH/3T3 cells with an aP2-PPRE-luc reporter plasmid in
the presence of TR100-PPAR-? (data not shown).
We also performed reporter assays using the highly
specific Gal4-luc system, in which the PPAR-? ligand-
binding domain is fused to the Gal4 DNA-binding domain
and a luciferase reporter gene is under the control of four
Gal4 DNA-binding elements. In this case also, we did not
observe activation of PPAR-? by curcumin (Figure 1C).
B. Curcumin does not bind to the ligand-
binding domain of PPAR-? or stimulate
binding of PPAR-? to DNA
Figure 1. Curcumin is inactive in reporter assays. CV-1 cells
To directly determine whether curcumin binds to the
were transiently transfected with pRL-SV40 and with one of the
PPAR-? activating site, we quantified displacement of
following constructs: (A) PPAR-dependent luciferase reporter,
bound [3H]rosiglitazone by unlabeled rosiglitazone or
pFATP-luc; (B) PPAR-? expression plasmid, pTR100-PPAR-?,
curcumin. The Ki for rosiglitazone was found to be ~50
along with pFATP-luc; (C) PPAR-? GAL4 reporter system,
nM, consistent with reported values (Schopfer et al, 2005).
UASG × 4 TK-luciferase + GAL4-PPAR-?. Cells were then
By contrast, curcumin displayed no competition for the
incubated with vehicle (DMSO), curcumin (Cur; 1-20 ?M) or
binding site at concentrations up to 10 ?M (Figure 2A) or
ciglitazone (Cig; 10 ?M). After 24 h, the relative luciferase
even as high as 40 ?M (data not shown).
activity was calculated by normalizing firefly luciferase activity
to that of Renilla luciferase. *P < 0.05 vs. vehicle.
Gene Therapy and Molecular Biology Vol 13, page 23
D. PPAR-? antagonists do not block
As a further test of the extent to which biological
effects of curcumin may be mediated by PPAR-?
activation, we examined inhibition of the TGF-?-induced
myofibroblasts. PPAR-? activation has been shown to
inhibit this differentiation, signaled by appearance of ?-
smooth muscle actin (?-SMA) (Burgess et al, 2005;
Milam et al, 2008). We treated serum-starved IMR-90
fibroblasts with curcumin (10 ?M) for 1 h followed by
TGF-? (2 ng/ml), finding that curcumin inhibited the
expression of ?-SMA. To determine whether this
inhibition is mediated through PPAR-?, we added one of
four different PPAR-? antagonists 1 h prior to curcumin.
immunoblotting and quantified by densitometric scanning
of the blots (Figure 3C). None of the antagonists reduced
the ability of curcumin to inhibit myofibroblast
Previous studies have suggested that certain
curcumin effects involved an increase in PPAR-? activity.
Some investigators have suggested that this increased
activity may represent direct ligand-binding activation of
the receptor by curcumin, although this remains
controversial. Our results conclusively address this issue
utilizing a variety of rigorous assays.
At the molecular level, ligand-induced activation of
PPAR-? is reflected in increased binding to its response
elements. We find, however, that incubation with
Figure 2. Curcumin does not bind to or activate PPAR-?. (A)
curcumin does not increase binding to the consensus
Competitive binding assay was performed using GST-PPAR-?
PPRE in a transcription factor assay, nor does it increase
ligand-binding domain and [3H]rosiglitazone in the presence of
transcriptional activity in any of four different reporter
unlabeled curcumin (Cur) or rosiglitazone (Rosi). In a separate
assays. Furthermore, definitively, curcumin does not
experiment, PPAR-? activation was analyzed by DNA-binding
displace a standard synthetic PPAR-? ligand from the
assay in (B) CV-1 and (C) IMR-90 cells. *P < 0.05 vs. vehicle.
receptor’s binding site. At the cellular level, we
investigated the ability of curcumin to induce PPAR-?-
mediated differentiation of preadipocytes to adipocytes.
differentiation of 3T3-L1 preadipocytes
To investigate PPAR-?-mediated biological effects
Furthermore, although curcumin reduces the ability of
of curcumin, we employed a well established model of
TGF-? to induce fibroblast differentiation, as do PPAR-?
adipocyte differentiation. PPAR-? plays an essential role
ligands, a variety of different PPAR-? antagonists have no
in the differentiation of adipocytes (Tontonoz et al, 1994),
effect on curcumin’s inhibitor activity. Thus, at both the
with selective disruption of PPAR-? resulting in impaired
molecular and cellular levels, our results support the
development of adipose tissue (Evans et al, 2004). 3T3-L1
conclusion that the known biological activities of
preadipocytes were treated with curcumin (5 and 10 ?M)
curcumin do not involve binding to, and activation of, the
or rosiglitazone (5 ?M) for 2 weeks. Adipocyte
nuclear transcription factor PPAR-?.
differentiation was assessed both morphologically and by
Studies in hepatic stellate cells (Xu et al, 2003;
means of Oil Red O staining, which reveals the
Zheng and Chen, 2004; Lin and Chen, 2008), in a rodent
accumulation of intracellular lipids (Figure 3A).
model of sepsis (Siddiqui et al, 2006), and in Moser colon
Expression of PPAR-?, which is up-regulated during
cancer cells (Chen and Xu, 2005) have suggested that
differentiation, was also assessed (Figure 3B). On both
PPAR-? signaling is required for curcumin to exert the
assessments, vehicle and curcumin did not induce
effects observed. In Moser cells, it was found that
differentiation, while rosiglitazone treatment produced the
curcumin reduced phosphorylation and consequent
expected PPAR-?-dependent differentiation.
inactivation of PPAR-? (Chen and Xu, 2005).
Narala et al: Curcumin is not a ligand for PPAR-?
Figure 3. Curcumin has no effect on preadipocyte differentiation and effects on fibroblast differentiation are not blocked by PPAR-?
antagonists. (A, B) 3T3-L1 preadipocytes were treated with curcumin (Cur; 5 and 10 ?M) or rosiglitazone (Rosi; 5 ?M) for 2 weeks.
Adipocyte differentiation was assessed (A) both morphologically and via oil red O staining and (B) by relative expression of PPAR-?
mRNA. The MDI differentiation protocol (isobutylmethylxanthine + dexamethasone for 48 h, followed, after their removal, by insulin +
the test compound) was used in all experiments. *P < 0.05 vs. vehicle. (C) Confluent, serum-deprived human fetal lung fibroblasts
(IMR-90) were pretreated with PPAR-? antagonists (GW: GW9662, T007: T0070907, and Ant. III: Antagonist III) for 1 h, then with
curcumin for 1 h, after which cells were stimulated with TGF-? (2 ng/ml). After an additional 24 h, cell lysates were subjected to SDS-
PAGE and Western blotting. Membranes were probed first with anti–?-SMA antibody, then reprobed with anti-GAPDH antibody to
confirm equal protein loading. The blots were scanned densitometrically. *P < 0.05 vs. vehicle.
available high-purity curcumin formulations (data not
demonstrated in hepatic stellate cells (Cheng et al, 2007;
shown), this group conducted preadipocyte differentiation
Lin and Chen, 2008; Xu et al, 2003; Zheng and Chen,
studies and some ligand-binding studies with ethanolic
2004; Zhou et al, 2007), in a macrophage cell line
extracts of turmeric. Other ligand-binding studies were
(Siddiqui et al, 2006), and in colonic mucosal cells from a
performed with curcumin purified in their laboratories.
rodent model of colitis induced by trinitrobenzene sulfonic
acid (Zhang et al, 2006). One study found that this up-
standardized, the possible role of other compounds present
regulation of PPAR-? expression was secondary to
in these formulations cannot be ruled out. Recently, it has
inhibition of PDGF and EGF signaling pathways (Zhou et
also been shown that curcumin down-regulates PPAR-?
al, 2007). Furthermore, in the rat model of colitis induced
expression in preadipocytes, thus actively inhibiting their
by trinitrobenzene sulfonic acid, curcumin was observed
differentiation (Lee et al, 2009). This observation further
to increase levels of the endogenous PPAR-? ligand 15d-
supports our conclusions.
PGJ2 (Zhang et al, 2006). None of these studies directly
In summary, our results conclusively show that
examined possible binding of curcumin to the PPAR-?
curcumin is not a PPAR-? ligand. Thus, any observed
ligand-binding site, however. Although the reported
PPAR-?-mediated effects of curcumin must be indirect
increases in amount of receptor, and possibly of its
and mediated through effects of receptor expression or
endogenous ligands, appear to be plausible explanations
levels of endogenous ligands that are mediated through
for the results obtained, the possibility that curcumin also
other pathways. Since we have now ruled out one
bound to and directly activated PPAR-? had been
suggested mechanism for curcumin, further study of
suggested (Chen and Xu, 2005; Jacob et al, 2007).
alternative mechanisms is warranted.
In direct contrast to our results, one group has
specifically asserted that curcumin is a PPAR-? ligand
(Kuroda et al, 2005; Nishiyama et al, 2005). This group
Supported by National Institutes of Health grants
reported increased activity in a GAL4-PPAR-? chimeric
HL070068 and AI079539, a University of Michigan
assay in CV-1 cells. These researchers also noted that
Global REACH International Grant, and the Martin E.
curcumin induced differentiation of preadipocytes, which
Galvin Fund and Quest for Breath Foundation (all to
we did not observe, although these were primary human
preadipocytes rather than the standard 3T3-L1 cells that
were employed in this study. Furthermore, while we
repeated all experiments with three different commercially
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