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PPAR: its role in the human

metabolic syndrome
Salman Azhar† &
Glen Kelley
†
Author for correspondence
GRECC-182BVA Palo Alto
Health Care System, Division
of Gastroenterology &
Hepatology, Department of
Medicine, Stanford
University School of
Medicine, 3801 Miranda
Avenue, Palo Alto,
CA 94304, USA
Tel.: +1 650 858 3933;
+1 650 493 5000;
ext. 65365;
Fax: +1 650 496 2505;
+1 650 849 0484;
salman.azhar@va.gov
The metabolic syndrome, also known as ‘syndrome X’ or ‘insulin-resistance syndrome’, has
emerged as a constellation of risk factors that markedly increase the risk of Type 2 diabetes
and cardiovascular disease (CVD). The metabolic syndrome is characterized by central
obesity, elevated blood pressure, insulin resistance, impaired glucose tolerance or diabetes
mellitus and atherogenic dyslipidemia. Nonalcoholic fatty liver disease is strongly
associated with the metabolic syndrome and recently both a proinflammatory state and a
prothrombotic state have been added as independent components of this syndrome. Since
the prevalence of diabetes and obesity is rising at an alarming rate, the incidence of this
morbid syndrome is also expected to continue to grow, both in the USA and worldwide, and
will likely impact heavily on the incidence of CVD, the leading cause of morbidity and
mortality around the world. Peroxisome proliferator-activated receptor (PPAR) is a member
of the nuclear receptor superfamily, that includes other PPAR isoforms (PPPAR/  and PPAR)
and the estrogen, androgen and glucocorticoid receptors. PPAR is a master transcription
factor that regulates genes involved in lipid metabolism, glucose homeostasis,
inflammation and atherosclerosis, and is the principal regulator of energy homeostasis.
Fibrates are hypolipidemic drugs that are weak ligands for PPAR. The lipid (triglyceride)-
lowering actions of this class of drugs are mediated by modulation of lipid metabolism
through molecular actions of PPAR. Fibrates and other PPAR ligands also exert anti-
inflammatory and anti-thrombotic actions in the constituent cells of the vessel wall. Thus,
PPAR agonists interfere with the progression of atherosclerosis by modulating the function
of various components of the metabolic syndrome and through their anti-inflammatory
properties. Several clinical trial studies with fibrates further confirmed that these drugs have
a significant protective effect against CVD. This article focuses on the current understanding
of the critical role of PPAR in regulating fatty-acid -oxidation, lipoprotein metabolism,
insulin secretion and sensitivity, vascular inflammation and the cardiovascular system.
Furthermore, an overview of the metabolic syndrome, its historical perspective and recent
developments about the functional relevance of PPAR to the pathophysiology of the
metabolic syndrome are reviewed.

Keywords: adipose tissue,
cardiovascular disease,
dyslipidemia, fatty acids,
glucose metabolism, heart,
insulin resistance, lipid
homeostasis, liver, obesity,
pancreas, skeletal muscle,
triglycerides, Type 2 diabetes
part of
The metabolic syndrome
Cardiovascular disease (CVD) is the leading cause
of morbidity and mortality worldwide, and has
become a true epidemic [1,2]. Obesity [3,4] and
Type 2 diabetes [5,6] are associated with an
increased risk for the development of CVD, both
of which are also increasing in epidemic propor-
tions globally [7–12]. These trends can be expected
to translate into even greater prevalence of cardio-
vascular disease in the future. Insulin resistance is a
fundamental defect of Type 2 diabetes [13–15],
whereas obesity is now recognized as a strong risk
factor for the development of both insulin resist-
ance and Type 2 diabetes [11,16,17]. Moreover,
hyperinsulinemia associated with insulin resistance
appears to be an independent risk factor for cardi-
ovascular disease [18,19]. Recent evidence suggests
that up to one-third of the American population is
insulin resistant [20], and approximately 90% of
individuals with Type 2 diabetes are obese [11]. It is
now well recognized that obesity, insulin resistance
and the compensatory state of hyperinsulinemia
promote many metabolic abnormalities that occur
together commonly enough to be identified as a
‘syndrome’ [21]. These interrelated metabolic
abnormalities have been referred to by a variety of
names, including ‘syndrome X’, ‘insulin-resistance
syndrome’, the ‘deadly quartet’, ‘syndrome X plus’,
‘metabolic cardiovascular syndrome’ and, more
recently, ‘metabolic syndrome’ [22–24]. Indeed, met-
abolic syndrome has emerged as a clustering of risk
factors (Figure 1; Box 1) that, in the aggregate,
sharply increase the risk of CVD [25–31]. Thus,
metabolic syndrome may be an earlier indication
of increased risk for the development of Type 2
diabetes and/or cardiovascular disease [29,31–33].
The metabolic syndrome is highly prevalent in
the USA as well as in other developed and devel-
oping countries [29,34–36]. The Third National
Health and Nutrition Examination Survey

10.2217/17460875.2.1.31 2007 Future Medicine Ltd ISSN 1746-0875 Future Lipidol. (2007) 2(1), 31–53 31
SPECIAL REPOR T – Azhar & Kelley

Table 1. Chronology of observations that led to identification of the syndrome as a clustering of key
metabolic and clinical abnormalities that increase the risk of cardiovascular disease and Type 2 diabetes.
Year Syndrome name and/or description Ref.
1921 Karl Hitzenberger and Martin Richter-Quittner made clinical observations linking metabolic [62]
abnormalities with hypertension and diabetes.
Eskil Kylin described the clinical implications of clustering hypertension, hyperglycemia and [63,64]
diabetes mellitus.
1922 Gregorio Marañon also reported an association between hypertension, hyperglycemia and [65]
diabetes mellitus.
1923 Kylin added high uric acid levels as a component of the syndrome. He referred to this syndrome as [66]
‘hypertension–hyperglycemia–hyperuricemia syndrome’.
1936 Sir Harold Himsworth defined the basis for two clinical forms of diabetes: insulin-sensitive (Type 1 [67]
diabetes) and insulin-insensitive (Type 2 diabetes).
1947 and 1956 Jean Vague established that ‘android obesity’ (i.e., upper body adiposity) was associated with the [68,69]
development of diabetes, hypertension and atherosclerosis.
1965 Albrink and Meigs emphasized the importance of regional fat distribution by demonstrating an [70]
association between dyslipidemia and upper body (abdominal) skin fold thickness.
1966 Camus described a ‘metabolic trisyndrome’ consisting of gout, diabetes and hyperlipidemia. [71]

Welborn and colleagues provided a potential link between hyperinsulinemia, hypertension and [72]
peripheral vascular disease.
1967 Avogaro and Crepaldi describe the clustering of obesity, diabetes and hyperlipidemia in patients with [73]
hypertension and cardiovascular disease. They named this syndrome ‘plurimetabolic syndrome’.
1968 Mehnett and Kuhlmann linked the increased prevalence of plurimetabolic syndrome with the rich food [74]
and lifestyle habits of the Western world. They renamed this syndrome the ‘syndrome of affluence’.
1981 Hanefield and Leonhardt first coined the term ‘the metabolic syndrome’ to describe the clustering of [75]
obesity, hyperlipoproteinemia, diabetes, gout and hypertension together with increased incidence of
ischemic cardiovascular disease, fatty liver and cholelithiasis.
1982 Kissebah and colleagues found that females with predominantly upper-body fat were prone to glucose [78]
intolerance and hyperinsulinemia.
1983 Per Bjorntorp and associates introduced the waist-to-hip circumference ratio as an index of [76,77]
abdominal obesity.
1985 Modan and colleagues proposed insulin resistance or hyperinsulinemia syndrome as a central [79]
pathophysiologic entity accounting for the common occurrence of obesity, glucose intolerance, Type 2
diabetes and hypertension.
1988 Reaven proposed that the combination of insulin resistance and compensatory hyperinsulinemia [83]
predisposes the individuals to hypertension, dyslipidemia characterized by an elevated plasma TG and
low HDL-C and Type 2 diabetes. He named this constellation of risk factors ‘syndrome X’.
1989 Norman Kaplan, used the term ‘deadly quartet’ to describe an association between upper-body obesity, [84]
glucose intolerance, hypertriglyceridemia and hypertension, in which hyperinsulinemia was suggested
as being central to the pathogenesis.
1991 DeFronzo and Ferrannini used the name ‘insulin-resistance syndrome’ to refer to the syndrome [85]
consisting of Type 2 diabetes, hypertension, dyslipidemia and atherosclerotic cardiovascular disease.
Zimmet identified the syndrome as ‘syndrome X plus’ to refer to a cluster of cardiovascular risk factors [86]
that included the components of syndrome X plus upper-body adiposity, hyperuricemia, physical
inactivity and aging.
1992 Hjerrman suggested the presence of atherogenic small, dense LDL-C, low HDL-C and [87]
elevated triglycerides and prothrombotic state as additional components of the syndrome.
He suggested renaming the syndrome the ‘metabolic cardiovascular syndrome’ or the
‘atherothrombogenic syndrome’.
2000–Present Syndrome X, insulin resistance syndrome or atherothrombogenic syndrome is now more popularly
referred to as ‘the metabolic syndrome’.
HDL-C: High-density lipoprotein cholesterol; LDL-C: Low-density lipoprotein cholesterol; TG: Triglyceride.

32 Future Lipidol. (2007) 2(1) future science group

 PPAR and the metabolic syndrome – SPECIAL
(NHANES III) conducted between 1988 and
1994 indicated that approximately 24% (47 mil-
lion) of the adult US population had metabolic
syndrome [37]. A more recent analysis of
NHANES III established that approximately
44% of Americans above 50 years of age have the
metabolic syndrome [29,36,38]. Surprisingly,
NHANES III also demonstrated that approxi-
mately 4% of all adolescents and 29% of over-
weight adolescents fell within the modified Adult
Treatment Panel III criteria for the metabolic
syndrome [39,40].
The syndrome is characterized by hyper-
insulinemia, central (abdominal) obesity but also
generalized obesity, insulin resistance with or with-
out hyperglycemia, hypertension and atherogenic
dyslipidemia [25–31]. Atherogenic dyslipidemia
consists of a battery of circulating lipoprotein
abnormalities, including elevated high triglycer-
ides and apolipoprotein (Apo)B levels, small,
dense low-density lipoprotein (LDL) and a
reduced level of low high-density lipoprotein
(HDL)-cholesterol [26,27,29,31,41]. Metabolic syn-
drome is associated with both a proinflammatory
state and a prothrombotic state [26,27,29,31,41].
There is also evidence to suggest that nonalcoholic
steatohepatitis (or fatty liver) is an important fea-
ture of this syndrome [42,43]. In addition, it is clear
that lipid accumulation (lipotoxicity) in the heart,
skeletal muscle, pancreas, liver and kidney plays an
important role in the pathogenesis of obesity, dia-
betes and CVD [44–49]. More recent evidence now
suggests that the metabolic syndrome is associated
Box 1. Conditions and factors associated with the
metabolic syndrome*.
• Insulin resistance
• Obesity
• Impaired glucose tolerance and/or Type 2 diabetes mellitus
• Hypertension
• Sleep disordered breathing
• Endothelial dysfunction
• Inflammation: increased C-reactive protein and other
inflammatory markers
• Atherosclerotic cardiovascular disease
• Hyperinsulinemia
• Dyslipidemia
• Nonalcoholic fatty liver disease
• Certain forms of cancer
• Polycystic ovary syndrome
• Renal dysfunction
• Hypercoagulation: increased fibrinogen and plasminogen
activator inhibitor-1
• Stress: hypothalamic–pituitary–adrenal axis
*Modified from [29].
future science group www.futuremedicine.com
REPOR T
with stress and involves stress hormone and corti-
sol through the activation of the hypo-
thalamic–pituitary–adrenal axis (the stress
response) [50,51]. Although the molecular pathways
leading to such a wide spectrum of defects involv-
ing metabolic abnormalities, including insulin
resistance, dyslipidemia, glucose intolerance,
inflammatory components and a prothrombotic
state, have been difficult to understand, it appears
that the pathogenesis of the syndrome has multi-
ple origins. Among these, obesity [29,30,52] and die-
tary components (i.e., excessive caloric intake [53]
as a result of increased consumption of refined
carbohydrates that contain high levels of fructose
and processed food products with a high fat con-
tent [52,54–56], increased portion sizes [53], seden-
tary lifestyle [57] and unknown genetic factors
[58,59]) clearly interact to produce the syndrome.
Moreover, in recent years, studies have indicated a
strong role for adipose tissue in this syndrome,
particularly in the development of insulin resist-
ance through local as well as systemic effects,
mediated by the augmented production of proin-
flammatory adipokines and free fatty acids, along
with diminished secretion of the ‘protective
adipokines’, adiponectin and leptin [41,60,61].
Brief historical overview
Although Gerald Reaven has been rightfully
credited for popularizing syndrome X [21,31],
insulin-resistance syndrome or the metabolic
syndrome, the concept of this type of syndrome
has been in existence for approximately 80 years
(Table 1) [22–25,62–79]. The reviewers provide a brief
chronology in Table 1 detailing the historical
developments and the evolution of the nomen-
clature of the field [80–100]. This table also serves
as an illustration of some of the current contro-
versy as to how to define and treat a hetero-
genous disorder, which is discussed further in the
next section.
Definitions of the metabolic syndrome
In recent years, several national and international
professional societies as well as the WHO have
developed definitions for the metabolic syn-
drome that include somewhat different compo-
nents and cut-off levels (Table 2). For a more
comprehensive review, the readers may consult
references [25,29,30,33,88,97,101–108]. Table 2 illus-
trates that it is quite apparent that there is no
consensus about the appropriate clinical defini-
tion that could aid in the diagnosis and develop-
ment of preventive and therapeutic strategies for
this syndrome. In a recent joint statement, the
33
SPECIAL REPOR T – Azhar & Kelley

Table 2. Comparison of proposed definitions of the metabolic syndrome*.

Clinical measure WHO (1998) EGIR (1999) ATP III (2001) AACE (2003) IDF (2005)
Insulin resistance IGT, IGF, T2DM or Plasma insulin None but any three IGT or IFG plus any None
lowered insulin >75th percentile of the following of the following
sensitivity plus any plus any two of the five features based on clinical
two of the following judgment
following
Body weight Men: waist-to-hip WC 94 cm in men WC 102 cm in BMI 25 kg/m2 Increased WC
ratio >0.90; or 80 cm in men or 88 cm in (population
women: waist-to- women women specific) plus any 2
hip ratio >0.85 of the following
and/or BMI
>30 kg/m2
Lipid TG 150 mg/dl TG >150 mg/dl TG 150 mg/dl and TG >150 mg/dl and TG >150 mg/dl or
and/or HDL-C 35 and/or HDL-C HDL-C <40 mg/dl HDL-C <40 mg/dl on TG Rx; HDL-C
mg/dl in men or <39 mg/dl in men or <50 mg/dl in or <50 mg/dl in <40 mg/dl in men
39 mg/dl in or women women women or <50 mg/dl in
women women or on
HDL-C Rx
Blood pressure 140/90 mm Hg 140/90 mm Hg or 130/85 mm Hg 130/85 mm Hg 130 mm Hg
on hypertension Rx systolic or 85 mm
Hg diastolic or on
hypertension Rx
Glucose IGT, IFG or T2DM IGT or IFG (but not >110 mg/dl IGT or IFG (but not >100 mg/dl
diabetes) (includes diabetes)* diabetes) (includes diabetes)
Other Microalbuminuria Other features of
insulin resistance‡
*The 2001 definition identified fasting plasma glucose of 110 mg/dl (6.1 mmol/l) as elevated. This was modified in 2004 to be >100 mg/dl
(5.6 mmol), in accordance with the American Diabetes Association’s updated definition of IFG.
‡
Includes family history of Type 2 diabetes mellitus, polycystic ovary syndrome, sedentary lifestyle, advancing age and ethnic groups susceptible to
Type 2 diabetes.
AACE: American Association of Clinical Endocrinologists; ATP III: Adult Treatment Panel III; BMI: Body mass index; EGIR: European Group for Study
of Insulin Resistance; HDL-C: High-density lipoprotein-cholesterol; IDF: International Diabetes Foundation; IFG: Impaired fasting glucose;
IGT: Impaired glucose tolerance; NCEP: National Cholesterol Education Program; T2DM: Type 2 diabetes mellitus; TG: Triglycerides;
WC: Waist circumference.
Adapted from [88].

American Diabetes Association and the European
Association for the Study of Diabetes have, in
fact, questioned the very diagnosis of the meta-
bolic syndrome as a cluster of risk factors when
they stated, “metabolic syndrome has been impre-
cisely defined, there is lack of certainty regarding
its pathogenesis, and there is considerable doubt
regarding its value as a CVD risk marker” [23].
Regardless, they caution clinicians that ‘until
much needed research is completed, they should
evaluate and treat all CVD risk factors without
regard to whether a patient meets the criteria for
diagnosis of the metabolic syndrome’ [23].
Peroxisome proliferator-activated
receptor
Peroxisome proliferator-activated receptors
(PPARs) are ligand-activated transcription factors
of the nuclear hormone superfamily, which are
functionally and structurally related to retinoid,
steroid and thyroid-hormone receptors [109–113].
They play major regulatory roles in the func-
tional expression of key genes involved in lipid
metabolism, adipogenesis and carbohydrate
homeostasis and energy consumption
[109,110,112–114]. More recent evidence suggests
that PPARs are also involved in the events con-
nected with inflammation [115–117] and athero-
sclerosis [118–120], as well as in the regulation of
several key components of the metabolic syn-
drome [121–124]. To date, three mammalian sub-
types, PPAR (NR1C1), PPAR/ (NR1C2)
and PPAR (NR1C3), have been described, each
being coded for by a distinct gene [109,111–113].
These isoforms are differentially expressed in
select tissues, with expression levels depending on
cellular processes (Table 3) [109,111–113]. PPAR is
now considered to be a master regulator of

34 Future Lipidol. (2007) 2(1) future science group

 PPAR and the metabolic syndrome – SPECIAL REPOR T

diverse biological processes, including glucose Molecular characteristics of PPAR

and lipid metabolism, insulin sensitivity, inflam- PPAR, like other members of the nuclear recep-
matory response and growth and differentiation tor superfamily, contains four major functional
atherosclerosis [112,114,115,118–120,126,127]. A ligand- domains [118,125]:
activated form of PPAR induces the transcrip- • The N-terminal consists of a ligand-
tion of genes involved in peroxisomal and mito- independent transactivation domain (A/B);
chondrial -oxidation pathways, and the • The PPAR DNA-binding domain (or C),
microsomal  -oxidation pathway [128,129], in which contains two highly conserved zinc
addition to genes for fatty-acid transporter pro- finger motifs;
teins [130]. It promotes both gluconeogenesis and
• A hinge region or the cofactor docking
ketogenesis [126,128]. PPAR is also implicated in
lipoprotein and cholesterol metabolism [128]. domain (D);
Owing to these divergent actions, it is becoming • C-terminal E/F domain containing a ligand-
increasingly clear that PPAR plays an impor- binding domain and a ligand-dependent
tant role in the pathophysiology of many com- transactivation domain (AF2) (Figure 2).
ponents of the metabolic syndrome, such as Upon ligand binding, PPAR heterodimerizes
dyslipidemia, insulin resistance, glucose intoler- with the 9-cis-retinoic acid receptor (RXR), and
ance, hypertension, inflammation and obesity binds to specific cis-activating DNA response ele-
and, as a consequence, in Type 2 diabetes and ments, termed peroxisome proliferators response
atherosclerosis. In the following sections we will elements (PPRE). PPREs consist of direct repeats
attempt to describe the characteristics of PPAR, of the consensus hexameric motif TGACC(T/C)
its metabolic actions and relevance to various separated by one base pair (DR1) (Figure 2, Table 3)
components of the metabolic syndrome, in addi- [109,112,113,129]. The four nucleotides immediately
tion to its involvement in the etiology of Type 2 5´ of the DRI motif are also highly conserved
diabetes and atherosclerosis. among known PPREs and exhibit a consensus of
A(A/T)CT [129]. As is the case with other nuclear
Figure 1. Salient features of metabolic syndrome. The insulin receptors, the functional expression of PPARs is
resistance is considered to be a central component in the also modulated by various coactivators and
progression of metabolic syndrome. corepressors [130–132]. PPAR is predominantly
expressed in tissues involved in high fatty-acid
oxidation, such as the liver, brown fat, kidney,
Smoking heart, skeletal muscle and intestine, and at lower
levels in other tissues, including the pancreas [109].
Met abolic syndrome Gene Furthermore, PPAR expression has been
itio n reported in monocytes/macrophages, endothelial
os cells, and vascular smooth muscle cells and in the
isp
ed atherosclerotic lesions [118,132].
Atherosclerosis tic isp
cp
pr
boli
tion PPAR ligands
Meta Hyper-
Dyslipidemia osi
PPAR is activated by a variety of natural and
glycemia/
Diabetes synthetic ligands (Figures 3 & 4). The natural lig-
ands include both mono- and long-chain
Insulin
resistance
polyunsaturated fatty acids and eicosanoids
(derivatives of polyunsaturated fatty acids),
including 8(S)-hydroxyeicosatetranoic acid
Sedred Obesity Hypertension
(8[S]HETE), 8(S)-hydroxyeicosapentaenoic acid
ent
Pro- (8[S]HEPE) and leukotriene (LT)B4, peroxi-
ar Die some proliferators and nonsteroidal anti-inflam-
yl inflammatory
ife state matory drugs [109,112,133]. Long-chain fatty acyl-
e
coenzyme A (CoA) derivatives and saturated
fatty acids can stimulate PPAR activity
st
yl (Figure 3). However, polyunsaturated fatty acids
Stress exhibit relatively high affinities for, and are more
Future Lipidology potent activators of, PPAR than saturated fatty
acids, although the extent of unsaturation does
t
future science group www.futuremedicine.com 35
SPECIAL REPOR T – Azhar & Kelley

not appear to have a marked effect on activity. fibrate treatment leads to a reduction of coronary
The synthetic pharmacological ligands include the events and delays progression of coronary artery
fibrate group of hypolipidemic drugs and other disease [122,137,138]. Recently, several more potent
experimental compounds (Figure 4) [111,134–136]. and specific PPAR agonists, such as ureidothio-
Fibrates, such as fenofibrate, gemfibrozil and ben- isobutyric acid, GW-9578 and LY518674, have
zafibrate, although showing low affinity for been reported (Figure 4) [111,134]. A nonfibrate,
PPAR, are currently used to treat hypertriglyceri- dodecanoic acid analog, K-111 or BM 17.0744,
demia and mixed dyslipidemia [137]. They are with a relatively high affinity and potency for
highly effective in lowering elevated plasma trig- PPAR, was reported to enhance insulin sensi-
lyceride levels and LDL-cholesterol, and increas- tivity, reduce plasma triglyceride levels and cause
ing HDL-cholesterol levels. A number of clinical a reduction in body weight [139,140]. Another,
trials, including the Helsinki Heart study, Benzaf- nonfibrate compound, NS-220, with greater
ibrate Infarction Prevention (BIP) study and the than 500-fold affinity for PPAR compared with
Veterans Affairs High-density lipoprotein Inter- other PPAR isoforms, was also reported to be
vention Trials (VA-HIT), have established that effective in lowering plasma triglygerides and
increasing HDL-cholesterol in experimental
Figure 2. Schematic representation of the functional domains rodents [134].
Currently, there are two PPAR agonist classes of
of PPARs and the mechanism of action of PPAR.
drugs available for treating metabolic diseases, the
PPAR agonist fibrates and the potent PPAR
A/B C D E/F PPAR isoforms agonists thiazolidinediones, such as pioglitazone,
troglitazone and rosiglitazone. PPAR agonists
1 101 166 244 468
markedly reduce insulin resistance and improve
AF1 DBD AF2LBD PPAR insulin action in peripheral tissues, attenuate
hyperinsulinemia and reduce circulating lipid lev-
1 72 137 215 441 els, as well as improving dyslipidemia [137,141].
DBD PPAR Unfortunately, PPAR agonists also lead to weight
AF1 LBD 70% AF2
83% gain, which is obviously undesirable in these
patients. Currently, new classes of drugs are being
1 110 175 251 447 clinically tested that are dual agonists of both
AF1 DBD LBD 70% AF2 PPAR PPAR and PPAR. The theory behind this new
83%
paradigm is to receive the potent insulin-sensitiz-
ing benefit of PPAR without the weight gain asso-
ciated with the PPAR-specific drugs. Moreover,
since insulin resistance and dyslipidemia are major
components of the metabolic syndrome and asso-
PPAR ligands
9-cis-retinoic acid ciated Type 2 diabetes, the dual specificity drugs
Fatty acids
may provide broader metabolic improvements. To
Eicosanoids
Synthetic PPAR date, there are several dual PPAR/ agonists, such
agonists as MK-0767, ragaglitazar, harglitazar, navaglitar,
tesaglitazar and muraglitazar among others, which
PPAR RXR are either under different stages of development or
undergoing clinical trials. For more comprehensive
information, please see the following reviews and
Co-activator
references therein [135,141].
Activation/repression
PPAR RXR PPAR & regulation of lipid metabolism
Gene transcription
Hepatic lipid metabolism
Target gene
5´ -A (A/T) CT (A/G) GGNCAAA (G/T) GTCA - 3´ The liver plays a central role in the maintenance
3´ -T (T/A) GA (T/C) CCNGTTT (C/A) CAGT - 5´
PPRE of systemic lipid homeostasis. It coordinates syn-
thesis of fatty acids, esterification of fatty acids to
AF: N-terminal transactivation domain; DBD: DNA-binding domain; produce triacylglycerides and their packaging into
LBD: Ligand-binding domain; PPAR: Peroxisome proliferator-activated receptor;
very low-density lipoprotein (VLDL) for export
PPRE: Peroxisome proliferator response element; RXR: 9-cis-retinoic acid receptor.
Modified from [114,196].
to peripheral adipose tissue for storage during the
fed state, while during fasting it controls the rates

36 Future Lipidol. (2007) 2(1) future science group

 PPAR and the metabolic syndrome – SPECIAL REPOR T

Table 3. Some key characteristics of the PPAR nuclear receptor.

Molecular characteristics PPAR
Other designations NR1C1
Isoforms None
Size (aa) 468 aa (human)
Gene cloned from Mouse, rat, guinea pig, frog and human
Tissue/cell expression Liver, brown adipose tissue, heart, kidney, adrenal, skeletal muscle and vasculature (endothelial
cells, smooth muscle cells and macrophages)
Heterodimer partner* RXR , RXR and RXR
Consensus recognition 5´-A(A/T)CT(A/G)GGNCAAAG(G/T)TCA-3´‡
sequence (PPRE) for PPAR/RXR
Natural ligands Poly- and mono-unsaturated fatty acids; branched chain fatty acids, conjugated fatty acids;
eicosanoids (e.g., 8(S)-HETE and LTB4)
Synthetic (pharmacologic) Fibrates: fenofibric acid, clofibric acid and benzafibrate; WY-14643; GW-9578; LY-518674; K-111
agonists§ (BM-17.0744); TTA; NS-220, endomethacin and other NSAIDs
Metabolic function Increased fatty-acid uptake and oxidation, increased apolipoprotein synthesis, increased TG
hydrolysis and clearance, decreased amino acid catabolism, increased ketogenesis, increased GSIS,
decreased (regression of) atherosclerosis (increased plaque stability and decreased thrombosis,
decreased cell recruitment and activation, decreased vasoconstriction and cell migration, increased
cholesterol efflux and decreased foam-cell formation and decreased inflammatory response)
Therapeutic actions of Decreased dyslipidemia
specific agonists Decreased TG
Increased HDL-cholesterol,
No change in LDL-cholesterol, decreased LDL-cholesterol
Anti-inflammatory
Reduction in cardiovascular disease and associated complications in patients with
metabolic syndrome
Antitumor (human breast, bladder, gastric and colon cancer?)
*RXR ligands: 9-cis-retinoic acid, LG-100754, LG-101506, LG-101305 and LG-1000364.
‡
The consensus PPRE includes both a 5´-extension and a direct repeat (DR1) comprised of two canonical core recognition sequences (bolded) for
nuclear receptor zinc fingers separated by a single nucleotide spacer.
§ PPAR /dual agonists: KRP-297, MK-0767, muraglitazar, naveglitazar, rasaglitazar, farglitazar and tesaglitazar; PPAR/ dual agonists, optically
active-ethylphenylpropanoic acid derivatives.
AA: Amino acid; GSIS: Glucose-stimulated insulin secretion; HETE: Hydroxyeicosatetraenoic acid; HDL: High-density lipoprotein;
HODE: Hydroxyoctadecadienoic acid; LDL: Low-density lipoprotein; LT: Leukotriene; NR1C1: Nuclear receptor 1c1; NSAIDs: Nonsteroidal anti-
inflammatory drugs; PPRE: Peroxisome-proliferator response element; RXR: Retinoid X receptor; TG: Triglyceride; TTA: Tetradecylthioacetic acid.

of fatty-acid -oxidation and ketogenesis. Thus,
under normal physiological conditions, by bal-
ancing these processes, the liver handles large
amounts of fat without accumulating triacyl-
glycerol and causing peripheral tissue lipotoxicity.
PPAR is essential for high rates of fatty-acid
catabolism in the liver [126,127]; it regulates virtu-
ally every gene that participates in hepatic  - and
-oxidation of fatty acids in addition to genes
involved in fatty-acid uptake and intracellular
transport (Figure 5). Indeed, PPAR acts as a gen-
eral sensor of overall hepatic fatty-acid load,
inducing coordinated changes in gene expression
of proteins and enzymes involved in fatty-acid
transport and oxidation in an effort to prevent
excessive triglyceride accumulation in the liver
(and other tissues), and subsequent development
of obesity, insulin resistance and Type 2 diabetes.
Increased levels of hepatic fatty acids activate
PPAR, which, in turn, transcriptionally acti-
vates the fatty-acid transport proteins (discussed
below) and enzymes involved in mitochondrial,
peroxisomal and microsomal fatty-acid oxida-
tion systems. The first step in fatty-acid meta-
bolism is the activation of fatty acids into acyl-
CoA thioesters, catalyzed by acyl-CoA synthase
(ACS), which itself is induced by PPAR.
Depending on the chain-length, the activated
fatty acyl-CoAs are then either transported into
mitochondria or peroxisomes for further
metabolism to acetyl-CoA via the -oxidation
process; mitochondria preferentially oxidize
short- (C4–C6), medium- (C8–C12) and long-
chain fatty acids (C14–C20), while pero-
xisomes primarily utilize very long chain fatty
acids (>C20).

future science group www.futuremedicine.com 37

SPECIAL REPOR T – Azhar & Kelley

Figure 3. Natural ligands for PPAR: fatty acids and eicosanoids.

O R O R

Palmitic acid Stearic acid

O R O R

Palmitoleic acid Oleic acid

O O OH OH O

R R R

Arachidonic acid Linoleic acid LTB4

OH
O O P O OH

R HS O
NH O OH
O O N N

8S-HETE O NH O P O O
P N
HO O NH2
OH N
Coenzyme A

O R O R

O2N
Regiosomers of nitrated oleic acid (OA-NO2) NO2

8S-HETE: 8(S)-hydroxyeicosatetranoic acid; LT: Leukotriene.

Modified from [111,134].

Mitochondrial fatty-acid oxidation is initiated direct target of PPAR [126,142–144]. Additional

by carnitine-mediated translocation of activated
long-chain fatty acids (long-chain acyl-CoAs)
into the mitochondria, (note that carnitine is not
required for the permeation of medium-chain
acyl-CoAs into the mitochondria). This rate lim-
iting step in the mitochondrial long-chain fatty-
acid -oxidation pathway is performed by carni-
tine palmitoyltransferase (CPT) I, which is a
steps involved in mitochondrial fatty-acid -oxi-
dation are also under PPAR regulation [145]. The
short-, medium-, long- and very long-acyl-CoA
dehydrogenases, coded by four different enzymes,
catalyze the first step in mitochondrial fatty-acid
oxidation (i.e., oxidation of acyl-CoA to trans-2-
enoyl CoA). Although all four dehydrogenases
are regulated by PPAR and/or its agonist, to

38 Future Lipidol. (2007) 2(1) future science group

 PPAR and the metabolic syndrome – SPECIAL REPOR T

date only a bonafide PPRE has been identified
and characterized in the medium-chain acyl-CoA
dehydrogenase (MCAD) gene [145]. The acetyl-
CoA generated in mitochondria as a byproduct
of -oxidation (i.e., through acyl-CoA oxidation
followed by hydration, oxidation and thiolysis) is
also utilized for the production of ketone bodies,
which serve as an important source of energy for
the peripheral tissues, such as the brain, renal
cortex, heart and skeletal muscle. The mitochon-
drial 3-hydroxymethylglutaryl-CoA synthase, a
central enzyme in ketone bodies formation, is
also directly activated by PPAR [146].
All three enzymes involved in peroxisomal
-oxidation have been demonstrated to be
directly activated by PPAR through its binding
to PPRE elements in the promoter region of
these genes. These genes include the rate limiting
enzyme acyl-CoA oxidase (ACO) [146,147], enoyl
CoA hydratase/dehydrogenase multifunctional
enzyme (HD) [148], keto-acyl-CoA thiolase [149]
and CYP4A1 [150].
The pivotal role of PPAR in the regulation
of fatty-acid -oxidation is further established
by studies involving the use of mice gene-
ablated for PPAR. Mice deficient in PPAR
exhibit low rates of hepatic -oxidation, express
decreased expression of fatty-acid oxidation
genes and do not respond to PPAR agonists in
upregulating the -oxidative pathway [151–153].
Furthermore, the loss of PPAR function leads
to elevated serum cholesterol levels in young

Figure 4. Synthetic PPAR agonists.

O
CI O CI
OH

O COOH

Fenofibric acid O
Clofibric acid

O CI
O
N
N
H H3C N N S COOH
H
CI CH3
Bezafibrate WY-14643

F
H COOH
N N

O OH O
F S

GW-9578 O

CI O N
OH N
NH
(CH2)10 CI
CI O
LY-518674
K-111 (BM-17.0744)
O

O OH
O O
N

NS-220

Modified from [111,134].

future science group www.futuremedicine.com 39

SPECIAL REPOR T – Azhar & Kelley
mature mice and increased serum triglycerides
and steatosis in aging mice [154]. Other studies
have provided evidence that prolonged starva-
tion of PPAR-null mice leads to severe
hypoglycemia in association with elevated
plasma free fatty acid levels along with hepatic
and cardiac stetosis, and hypoketonemia, con-
sistent with the impaired ability of mice to ade-
quately upregulate hepatic fatty-acid oxidation
and gluconeogenesis in response to fasting
challenge [151–153,155,156].
PPAR also plays a regulatory role in the  -oxi-
dation of fatty acids and eicosanoids [126]. The
cytochromes P450 (CYP) 4A are the key enzymes
involved in this process and, at least in rodents,
PPAR was demonstrated to directly upregulate
the expression of hepatic CYP4A1 through a well-
conserved PPRE [126,157]. Although theoretical,
alteration of the metabolic processing of eico-
sanoids could be one mechanism through which
suppressed PPAR activity leads to an increased
inflammatory state.
Hepatic lipid synthesis
In addition to its critical role in lipid metabolism,
the liver is the central organ responsible for lipo-
genesis. By balancing gluconeogensis, glycolysis,
lipogenesis and lipolysis, the liver acts as a pri-
mary regulator of energy homeostasis. Lipogene-
sis occurs when excess nutrients, predominantly
carbohydrates, are available and not immediately
required to support the energetic requirements of
the organism. It is now appreciated that the West-
ernized diet, which is high in both carbohydrates
and fat, significantly contributes to lipogenesis
and hence obesity. One of the critical carbo-
hydrates responsible for increased lipogenesis is
fructose, which is almost exclusively metabolized
by the liver. Fructose is absorbed primarily in the
jejunum and is transferred into the portal circula-
tion where it is delivered to the liver [158]. Fructose
is incorporated into fatty acids at a greater rate
than glucose [159], and its consumption has been
demonstrated to increase adiposity in mice [160].
Recent epidemiological data have linked the con-
sumption of high-fructose corn syrup with the
increasing prevalence of obesity in the USA [56].
Fructose is metabolized by fructokinase and
aldolase to yield dihydroxyacetone phosphate
and D-glyceraldehyde, two metabolic intermedi-
ates that are utilized in triglyceride synthesis.
Dietary models utilizing high levels of fructose
demonstrate that genes and transcription factors
associated with lipogenesis, such as sterol-regula-
tory-element binding protein (SREBP)-1,
40 Future Lipidol. (2007) 2(1)
acetyl-CoA carboxylase and fatty acid synthase
(FAS) genes, are upregulated in the liver in
response to fructose feeding, while lipolytic
genes, such as acetyl-CoA oxidase (ACO) and
CPT-I, are suppressed. Importantly, PPAR
which is critical in controlling fatty-acid oxida-
tion, is suppressed upon high-fructose feeding.
Thus, at the genetic level, the balance of lipid
homeostasis is shifted towards lipogenesis by
high levels of dietary fructose. Treatment of
fructose-fed animals with a fibrate drug
increased the expression of lipogenic genes and
normalized the metabolic dysfunction, includ-
ing insulin resistance and dyslipidemia, associ-
ated with a high-fructose diet [161]. The
dysregulation of lipid homeostasis or the altera-
tion of genetic profiles associated with the high
fructose diet, particularly that of PPAR, inevi-
tably leads to hepatic insulin resistance and also
augmentation of genes associated with inflam-
matory pathways, such as c-Jun N-terminal
kinase and activator protein (AP)-1 [162,163].
Activation of these genes, in addition to
increased triglycerides, stabilized ApoB and
higher levels of microsomal triglyceride transfer
protein leads to greater assembly of VLDL parti-
cles [164]. Increased production of VLDL may be
the mechanism by which high-fructose diets
induce systemic insulin resistance, despite the
fact that fructose is not readily metabolized by
muscle and other tissues.
Cardiac lipid metabolism
The mammalian heart is highly metabolically
active and relies on fatty-acid oxidation for a
large percentage of its energy. Fatty-acid oxida-
tion provides approximately 60–90% of energy
in the form myocardial ATP, while the remain-
ing 10–40% of energy is derived from oxidative
metabolism of glucose and lactate [165] . Similar
to the liver, fatty-acid catabolism in the heart
primarily occurs in the mitochondrial matrix
by the -oxidation process, whereas pyruvate
generated from either glucose via glycolysis or
lactate is oxidized by the mitochondrial pyru-
vate dehydrogenase complex. The acetyl-CoA
produced as a result of fatty acid, glucose and
lactate oxidation is subsequently metabolized
via the Krebs cycle to generate nicotinamide
adenine dinucleotide and 5,10-methylenetet-
rahydrofolate reductase 2, which, in turn, are
used to generate ATP through an oxidative
phosphorylation process. Although fatty-acid
oxidation is the principal source of energy
production in cardiac tissue, the heart has a
future science group
 PPAR and the metabolic syndrome – SPECIAL
very limited fatty-acid storage capacity under
normal physiological conditions. Therefore, the
heart has evolved multiple carrier/transport pro-
tein-mediated fatty-acid shuttling systems (see
below) for the rapid delivery of fatty acids to car-
diac cells and the mitochondrial matrix [126,165].
Extensive evidence demonstrates that both myo-
cardial fatty-acid uptake and oxidation are
tightly linked, and in this association allows car-
diac tissues to continuously maintain a high rate
of fatty-acid oxidation.
PPAR being a lipid sensor, plays a critical
role in the regulation of cardiac lipid and
energy metabolism [166]. Recent evidence based
on genetic strategies has clearly demonstrated
that PPAR regulates virtually every gene
involved in fatty-acid metabolism, including
fatty-acid uptake, thioesterification to fatty
acyl-CoA, translocation to mitochondria and
mitochondrial fatty-acid -oxidation [165]. Con-
stitutive expression of genes facilitate cardiac
fatty-acid uptake (CD36/fatty acid transporter
and fatty acid transport protein), fatty acyl-CoA
synthase-1 proteins involved in the trans-
location of fatty acids to mitochondria (CPT I
and II), and -oxidation (MCAD, very long-
chain acyl-CoA dehydrogenase, short-chain acyl-
CoA dehydrogenase, short-chain L-3-hydroxy
acyl-CoA dehydrogenase and trifunctional
protein ) [167,168].
Evaluation of transgenic animals with either
eliminated PPAR or overexpressed PPAR in
heart tissue have been used to study the role of
this PPAR isoform in heart metabolism and
pathogenesis. In PPAR-/- mice, myocardial
long-chain fatty-acid uptake rates are substan-
tially reduced in the heart [168,169]. Further-
more, fasting leads to hypoglycemia and
increased cardiac triglyceride accumulation in
PPAR-/- mice in contrast to wild-type mice,
which exhibit rapid induction of cardiac -oxi-
dation enzyme genes [165,170]. Also, PPAR-/-
mice develop cardiac fibrosis, myofibrillar frag-
mentation and mitochondrial ultrastructural
abnormalities with advancing age (Figure 5) [168] .
Gain-of-function genetic studies have demon-
strated that mice with heart-specific over-
expression of PPAR (myosin heavy chain
[MHC]-PPAR) exhibit increased rates of car-
diac fatty-acid uptake and oxidation along with
the transcriptional activation of genes that par-
ticipate in fatty-acid utilization [171–173].
Importantly, MHC-PPAR mice develop
cardiomyopathy with enhanced sensitivity to
myocardial ischemic insult, exhibit insulin
future science group www.futuremedicine.com
REPOR T
resistance in the heart and liver and show
reduced expression of genes involved in cardiac
glucose utilization (Figure 5) [171–173]. It is interest-
ing to note that two major metabolic conditions
observed in this transgenic model, such as
increased cardiac lipid oxidation and reduced
glucose utilization, are also shared by the diabetic
heart [173].
PPAR-regulated fatty-acid metabolism is
also greatly altered under various pathophysio-
logical conditions. In hypertrophied hearts, the
expression and activity levels of PPAR are sub-
stantially reduced, leading to a corresponding
loss of fatty-acid oxidation capacity and
increased rates of glucose utilization [174,175].
Likewise, the functional expression of both
PPAR and its heterodimer partner RXR is
greatly reduced in cardiac myocytes in response
to hypoxia [176,177]. By contrast, the activity of
PPAR and the metabolic functions of its down-
stream target are considerably increased in dia-
betic hearts, resulting in enhanced rates of fatty-
acid uptake and -oxidation [178]. It is not clear
whether enhanced diabetic heart -oxidation
would lead to the cardiomyopathy described for
transgenic mice overexpressing heart-specific
PPAR [170,172].
Lipoprotein metabolism
As discussed above, the fibrate class of synthetic
PPAR agonists are widely used as effective
drugs in lowering plasma triglycerides, triglycer-
ide-enriched ApoB-containing VLDL-TG par-
ticles and LDL-cholesterol and raising HDL-
cholesterol [113,135–137]. These agents promote
triglyceride catabolism by enhancing the expres-
sion of genes involved in fatty-acid uptake and
oxidation, resulting in increased channeling of
fatty acids to the -oxidative pathway. This
causes the decreased availability of fatty acid
CoA-thioesters for triglyceride synthesis and,
thus, reduction in triglyceride levels [114,122]. In
addition, fibrates inhibit hepatic ApoCIII pro-
duction, a potent inhibitor of lipoprotein lipase
(LPL), leading to enhanced LPL-mediated
catabolism of VLDL particles [113,122]. Recently,
a newly identified Apo, termed ApoA-V [179],
has gained attention as a regulator of triglycer-
ides through loss- and gain-of-function studies
in genetically altered mice; transgenic expres-
sion of human ApoA-V in mice decreased circu-
lating triglyceride levels by 50–70%, whereas
deletion of the mouse ApoA-V gene resulted in
an approximately fourfold increase in plasma
TG levels [179,180]. Furthermore, it has been
41
SPECIAL REPOR T – Azhar & Kelley

Figure 5. Metabolic actions of PPAR in liver, heart, skeletal muscle, pancreas and cardiovascular system.

Artery Connective tissue

Lumen Connective tissue Atherosclerotic plaque
Lumen
Atherosclerosis

Decreased: Atherosclerosis,
inflammatory response, monocyte
recruitment, thrombosis
Increased: reverse cholesterol transport
Endothelium (RCT; cholesterol efflux) Endothelium

Macrophage foam cells

Smooth muscle cells
Decreased: NF-B, IL-6, PGF1,
iCOX-2, IB, proliferation
Increased: TNF-
Endothelial cells
Decreased: NF-B, AP-1, indMCP-1,
VCAM-1, ET-1, E-selectin, IL-6
Increased: eNOS, IL-8, basal MCP-1
Decreased: NF-B, AP-1, SR-A, TF, MMP-9,
CE formation
Increased: Apoptosis, iNOS, LXR, ApoE, ABCA1,
SR-BI, NPC1/NPC2, ABCG1, Cu, Zn-SOD

Liver Heart
Decreased: VLDL (TG) production, ApoC-III, Decreased: Glucose oxidation,
HL, LCAT, acute-phase reactants, inflammation, cardiomyopathy, glucose uptake
amino acid metabolism and glucose transporter gene
Increased: Fatty acid (FA) uptake (FATP, FAT/CD36, expression (heart-specific PPAR
L-FABP), FA oxidation (mitochondrial -oxidation, transgenic mice)
peroxisomal -oxidation, microsomal  -oxidation), Increased: FA uptake, FA oxidation,
fatty acid activation (LCAS), ApoA-I, lipolysis, ApoA-II, cardiomyopathy, lipotoxicity and insulin
ApoA-V, RCT, ketogenesis, gluconeogenesis, cholesterol resistance (heart-specific PPAR transgenic mice)
catabolism, TG clearance, phospholipid secretions

Ligand-activated
PPAR

Pancreas Skeletal muscle

Decreased: Reversal of high-fat feeding-induced insulin Decreased: Glucose utilization, glucose
secretion in vivo, fasting-induced insulin secretion, uptake and glucose transporter
glucose-induced hypersecretion of insulin secretion gene expression
in vivo during pregnancy Increased: FA uptake, FA oxidation,
Increased: FA oxidation, FA transport, glucose-stimulated TG hydrolysis, (heart-specific
insulinsecretion (GSIS), UCP2 PPAR transgenic mice)

ABCA1: ATP-binding cassette A1; AP: Activator protein; Apo: Apolipoprotein; CE: Cholesteryl ester; eNOS: Endothelial nitric oxide
synthase; ET: Endothelin; FABP: Fatty acid binding protein; FAT: Fatty acid transporter; FATP: Fatty acid transport protein; IB: Inhibitory
protein B; iCOX: Inducible cyclooxygenase; IL: Interleukin; iNOS: Inducible nitric oxide synthase; LCAS: Lipoprotein and Coronary
Atherosclerosis Study; LCAT: Lecithin:cholesterol acyltransferase; LXR: Liver X receptor; MCP: Monocyte chemoattractant protein;
MMP: Matrix metalloproteinase; NF-B: Nuclear factor-B; PG: Prostaglandin; PPAR: Peroxisome proliferator-activated receptor;
SOD: Superoxide dismutase; SR-A: Scavenger receptor class A; SR-BI: Scavenger receptor class B, type I; TF: Tissue factor; TG: Triglyceride;
TNF: Tumor necrosis factor; UCP: Uncoupling protein; VCAM: Vascular cell adhesion molecule.

recently shown that administration of a potent [181].

and selective PPAR agonist to cynomolgus
monkeys results in increased levels of plasma
ApoA-V, which inversely correlates with
decreased triglycerides, VLDL and VLDL-TGs
Although the actual mechanism by which
ApoA-V decreases triglyceride levels has not yet
been worked out, it has been demonstrated to
inhibit VLDL production and to promote
LPL-mediated VLDL-TG hydrolysis [182].

42 Future Lipidol. (2007) 2(1) future science group

 PPAR and the metabolic syndrome – SPECIAL
As PPAR agonists, fibrates increase the levels
of HDL and stimulate the synthesis of its constit-
uent proteins ApoA-I and A-II [113]. PPAR reg-
ulates reverse cholesterol transport (RCT)
through increased transcriptional activation of
the hepatic ApoA-I [136]. PPAR also promotes
HDL remodeling by upregulating the expression
of phospholipid transfer protein [136]. Several
other proteins involved in lipoprotein metabo-
lism, such as scavenger receptor (SR)-BI or its
human homolog CLA-1, hepatic lipase, lecithin
cholesterol acyltransferase (LCAT) and ATP-
binding cassette (ABC)A1 are also regulated by
PPAR [113,121,122,126,136].
-cells insulin secretion &
insulin sensitivity
PPAR plays a complex role in the regulation of
both glucose-stimulated insulin secretion and
tissue insulin sensitivity (Figure 5). It may
directly modulate insulin secretion by altering
the relative levels of glucose and fatty acid sen-
sors [183–185] or indirectly by controlling the
-cell fatty-acid oxidation and/or glucose
homeostasis [121,126,186]. Furthermore, condi-
tions which downregulate the PPAR expres-
sion in -cells lead to a corresponding reduction
in insulin secretory rates. For example, Zhou
and colleagues reported that expression of
PPAR and enzymes of -oxidation is markedly
reduced in the fat (TG)-laden, -cell-dysfunc-
tional islets of obese, prediabetic Zucker dia-
betic fatty (fa/fa) rats with mutated leptin
receptors (OB-R) [187]. Overexpression of nor-
mal OB-R in islets of fa/fa rats corrected these
abnormalities and raised the possibility that
PPAR is an OB-R-regulated factor required
for normal lipid homeostasis and -cell func-
tion [188]. In another study, chronic exposure of
islets or the INS(832/13) -cell line to high glu-
cose levels resulted in a 60–80% reduction in
PPAR mRNA expression and downregulation
of PPAR target genes along with elevated lev-
els of malonyl-CoA and altered rates of insulin
secretion [186,188]. Likewise, islets isolated from
the PPAR-/- mice demonstrated an approxi-
mate 50% reduction in fatty-acid oxidation,
but normal glucose usage and enhanced glu-
cose-induced insulin secretion [189]. Recently,
Ravnskjaer and colleagues provided evidence
for PPAR subtype specificity in -cell function
by demonstrating that PPAR potentiates,
whereas PPAR attenuates, glucose-stimulated
insulin secretion by pancreatic -cells [190].
future science group www.futuremedicine.com
REPOR T
Genetic and nutritional models demonstrate
a modest effect of PPAR on insulin sensitivity,
consistent with PPAR’s main role in lipid
homeostasis. Mice that are deleted for the
PPAR gene display no gross abnormalities in
terms of insulin sensitivity [191] , however, pro-
longed (24 h) fasting leads to hyperinsulinemia
and the insulin-resistant state [192]. Experimen-
tal evidence based on the data obtained with
various models of insulin resistance, glucose
intolerance and diabetes, such as the high-fat
fed rat (nutrition model), Zucker obese fa/fa rat
(genetic), A-ZIP/F-1 (lipoatrophic model),
OLETF rat (insulin resistant obese) and db/db
mice (Type 2 diabetic), suggest that PPAR is
an important regulator of insulin sensitivity
[191,193–196]. PPAR agonist treatment dramati-
cally improves insulin resistance (i.e., insulin
sensitivity) and hyperglycemia in Type 2 dia-
betic db/db mice and OLETF rats [139,195,196].
Chronic dietary administration of PPAR ago-
nists, such as fenofibrate, reduced high-fat
induced hyperinsulinemia, hyperglycemia and
leads to increased adipose tissue mass in
C57BL/6 mice [191]. Likewise, administration
of another PPAR activator, ciprofibrate, as
part of the diet improved hyperinsulinemia
without causing any glucose intolerance during
an intravenous glucose tolerance test, indicat-
ing enhanced insulin sensitivity [191]. Similarly,
ciprofibrate treatment decreased the body-
weight gain as well as epididymal adipose tissue
weight [191]. Furthermore, PPAR activation by
the WY14,643 agonist lowers muscle lipids and
increases insulin sensitivity in high-fat-fed rats
[193]. Another study suggests that WY14,643
treatment improves hepatic and muscle steato-
sis and reverses insulin resistance in
lipoatrophic A-ZIP/F-1 mice [194]. More
recently, it has been demonstrated that the
PPAR agonist fenofibrate prevents the progres-
sion of diabetes in insulin-resistant obese
OLETF rats [195,196], and that fenofibrate and
another potent agonist (GW7647) improve
insulin sensitivity in LDL-receptor deficient
mice [197,198]. Interestingly, agonist-mediated
PPAR activation attenuates glucose-stimu-
lated insulin secretion in vivo by enhancing
insulin sensitivity [199]. These various studies
support the notion that PPAR plays an obliga-
tory role in regulating insulin sensitivity in vivo,
and that its activation by specific agonists may
alleviate insulin resistance and slow down the
onset and progression of Type 2 diabetes.
43
SPECIAL REPOR T – Azhar & Kelley
Inflammation, Type 2 diabetes mellitus
& atherosclerosis
Considerable evidence now suggests that
inflammation may contribute to the patho-
physiology of insulin resistance, Type 2 diabetes
and associated cardiovascular complications
[5,6,18,19,200,201] . Inflammation, similarly to insu-
lin resistance and dyslipidemia, is an important
component of the metabolic syndrome
[26,27,29,31] , and atherosclerotic cardiovascular
disease itself is now viewed as both a disorder of
lipid metabolism and a chronic inflammatory
disease [202–204]. Emerging evidence now sup-
ports a beneficial role for PPARs, especially
PPAR in inflammation, Type 2 diabetes and
the atherosclerosis triad [115,200,204,205].
The pathogenesis of atherosclerotic disease
represents a complex process initiated by the
recruitment of monocytes into the arterial wall
and their differentiation into macrophages.
The causal relationship between atherosclerosis
and inflammation is not clear. In atherosclero-
sis, macrophages take up atherogenic oxidized
LDL [206] , resulting in their transformation
into lipid-loaded macrophages or foam cells
(Figure 5). The formation of foam cells and con-
comitant activation of the different vascular
cell types leads to a chronic inflammatory
process [208] .
In recent years, several clinical trials, includ-
ing the BEnzafibrate Coronary Atherosclerosis
Trial (BECAT), the Helsinki Heart study, the
BIP study, the BEnzafibrate Coronary Athero-
sclerosis Intervention Trial (BECAIT) and the
VA-HIT have demonstrated that hypolipidemic
fibrates have favorable effects of slowing the
progression of atherosclerosis and reducing the
risk of coronary artery disease in high-risk
patients (for review see [122,137,138]). PPAR is
expressed in the cardiovascular system, includ-
ing the heart [109,118,119,133,178], vascular
endothelial cells [207], vascular smooth muscle
cells [208] and circulating monocytes/macro-
phages [209], and in atherosclerotic plaques [210],
where it exerts direct anti-atherogenic and anti-
inflammatory actions [115,116,118,133]. It is likely
that PPAR influences inflammation by the
regulation of genes affecting:
• Monocyte recruitment (monocyte chemotactic
protein-1 [211]; endothelin [212]);
• Adhesion molecules (vascular cell adhesion
molecule-1) [213,214];
• Transmigration proteases (matrix metallo-
proteinase-9) [215] ;
44 Future Lipidol. (2007) 2(1)
• Foam cell formation (SR-BI and SR-BIor
CLA-1 [212]);
• RCT (LXR and ABCA1 [216,218]);
• Thrombogenicity (tissue factor) (Figure 5)
[217,218].
PPAR also modulates atherosclerosis
through its anti-inflammatory actions. Staels
and colleagues, have demonstrated that PPAR
inhibits expression of interleukin-6, prosta-
glandin and inducible cyclooxygenase-2 in aor-
tic smooth muscle cells [208]. These anti-
inflammatory actions occur as a consequence of
PPAR inhibition of signaling by the proinflam-
matory mediator nuclear factor (NF)-B and
induction of apoptosis [210]. In addition, IB
levels (endogenous inhibitor of NF-B activity)
are induced in vascular smooth muscle cells by
fibrates, thereby demonstrating another poten-
tial anti-inflammatory mechanism for PPAR
agonists [219]. Moreover, other studies have dem-
onstrated that PPAR activation inhibits both
AP-1 and NF-B inflammatory-cytokine signal-
ing pathways [220,221]. Furthermore, the PPAR
agonist, fenofibrate, lowered plasma levels of
cytokines interferon- and tumor necrosis fac-
tor- in patients with atherosclerosis and hyper-
lipoproteinemia IIb [222]. Fenofibrate is also
known to upregulate the expression and activity
of the endothelial type nitric oxide synthase
(eNOS) [223]. Its reaction product, nitric oxide,
is an important mediator of the events involved
in cardiovascular protection [224] and possesses
anti-inflammatory and antiatherogenic proper-
ties [225]. Interestingly, this stimulation of eNOS
expression does not occur through effects on
eNOS gene promoter activity, but rather
through increases in mRNA stability [223].
In contrast to the protection offered by
PPAR agonists against the development of
atherosclerosis, the ‘reverse’ translational stud-
ies aimed at delineating the beneficial action of
PPAR on the progression of atherosclerosis in
rodent models of atherosclerosis have yielded
conflicting information [119,226]. PPAR-null
mice exhibit a greater inflammatory response
when challenged with bacterial lipopoly-
saccharide [220,227,228]. Surprisingly, double
knockout mice lacking both ApoE and PPAR
(ApoE-/-/PPAR-/-) mice exhibited more
atherosclerosis than mice gene-ablated for
ApoE (ApoE-/-) alone (control) [229], suggesting
a proatherogenic function of PPAR. Further-
more, total cholesterol, HDL-cholesterol and
ApoAI and AII levels were higher in PPAR
future science group
 PPAR and the metabolic syndrome – SPECIAL
null mice, but were shown to be more insulin
sensitive and less hypertensive compared with
wild-type controls [130]. Another study con-
ducted on atherosclerosis-prone ApoE-/- mice
indicated that treatment with the PPAR ago-
nist ciprofibrate accelerated the high-fat diet
induced hyperlipidemia and significantly
increased the extent of atherosclerosis [230]. By
contrast, studies reported by Claudel and col-
leagues [231] and Duez and colleagues [232] sug-
gest that although the PPAR agonist
fenofibrate exerted very little antiatherogenic
actions in ApoE-/- mice, it exhibited a very
robust effect in ApoE-/- transgenic mice carrying
a fenofibrate–inducible human ApoA-I trans-
gene. Two more recent studies further con-
firmed that activation of PPAR by specific
agonists (fenofibrate and GW7647) reduced the
extent of atherosclerosis by approximately 50%.
Interestingly, treatment of hypercholesterolemic
mice with GW7647, a highly specific and
potent PPAR agonist, also blocked the forma-
tion of macrophage foam cells in the peritoneal
cavities of mice [178,206].
Conclusions
PPAR is a master regulatory transcription fac-
tor controlling lipid homeostasis and has been
demonstrated to regulate genes related to lipid
transport, packaging, synthesis and metabolism.
Its role in regulating fatty-acid oxidation has
been confirmed in the liver, heart, skeletal mus-
cle and the pancreas; it is highly likely that
PPAR controls fatty-acid oxidation in other tis-
sues as well. Owing to its role in lipid homeo-
stasis, PPAR plays a major role in energy
homeostasis, which can be observed by the
effects of PPAR on insulin secretion and insulin
sensitivity. More recently, the PPARs, including
PPAR, have exhibited direct and indirect
effects on atherosclerosis and inflammatory sys-
tems. Concomitantly, with the understanding of
the diverse effects of PPAR, there is a growing
appreciation for the inter-relatedness of dyslipi-
demia, insulin resistance, hypertension, chronic
inflammation and atherosclerosis. This has made
the PPARs, and PPAR in particular, the subject
of intense drug development in search of new
drugs that can both treat the immediate meta-
bolic disorder, such as diabetes, and prevent the
long-term consequences of metabolic disease,
such as cardiovascular disease. Since the preva-
lence of diabetes, obesity and cardiovascular
disease are at epidemic proportions and these
future science group www.futuremedicine.com
REPOR T
diseases are major causes for morbidity and
mortality, the urgency for better understanding
of these complex systems and the transcription
factors that regulate them is readily appreciated.
Future perspective
The highly complex regulatory mechanism that
PPAR plays in an organism sometimes makes
interpretation of direct effects versus indirect
effects difficult to dissect. Understanding the
interplay of metabolic, inflammatory and
hypertensive systems will require evaluation of
genetic pathways using gene chip/multigene
arrays. In fact, this approach is already bearing
significant results in identifying genes that are
under PPAR control (directly or indirectly).
However, since these different systems may indi-
rectly affect one another, it is likely that full
understanding of PPAR regulation will only be
achieved in the context of multigene arrays eval-
uated from experiments conducted under
in vivo conditions. Evaluation of in vitro experi-
ments alone is not likely to address the critical
aspects connecting the interdependence of the
metabolic and inflammatory systems. Fortui-
tously, there are safe and effective PPAR drugs
available to conduct in vivo analysis at both the
preclinical and the clinical levels. It stands to
reason that future clinical studies using PPAR
will utilize gene chips with arrays that are
known, or suspected to be, PPAR responsive as
a mechanism to correlate clinical outcomes to
genetic control.
As we further understand and/or confirm the
role of PPAR in both energy homeostasis as
well as regulation of inflammation and arthero-
sclerosis, it is likely that development of more
potent -agonists will be warranted. The fibrate
class of drugs was developed to combat dyslipi-
demia without an understanding of their broader
importance. Fortuitously, these drugs were iden-
tified as PPAR agonists and have greatly facili-
tated our appreciation of the potential of PPAR
agonists as clinically useful medicines. Currently,
much of the focus is on diabetes with dual
PPAR/ agonists being developed. In this para-
digm, PPAR is seen as a secondary player to
PPAR, since the main thrust of these drugs is to
improve insulin sensitivity. Given a better under-
standing of the complex interplay of inflamma-
tion, metabolic function and cardiovascular
disease, it is highly likely that drug development
efforts will refocus on development of new
PPAR drugs.
45
SPECIAL REPOR T – Azhar & Kelley

Executive summary
• Peroxisome proliferators-activated receptor- (PPAR ) is a member of the nuclear receptor superfamily that includes other PPAR
isoforms (PPPAR/, PPAR) and the estrogen, androgen and glucocorticoid receptors.
• PPAR is a master transcription factor that regulates genes involved in lipid metabolism, glucose homeostasis, inflammation and
atherosclerosis, and is the principal regulator of energy homeostasis.
• Fibrates are hypolipidemic drugs that are weak ligands for PPAR . The lipid (triglyceride)-lowering actions of this class of drugs are
mediated by modulation of lipid metabolism through molecular actions of PPAR .
• Fibrates and other PPAR ligands also exert anti-inflammatory and antithrombotic actions in the constituent cells of the vessel
wall. Thus, PPAR agonists interfere with the progression of atherosclerosis by modulating the function of various components of
metabolic syndrome through their anti-inflammatory properties.
• In recent years, several clinical trials, including the BEnzafibrate Coronary Atherosclerosis Intervention Trial (BECAIT), the Helsinki
Heart study, the Benzafibrate Infraction Prevention (BIP) study, the BECAIT and the Veterans Affairs High-density lipoprotein
Intervention Trial (VA-HIT), have demonstrated that hypolipidemic fibrates have favorable effects on slowing the progression of
atherosclerosis and reducing the risk of coronary artery disease in high-risk patients.

Bibliography
Papers of special note have been highlighted as
either of interest (•) or of considerable interest (••)
to readers.
1. Okrainec K, Banerjee DK, Eisenberg MJ:
Coronary artery disease in the developing
world. Am. Heart J. 148, 7–15 (2004).
• Epidemiological review suggesting
that the developing world is currently
experiencing an epidemic of coronary
artery disease (CAD) and, if unchecked,
CAD-associated morbidity and mortality
rates are expected to continue to rise for the
foreseeable future.
2. American Heart Association: Heart disease
and stroke statistics – 2005 update; Dallas,
TX, USA. American Heart Association
(2005).
3. Rashid MN, Fuentes F, Touchon RC,
Wehner PS: Obesity and the risk for
cardiovascular disease. Prev. Cardiol. 6,
42–47 (2003).
• Review further emphasizes an association
between obesity and cardiovascular disease.
4. Scaglione R, Argano C, Di Chiara T,
Licata G: Obesity and cardiovascular risk:
the new public health problem of worldwide
proportions. Expert. Rev. Cardiovasc. Ther. 2,
203–212 (2004).
• Provides additional evidence to support the
concept that obesity is an independent risk
factor for CAD.
5. Resnick HE, Howard BV: Diabetes and
cardiovascular disease. Annu. Rev. Med. 53,
245–267 (2002).
• Excellent review covering a range of topics
related to epidemiology of diabetes and
cardiovascular disease.
6. Sobel BE, Schneider DJ: Cardiovascular
complications in diabetes mellitus. Curr.
Opin. Pharmacol. 5, 143–148 (2005).
7. Zimmet P, Alberti KGMM, Shaw J:
Global and societal implications of the diabetes
epidemic. Nature 414, 782–787 (2001).
• Represents a fairly comprehensive review on
the global diabetic epidemic, with special
emphasis on socio-economic implications.
8. Bonow RO, Gheorghiade M: The diabetes
epidemic: a national and global crisis. Am. J.
Med. 116(Suppl. 5A), S2–S10 (2004).
9. Engelgau MM, Geiss LS, Saaddine JB et al.:
The evolving diabetes burden in the United
States. Ann. Intern. Med. 140, 945–950
(2004).
10. Morrill AC, Chinn CD: The obesity
epidemic in the United States. J. Public
Health Policy 25, 353–366 (2004).
• Addresses the issue of the obesity epidemic in
both adults and children in the USA. It also
provides evidence implicating physical
inactivity and increasing consumption of
carbohydrate intake, especially in the form of
soft drinks and other foods high in ‘high-
fructose corn syrup’, as the two main
contributors to obesity.
11. Haslam DW, James WP: Obesity. Lancet
366, 1197–1209 (2005).
12. Prentice AM: The emerging epidemic of
obesity in developing countries. Int.
J. Epidemiol. 35, 93–99 (2006).
13. Lillioja S, Mott DM, Spraul M et al.: Insulin
resistance and insulin secretory dysfunstion
as precursors of non-insulin-dependent
diabetes mellitus. N. Engl. J. Med. 329,
1988–1992 (1993).
• This original paper provides evidence
that insulin resistance is a major risk factor
for the development of Type 2 diabetes.
14. Goldstein BL: Insulin resistance: from
benign to Type 2 diabetes mellitus. Rev.
Cardiovasc. Med. 4(Suppl. 6), S3–S10
(2003).
15. DeFronzo RA: Pathogenesis of Type 2
diabetes mellitus. Med. Clin. North Am. 88,
787–835 (2004).
16. Kahn BB, Flier JS: Obesity and insulin
resistance. J. Clin. Invest. 106, 473–481
(2000).
• Article eloquently summarizes the
association between obesity and Type 2
diabetes. The authors have also raised the
possibility that insulin resistance and
hyperinsulinemia, in addition to being
caused by obesity, may promote the
development of obesity.
17. Lazar MA: How obesity causes diabetes: not
a tall tale. Science 307, 373–375 (2005).
18. Despres J-P, Lamarche B, Mauriege P et al:
Hyperinsulinemia as an independent risk
factor for ischemic heart disease. N. Engl.
J. Med. 334, 952–957 (1996).
• Provides evidence that hyperinsulinemia
is an independent risk factor for CAD
in men.
19. Pyorala M, Miettinen H, Laako M,
Pyorala K: Hyperinsulinemia predicts
coronary heart disease risk in healthy
middle-aged men: the 22-year follow-up
results of the Helsinki Policemen Study.
Circulation 98, 398–404 (1998).
20. Miegs JB: Epidemiology of the insulin
resistance syndrome. Curr. Diab. Rep. 3,
73–79 (2003).
21. Reaven G: Role of insulin resistance in
human disease (syndrome X): an expanded
definition. Annu. Rev. Med. 44, 121–131
(1993).
• Summarizes the role of insulin resistance in
the pathophysiology of metabolic
syndrome and its relevance to the etiology
and clinical course of patients with Type 2
diabetes, hypertension and CAD.

46 Future Lipidol. (2007) 2(1) future science group


22. Leslie BR: Metabolic syndrome: historical
perspective. Am. J. Med. Sci. 330, 264–268
(2005).
• Brief chronology of historical events that
led to the development of modern concept
of the metabolic syndrome.
23. Kahn R, Buse J, Ferrannini E, Stern M: The
metabolic syndrome: time for a critical
appraisal. Joint statement from the American
Diabetes Association and the European
Association for the Study of Diabetes.
Diabetes Care 28, 2289–2304 (2005).
24. Sarafidis PA, Nilsson PM: The metabolic
syndrome: a glance at its history.
J. Hypertens. 24, 621–626 (2006).
• Short review that covers the history of the
metabolic syndrome and provides a
succinct summary about the various clinical
parameters used by different organizations
to define metabolic syndrome.
25. Eckel RH, Grundy SM, Zimmet PZ: The
metabolic syndrome. Lancet 265,
1415–1428 (2005).
• In this excellent review, the authors provide
a comparison of definitions of the
metabolic syndrome, worldwide prevalence
of the syndrome, various metabolic
parameters impacted by insulin resistance
and management of metabolic risk factors.
26. Gill H, Mungo M, Whaley-Connell A,
Stump C, Sowers JR: The key role of insulin
resistance in the cardiometabolic syndrome.
Am. J. Med. Sci. 330, 290–294 (2005).
27. Govindarajan G, Whaley-Connell A,
Mungo M, Stump C, Sowers JR: The
cardiometabolic syndrome as a
cardiovascular risk factor. Am. J. Med. Sci.
330, 311–318 (2005).
28. Hafidh S, Senkottaiyan N, Villarreal D,
Alpert MA: Management of the metabolic
syndrome. Am. J. Med. Sci. 330, 343–351,
(2005).
29. Miranda PJ, DeFronzo RA, Califf RM:
Metabolic syndrome: definition,
pathophysiology, and mechanisms. Am.
Heart J. 149, 33–45 (2005).
• Provides more recent understanding about
the criteria and definitions of metabolic
syndrome, the metabolic components of the
syndrome and the underlying mechanisms
involved in its pathophysiology.
30. Moller DE, Kaufman KD: Metabolic
syndrome: a clinical and molecular perspective.
Annu. Rev. Med. 56, 45–62 (2005).
• Useful update regarding the clinical and
molecular aspects of the metabolic syndrome.
31. Reaven GM: Insulin resistance, the insulin
resistance syndrome, and cardiovascular
disease. Panminerva Med. 47, 201–210
(2005).
future science group
PPAR and the metabolic syndrome – SPECIAL
• Addresses insulin resistance with
emphasis on a number of clinical
conditions that are known to be
associated with insulin resistance and
compensatory hyperinsulinemia.
32. Poole R, Byrne CD: The metabolic
syndrome and type 2 diabetes. Minerva
Endocrinol. 30, 139–159 (2005).
33. Grundy SM: Metabolic syndrome:
connecting and reconciling cardiovascular
and diabetes worlds. J. Am. Coll. Cardiol.
47, 1093–1100 (2006).
34. Cameron AJ, Shaw JE, Zimmet PZ: The
metabolic syndrome: prevalence in
worldwide populations. Endocrinol. Metab.
Clin. North Am. 33, 351–375 (2004).
35. Ford ES, Giles WH, Mokdad AK:
Increasing prevalence of the metabolic
syndrome among US adults. Diabetes Care
27, 2444–2449 (2004).
36. Haffner S, Taegtmeyer H: Epidemic obesity
and the metabolic syndrome. Circulation
108, 1541–1545 (2003).
37. Ford ES, Giles WH, Dietz WH: Prevalence
of the metabolic syndrome among US
adults: findings from the Third National
Health and Nutrition Survey. JAMA 287,
356–359 (2002).
38. Alexender CM, Landsman PB, Teutsch SM,
Haffner SM: NCEP-defined metabolic
syndrome, diabetes, and prevalence of
coronary heart disease among NHANES III
participants age 50 years and older. Diabetes
52, 1210–1214 (2003).
39. Cook S, Weitzman M, Auinger P,
Nguyen M, Dietz WH: Prevalence of a
metabolic syndrome phenotype in
aldolescents: findings from the third
National Health and Nutrition Examination
Survey, 1988–1994. Arch. Pediatr. Adolesc.
Med. 157, 821–827 (2003).
40. Grundy SM: A constellation of
complications: the metabolic syndrome.
Clin. Cornerstone 7, 36–45 (2005).
41. Ginsberg HN, Huang LS: The insulin
resistance syndrome: impact on lipoprotein
metabolism and atherothrombosis.
J. Cardiovasc. Risk 7, 325–331 (2000).
42. Adams LA, Angulo P, Lindor KD:
Nonalcoholic fatty liver disease. CMAJ 172,
899–905 (2005).
• Important review describing an association
between nonalcoholic fatty liver disease
and the metabolic syndrome.
43. Marchesini G, Babini M: Nonalcoholic fatty
liver disease and the metabolic syndrome.
Minerva Cardiol. 54, 229–239 (2006).
• Provides evidence in support of
nonalcoholic fatty liver disease as being a
component of the metabolic syndrome.
www.futuremedicine.com
REPOR T
44. McGarry JD: Banting lecture 2001:
dysregulation of fatty acid metabolism in the
etiology of Type 2 diabetes. Diabetes 51,
7–18 (2002).
• Implicates dysregulated fatty-acid
metabolism in the etiology of
Type 2 diabetes.
45. Goodpaster BH, Wolf D: Skeletal muscle
lipid accumulation in obesity, insulin
resistance, and Type 2 diabetes. Pediatric
Diabetes 5, 219–226 (2004).
46. Borradaile NM, Schaffer JE: Lipotoxicity in
the heart. Curr. Hypertens. Res. 7, 412–417
(2005).
47. Rhodes CJ: Type 2 diabetes—a matter of -
cell life and death? Science 307, 380–384
(2005).
48. Stumvoll M, Goldstein B, van Haeften TW:
Type 2 diabetes: principles of pathogenesis
and therapy. Lancet 365, 1333–1346
(2005).
49. Zhang R, Liao J, Morse S, Donelon S,
Reisin E: Kidney disease and the metabolic
syndrome. Am. J. Med. Sci. 330, 319–325
(2005).
50. Rosmond R: Role of stress in the
pathogenesis of the metabolic syndrome.
Psychoneuroendocrinology 30, 1–10 (2005).
51. Wang M: The role of glucocorticoid
action in the pathophysiology of the
metabolic syndrome. Nutr. Metab.
2, 3–16 (2005).
52. Unger RH: Minireview: weapons of lean
body mass destruction: the role of ectopic
lipids in the metabolic syndrome.
Endocrinology 144, 5159–5165 (2003).
53. Young LR, Nestle M: The contribution of
expanding portion sizes to the US obesity
epidemic. Am. J. Public Health 92, 246–249
(2002).
54. Bray GA, Popkin BM: Dietary fat intake
does affect obesity. Am. J. Clin. Nutr. 68,
1157–1173 (1998).
55. Johnson RK, Frary C: Choose beverages and
foods to moderate your intake of sugars: the
2000 dietary guidelines for
Americans – what’s all the fuss about?
J. Nutr. 131, S2766–S2771 (2001).
56. Bray GA, Nielsen SJ, Popkin BM:
Consumption of high-fructose corn syrup
beverages may play a role in the epidemic of
obesity. Am. J. Clin. Nutr. 79, 537–543
(2004).
• Evidence that overconsumption of
calorically sweetened soft drinks may be an
important contributor to the epidemic of
obesity, in part through the large portion
sizes of these beverages and through the
increased intake of fructose from
high-fructose corn syrup and sucrose.
47
SPECIAL REPOR T – Azhar & Kelley
57. Stone NJ, Saxon D: Approach to treatment
of the patient with metabolic syndrome:
lifestyle therapy. Am. J. Cardiol. 96,
E15–E21 (2005).
58. Corella D, Ordovas JM: The metabolic
syndrome: a crossroad for
genotype–phenotype associations in
atherosclerosis. Curr. Atheroscler. Rep. 6,
186–196 (2004).
59. Roche HM, Phillips C, Gibney MJ: The
metabolic syndrome: the crossroads of diet
and genetics. Proc. Nutr. Soc. 64, 371–377
(2005).
60. Wisse BE: The inflammatory syndrome: the
role of adipose tissue cytokines in metabolic
disorders linked to obesity. J. Am. Soc.
Nephrol. 15, 2792–2800 (2004).
61. Hutley L, Prins JB: Fat as an endocrine
organ: relationship to the metabolic
syndrome. Am. J. Med. Sci. 330, 280–289
(2005).
• Central theme of this review article is
that adipose tissue not only functions
as a lipid storage depot, but also plays
a crucial role in the development of the
metabolic syndrome and the progression
of metabolic disease.
62. Hitzenberger K, Richter-Quittner M: Ein
Beitrag zum Stoffwechsel bei der vaskulären
Hypertonie. Weiner Arch Innere Med. 2,
189–216 (1921).
63. Hitzenberger K: Über den Blutdruck bei
Diabetes Mellitus. Weiner Arch Innere Med.
2, 461–466 (1921).
64. Kylin E: Hypertonie and Zuckerkrankheit.
Zentralblatt für Innere Medizin 42, 873–877
(1921).
65. Marañon G: Über Hypertonie and
Zuckerkrankheit. Zentralblatt für Innere
Medizin 43, 169–176 (1922).
66. Kylin E: Studien über das Hypertoni-
Hyperglycemi-Hyperurikmi syndrom.
Zentralblatt für Innere Medizin 44, 105–112
(1923).
67. Himsworth H: Diabetes mellitus: a
differentiation into insulin-sensitive and
insulin-insensitive types. Lancet 1, 127–130
(1936).
68. Vague J: La differenciation sexuelle. Facteur
determinant des formes de l’ obésite. Presse
Méd. 55, 339–340 (1947).
69. Vague J: The degree of masculine
differentiation of obesities. A factor
determining predisposition to diabetes,
atherosclerosis, gout and uric calculous
disease. Am. J. Clin. Nutr. 4, 20–34 (1956).
70. Albrink MJ, Meigs JW: Interrelationship
between skinfold thickness, serum lipids and
blood sugar in normal men. Am. J. Clin
Nutr. 15, 255–261 (1964).
48
71. Cámus JP: Goutte, diabète, hyperlipémie:
un trisyndrome métabolique. Rev. Rhum.
33, 10–15 (1966).
72. Welborn TA, Breckenridge A,
Rubinstein AH, Dollery CT, Fraser TR:
Serum-insulin in essential hypertension and
in peripheral vascular disease. Lancet 1,
1336–1337 (1966).
73. Avogaro P, Crepaldi G: Plurimetabolic
syndrome. Acta Diabetol. Lat. 4, 572–580
(1967).
74. Mehnert H, Kuhlmann H: Hypertonie und
diabetes mellitus. Dtsch Med. J. 19,
567–571 (1968).
75. Hansfeld M, Leonhardt W: Das
metabolische syndrom. Dt. Gesundh-Wesen
36, 545–551 (1981).
76. Krotkiewski M, Björntorp P, Sjöström L,
Smith U: Impact of obesity on metabolism
in men and women: importance of regional
adipose tissue distribution. J. Clin. Invest.
72, 1150–1162 (1983).
77. Bjorntorp P: Metabolic implications of body
fat distribution. Diabetes Care 14,
1132–1143 (1991).
78. Kissebah AH, Vydelingum N, Murray R
et al.: Relation of body fat distribution to
metabolic complications of obesity. J. Clin.
Endocrinol. Metab. 54, 254–260 (1982).
79. Modan M, Halkin H, Almog S et al.:
Hyperinsulinemia: a link between
hypertension, obesity and glucose intolerance.
J. Clin. Invest. 75, 809–817 (1985).
80. DeFronzo RA, Simonson D, Ferrannini E:
Hepatic and peripheral insulin resistance: a
common feature of Type 2 (non-insulin-
dependent) and Type 1 (insulin-dependent)
diabetes mellitus. Diabetologia 23, 313–319
(1982).
81. Ferrannini E, Buzzigoli G, Bonadonna R
et al.: Insulin resistance in essential
hypertension. N. Engl J. Med. 317, 350–357
(1987).
82. Wingard DL, Barret-Connor E,
Criqui MH, Suarez L: Clustering of heart
disease risk factors in diabetes compared to
non-diabetic adults. Am. J. Epidemiol. 117,
19–26 (1983).
83. Reaven GM: Banting lecture 1988: role of
insulin resistance in human disease. Diabetes
37, 1595–1607 (1988).
• Classic paper in which Reaven introduced
the concept that insulin resistance is central
to the pathogenesis of Type 2 diabetes,
hypertention, dyslipidemia and CAD.
84. Kaplan NM: The deadly quartet:
upper-body obesity, glucose intolerance,
hypertriglyceridemia, and hypertension.
Arch. Intern. Med. 149, 1514–1520
(1989).
Future Lipidol. (2007) 2(1)
85. DeFronzo RA, Ferrannini E: Insulin
resistance: a multifaceted syndrome
responsible for NIDDM, obesity,
hypertension, dyslipidemia, and
atherosclerotic cardiovascular disease.
Diabetes Care 14, 173–194 (1991).
86. Zimmet PZ: Kelly West lecture 1991.
Challenges in diabetes
epidemiology – from west to the rest.
Diabetes Care 15, 232–252 (1992).
87. Hjermann I: The metabolic cardiovascular
syndrome: syndrome X, Reaven’s syndrome,
insulin resistance syndrome,
atherothrombogenic syndrome.
J. Cardiovasc. Pharmacol. 20(Suppl. 8),
S5–S10 (1992).
88. Grundy SM, Cleeman JI, Daniels SR et al.:
Diagnosis and management of the metabolic
syndrome: an American Heart
Association/National Heart, Lung, and
Blood Institute Scientific Statement.
Circulation 112, 2735–2752 (2005).
89. Ferrannini E, Haffner SM, Mitchell BD,
Stern MP: Hyperinsulinemia: the key
feature of a cardiovascular and metabolic
syndrome. Diabetologia 34, 416–422
(1991).
90. Reaven G: The metabolic syndrome or the
insulin resistance syndrome? Different
names, different concepts, and different
goals. Endocrinol. Metab. Clin. North Am.
33, 283–303 (2004).
91. Pouliot MC, Despres JP, Lemieux S et al.:
Waist circumference and abdominal saggital
diameter: best simple anthropometric
indexes of abdominal visceral adipose tissue
accumulation and related cardiovascular risk
in men and women. Am. J. Cardiol. 73,
460–468 (1994).
92. Lemieux I, Pascot A, Couillard C et al.:
Hypertriglyceridemic waist: a marker of the
atherogenic metabolic triad
(hyperinsulinemia: hyperapolipoprotein B;
small, dense LDL) in men? Circulation 102,
179–184 (2000).
93. Park YW, Zhu S, Palaniappan L,
Heshka S, Carnethon MR, Heymsfield SB:
The metabolic syndrome: prevalence and
associated risk factor findings in the US
population from the Third National Health
and Nutrition Examination Survey,
1988–1994. Arch. Intern. Med. 163,
427–436 (2003).
94. Carr DB, Utzschneider KM, Hull RL et al.:
Intra-abdominal fat is a major determinant
of the National Cholesterol Education
Program Adult Treatment III criteria for the
metabolic syndrome. Diabetes 53,
2087–2094 (2004).
future science group

95. Meigs JB, D’Agostina RB Sr, Wilson PW,
Cupples LA, Nathan DM, Singer DE: Risk
variable clustering in the insulin resistance
syndrome: the Framingham Offspring
Study. Diabetes 46, 1594–1600 (1997).
96. Hanley AJ, Karter AJ, Festa A et al.: Factor
analysis of metabolic syndrome using
directly measured insulin sensitivity: the
Insulin Resistance Atherosclerosis Study.
Diabetes 51, 2642–2647 (2002).
97. Alberti KGMM, Zimmet P, Shaw J:
The metabolic syndrome – a new
worldwide definition. Lancet 366,
1059–1062 (2005).
98. Reaven G: Insulin resistance, Type 2
diabetes mellitus, and cardiovascular disease:
the end of the beginning. Circulation 112,
3030–3032 (2005).
99. Gustat J, Srinivasan SR, Elkasabany A,
Berenson GS: Relation of self-rated
measures of physical activity to multiple risk
factors of insulin resistance syndrome in
young adults: the Bogalusa Heart Study.
J. Clin. Epidemiol. 55, 997–1006 (2002).
100. Apridonidze T, Essah PA, Iuorno MJ,
Nestler JE: Prevalence and characteristics
of the metabolic syndrome in women
with polycystic ovary syndrome. J. Clin.
Endocrinol. Metab. 90, 1929–1935
(2004).
• Authors conclude that the metabolic
syndrome and its components are common
in women with polycystic ovary syndrome,
placing them at a greater risk for
cardiovascular disease.
101. American Diabetes Association: Consensus
Development Conference on Insulin
Resistance. 5–6 November 1997. Diabetes
Care 21, 310–314 (1998).
102. Alberti KG, Zimmet PZ: Definition, diagnosis
and its complications, part 1: diagnosis and
classification of diabetes mellitus provisional
report of a WHO consultation. Diabet. Med.
15, 539–553 (1998).
103. Definition, Diagnosis and Classification of
Diabetes Mellitus and its complications.
Geneva, Switzerland: Department of
Noncommunible Disease Surveillance.
World Health Organization (1999).
104. Balkau B, Charles MA: Comment on the
provisional report from the WHO
consultation. European Group for the Study
of Insulin Resistance (EGIR). Diabet.
Metab. 16, 442–443 (1999).
105. Expert Panel on Detection, Evaluation, and
Treatment of High Blood Cholesterol in
Adults: Executive Summary of the third
Report of the National Cholesterol
Education Program (NCEP) Expert Panel
on Detection, Evaluation, and Treatment of
future science group
PPAR and the metabolic syndrome – SPECIAL
High Blood Cholesterol in Adults (Adult
Treatment Panel III). JAMA 285,
2486–2497 (2001).
106. Einhorn D, Reaven GM, Cobin RH et al.:
American College of Endocrinology position
statement on the insulin resistance syndrome.
Endocr. Pract. 9, 237–252 (2003).
107. Grundy S, Brewer HB, Cleeman J,
Smith SC, Lenfant C: For the conference
participants. Definition of metabolic
syndrome: report of the National Heart,
Lung, and Blood Institute/American Heart
Association on scientific issues related to
definition. Circulation 109, 433–438 (2004).
108. Gotto AM Jr, Blackburn GL, Dailey GE III
et al.: The metabolic syndrome: a call to
action. Coron. Artery Dis. 17, 77–80
(2006).
109. Desvergne B, Wahli W: Peroxisome
proliferator-activated receptors: nuclear
control of metabolism. Endocr. Rev. 20,
649–688 (1999).
• Excellent review that discusses molecular
and physiological aspects of peroxisome
proliferator-activated receptors (PPARs).
110. Lee C-H, Olson P, Evans RM:
Minireview: lipid metabolism, metabolic
diseases, and peroxisome proliferator-
activated receptors. Endocrinology 144,
2201–2207 (2003).
111. Willson TM, Brown PJ, Sternbach DD,
Henke BR: The PPARs: from orphan
receptors to drug discovery. J. Med. Chem.
43, 527–550 (2000).
• Describes the molecular characteristics and
physiological function of PPARs and
discusses the potential utility of PPARs as
molecular targets for the development of
drugs to treat human metabolic diseases.
112. Berger J, Moller DE: The mechanisms of
action of PPARs. Annu. Rev. Med. 53,
409–435 (2002).
• Covers the molecular mechanisms of PPAR
action and the involvement of PPARs in
the etiology and treatment of several
chronic diseases.
113. Francis GA, Fayard E, Picard F, Auwerx J:
Nuclear receptors and the control of
metabolism. Annu. Rev. Physiol. 65,
261–311 (2003).
• Broad description of nuclear receptors in
relation to the control of the metabolic
processes is presented.
114. Ferré P: The biology of peroxisome
proliferator-activated receptors:
relationship with lipid metabolism and
insulin sensitivity. Diabetes 53(Suppl. 1),
S43–S50 (2004).
• Emphasizes PPARs role as a major
regulator of lipid and glucose homeostasis.
www.futuremedicine.com
REPOR T
115. Tham DM, Wang Y-X, Rutledge JC:
Modulation of vascular inflammation by
PPARs. Drug News Perspect. 16, 109–116
(2003).
116. Castrillo A, Tontonoz P: Nuclear receptors
in macrophage biology: at the crossroads
of lipid metabolism and inflammation.
Annu. Rev. Cell Dev. Biol. 20, 455–480
(2004).
• Comprehensive review of nuclear receptors
literature with an emphasis on the roles of
PPARs and liver X receptors (LXRs) in the
regulation of macrophage lipid
homeostasis, inflammation and gene
expression, and their relevance to
cardiovascular disease.
117. Kosadinova R, Wahli W, Michalik L: PPARs
in diseases: control mechanisms of
inflammation. Curr. Med. Chem. 12,
2995–3009 (2005).
118. Chen YE, Fu M, Zhang J et al.: Peroxisome
proliferator-activated receptors and
cardiovascular system. Vit. Horm. 66,
157–188 (2003).
119. Marx N, Duez H, Fruchart J-C, Staels B:
Peroxisome proliferator-activated receptors
and atherogenesis: regulators of gene
expression in vascular cells. Circ. Res. 94,
1168–1178 (2004).
120. Li AC, Palinski W: Peroxisome proliferator-
activated receptors: how their effects on
macrophages can lead to the development of
a new drug therapy against atherosclerosis.
Annu. Rev. Pharmacol. Toxicol. 46, 1–39
(2006).
• Important review with primary
emphasis on the roles of PPARs
in macrophage biology, including
macrophage/foam-cell formation.
121. Lefebvre P, Chinetti G, Fruchart J-C,
Staels B: Sorting out the roles of
PPAR in energy metabolism and
vascular homeostasis. J. Clin. Invest.
116, 571–580 (2006).
122. Semple RK, Chatterjee VK, O’Rahilly S:
PPAR and human metabolic disease.
J. Clin. Invest. 116, 581–589 (2006).
123. Barish GD, Narkar VA, Evans RM:
PPAR: a dagger in the heart of the
metabolic syndrome. J. Clin. Invest.
116, 590–597 (2006).
• Provides evidence that PPAR may be a
new therapeutic target that may achieve
both triglyceride lowering as well as
improving insulin sensitivity.
124. Guan Y-F, Breyer MD: Peroxisome
proliferator-activated receptors (PPARs):
novel therapeutic targets in renal disease.
Kidney Int. 60, 14–30 (2001).
49
SPECIAL REPOR T – Azhar & Kelley
125. Mandard S, Müller M, Kersten S:
Peroxisome proliferator-activated receptor 
target genes. Cell. Mol. Life Sci. 61, 393–416
(2004).
• Provides an extensive list of
PPAR-regulated target genes.
126. Reddy JK: Peroxisome proliferators and
peroxisome proliferators-activated receptor
. Biotic and xenobiotic sensing. Am.
J. Pathol. 164, 2305–2321 (2004).
127. Barbier O, Torra P, Duguay Y et al.:
Pleiotropic actions of peroxisome
proliferator-activated receptors in lipid
metabolism and atherosclerosis.
Arterioscler. Thromb. Vasc. Biol. 22,
717–726 (2002).
128. Hsu M-H, Palmer CAN, Song W,
Griffin KJ, Johnson EF: A carboxyl-terminal
extension of the zinc finger domain
contributes to the specificity and polarity of
peroxisome proliferator-activated receptor
DNA binding. J. Biol. Chem. 273,
27088–27997 (1998).
129. Privalsky ML: The role of corepressors in
transcriptional regulation by nuclear
hormone receptors. Annu. Rev. Physiol. 66,
315–360 (2004).
• Most recent review on the
corepressor-mediated, negative regulation
of PPARs function.
130. Chakravarthy MV, Pan Z, Zhu Y et al.:
‘New’ hepatic fat activates PPAR to
maintain glucose, lipid and cholesterol
homeostasis. Cell Metab. 1, 309–322
(2005).
131. Spiegelman BM, Heinrich R:
Biological control through regulated
transcriptional coactivators. Cell 119,
157–167 (2004).
• Main focus of this article is on the
coactivator regulation of nuclear
hormone receptors.
132. Bishop-Bailey D: Peroxisome
proliferator-activated receptors in the
cardiovascular system. Brit. J. Pharmacol.
129, 823–834 (2000).
133. Akiyama TE, Meinke PT, Berger JP:
PPAR ligands: potential therapies for
metabolic syndrome. Curr. Diab. Rep. 5,
45–52 (2005).
134. Kuwabara K, Murakami K, Todo M et al.:
A novel selective peroxisome proliferator-
activated -agonist, 2-methyl-c-5-[4-[5-
methyl-2-(4-methylphenyl)-4-
oxazolyl]butyl]-1,3-dioxane-r-2-carboxylic
acid (NS-220), potently decreases plasma
triglyceride and glucose levels and modifies
lipoprotein profiles in KK-Ay mice.
J. Pharmacol. Exp. Ther. 309, 970–977
(2004).
50
135. Pelton PD, Patel M, Demarest KT: Nuclear
receptors as potential targets for modulating
reverse cholesterol transport. Curr. Top.
Med. Chem. 5, 265–282 (2005).
136. Staels B, Fruchart J-C: Therapeutic roles of
peroxisome proliferator-activated receptor
agonists. Diabetes 54, 2460–2470 (2005).
• Useful, systematic review that provides
clinical trial data about the PPAR agonists
in the management of dyslipidemia and
cardiovascular disease.
137. Israelian-Konaraki Z, Reaven PD:
Peroxisome proliferators-activated
receptor- and atherosclerosis: from basic
mechanisms to clinical implications.
Cardiology 103, 1–9 (2005).
138. Dumasia R, Eagle KA, Kline-Rogers E,
May N, Cho L, Mukherjee D: Role of
PPAR- agonist thiazolidinediones in
treatment of pre-diabetic and diabetic
individuals: a cardiovascular perspective.
Curr. Drug Targets Cardiovasc. Haematol.
Disord. 5, 377–386 (2005).
139. Aasum E, Belke DD, Severson DL et al.:
Cardiac function and metabolism in the
Type 2 diabetic mice after treatment with
BM 17.0744, a novel PPAR- activator. Am.
J. Physiol. Heart Circ. Physiol. 283,
H949–H957 (2002).
140. Schäfer SA, Hansen BC, Völkl A, Fahimi HD,
Pill J: Biochemical and morphological effects
of K-111, a peroxisome proliferator-actvated
receptor (PPAR) activator. Biochem.
Pharmacol. 68, 239–251 (2004).
141. Cheng PT, Mukherjee R: PPARs as targets
for metabolic and cardiovascular diseases.
Mini Rev. Med. Chem. 5, 741–753 (2005).
142. Brandt JM, Djouadi F, Kelley DP: Fatty
acids activate transcription of the muscle
carnitine palmitoyltransferase I gene in
cardiac myocytes via the peroxisome
proliferator-activated receptor . J. Biol.
Chem. 273, 23786–23792 (1998).
143. Mascaró C, Acosta E, Ortiz JA,
Marrero PF, Hegardt FG, Haro D:
Control of human muscle-type carnitine
palmitoyltransferase I gene transcription
by peroxisome proliferators-activated
receptor. J. Biol. Chem. 273, 8560–8563
(1998).
144. Barrero MJ, Camarero N, Marrero PF,
Haro D: Control of human carnitine
palmitoyltransferase II gene transcription
by peroxisome-activated receptor through
a partially conserved proliferator
proliferator-responsive element. Biochem. J.
369, 721–729 (2003).
145. Gulick T, Cresci S, Caira T,
Moore DD, Kelly DP: The peroxisome
proliferator-activated receptor regulates
Future Lipidol. (2007) 2(1)
mitochondrial fatty acid oxidative enzyme
gene expression. Proc. Natl Acad. Sci. USA
91, 11012–11016 (1994).
146. Rodriguez JC, Gil-Gomez G,
Hegardt FG, Haro D: Peroxisome
proliferator-activated receptor mediates
induction of the mitochondrial 3-hydroxy-
3-methylglutaryl-CoA synthase gene by
fatty acids. J. Biol. Chem. 269,
18767–18772 (1994).
147. Lee SS-T, Pineau T, Drago J et al.:
Targeted disruption of the  isoform of the
peroxisome proliferator-activated receptor
gene in mice results in abolishment of the
pleiotropic effects of peroxisome
proliferators. Mol. Cell. Biol. 15,
3012–3022 (1995).
148. Zhang B, Marcus SL, Sajjadi FG et al.:
Identification of a peroxisome
proliferator-responsive element upstream
of the gene encoding rat peroxisomal
anoyl-CoA hydratase/3-hydroxyacyl-CoA
dehydrogenase. Proc. Natl Acad. Sci. USA
89, 7541–7545 (1992).
149. Nicolas-Frances V, Dasari VK,
Abruzzi E, Osumi T, Latruffe N:
The peroxisome proliferator response element
(PPRE) present at positions
-681/-669 in the rat liver 3-ketoacyl-CoA
thiolase B gene functionally interacts
differently with PPAR and HNF-4. Biochem.
Biophys. Res. Comunn. 269, 347–351 (2000).
150. Aldridge TC, Tungwood JD, Green S:
Identification and characterization of DNA
elements implicated in the regulation of
CYP4A1 transcription. Biochem. J. 306,
473–479 (1995).
151. Peters JM, Hennuyer N, Staels B et al.:
Alterations in lipoprotein metabolism in
peroxisome proliferator-activated receptor
-deficient mice. J. Biol. Chem. 272,
27307–27312 (1997).
152. Aoyama T, Peters JM, Iritani N et al.:
Altered constitutive expression of fatty
acid-metabolizing enzymes in mice lacking
the peroxisome proliferator-activated
receptor  (PPAR). J. Biol. Chem. 273,
5678–5684 (1998).
153. Costet P, Legerdre C, More J, Edger A,
Galtier P, Pineau T: Peroxisome
proliferator-activated receptor -isoform
deficiency leads to progressive dyslipidemia
with sexually dimorphic obesity and steatosis.
J. Biol. Chem. 273, 29577–29585 (1998).
154. Tugwood JD, Issemann I, Anderson RG,
Bundell KR, McPheat WL, Green S: The
mouse peroxisome proliferator activated
receptor recognizes a response element in the
5´ flanking sequence of the rat acyl CoA
oxidase gene. EMBO J. 11, 433–439 (1992).
future science group

155. Kersten S, Seydoux J, Peters JM,
Gonzalez FJ, Desvergne B, Wahli W:
Peroxisome proliferator-activated receptor 
mediates the adaptive response to fasting.
J. Clin. Invest. 103, 1489–1498 (1999).
156. Leone TC, Weinheimer CJ, Kelly DP:
A critical role for the peroxisome
proliferator-activated receptor  (PPAR)
in the cellular fasting response: the
PPAR-null mouse as a model of fatty acid
oxidation disorders. Proc. Natl Acad. Sci.
USA 96, 7473–7478 (1999).
157. Huss JM, Kelly DP: Nuclear receptor
signaling and cardiac energetics. Circ. Res.
95, 568–578 (2004).
158. Riby JE, Fujisawa T, Kretchmer N:
Fructose absorption. Am. J. Clin. Nutr.
58, S748–S753 (1993).
159. Aoyama Y, Yoshida A, Ashida K: Effect of
dietary fats and fatty acids on the liver lipid
accumulation induced by feeding a
protein-repletion diet containing fructose to
protein-depleted rats. J. Nutr. 104, 741–746
(1974).
160. Jurgens H, Hass W, Castaneda TR et al.:
Consuming fructose-sweetened beverages
increases body adiposity in mice. Obes. Res.
13, 1146–1156 (2005).
161. Nagai Y, Nishio Y, Nakamura T,
Maegawa H, Kikkawa R, Kashiwagi A:
Amelioration of high fructose-induced
metabolic derangements by activation of
PPAR. Am. J. Physiol. Endocrinol. Metab.
282, E1180–E1190 (2002).
162. Kelley GL, Allan G, Azhar S: High dietary
fructose induces a hepatic stress response
resulting in cholesterol and lipid
dysregulation. Endocrinology 145, 548–555
(2004).
163. Wei Y, Wang D, Pagliassotti MJ: Fructose
selectively modulates c-jun N-terminal
kinase activity and insulin signaling in rat
primary hepatocytes. J. Nutr. 135,
1642–1646 (2005).
164. Basciano H, Federico L, Adeli K: Fructose,
insulin resistance, and metabolic
dyslipidemia. Nutr. Metab. (Lond.). 2, 5
(2005).
165. Berger PM, Kelly DP: PPAR signaling in the
control of cardiac energy metabolism. Trends
Cardiovasc. Med. 10, 238–245 (2000).
166. Djouadi F, Brandt J, Weinheimer CJ,
Leone TC, Gonzalez FJ, Kelley DP: The
role of the peroxisome proliferator-activated
receptor  (PPAR) in the control of cardiac
lipid metabolism. Prostaglandins Leukot.
Essent. Fatty Acids 60, 339–343 (1999).
167. Watanabe K, Fujii H, Takahashi T et al.:
Constitutive regulation of cardiac fatty acid
metabolism through peroxisome
future science group
PPAR and the metabolic syndrome – SPECIAL
proliferator-activated receptor  associated
with age-dependent cardiac toxicity. J. Biol.
Chem. 275, 22293–22299 (2000).
168. Campbell FM, Kozak R, Wagner A et al.:
A role for PPAR in the control of cardiac
malonyl-CoA levels: reduced fatty acid
oxidation rates and increased glucose
oxidation rates in the hearts of mice lacking
PPAR are associated with higher
concentrations of malonyl-CoA and reduced
expression of malonyl-CoA decarboxylase.
J. Biol. Chem. 277, 4098–4103 (2002).
169. Leone TC, Weinheimer CJ, Kelly DP: A
critical role for the peroxisome proliferator-
activated receptor  (PPAR) in the cellular
fasting response: the PPAR-null mouse as a
model of fatty acid oxidation disorders. Proc.
Natl Acad. Sci. USA 96, 7473–7478 (1996).
170. Finck BN, Lehman JJ, Leone TC et al.:
The cardiac phenotype induced by PPAR
overexpression mimics that caused by
diabetes mellitus. J. Clin. Invest. 109,
121–130 (2002).
171. Finck BN, Han X, Courtois M et al.:
A critical role for PPAR-mediated
lipotoxicity in the pathogenesis of diabetic
cardiomyopathy: modulation by dietary fat
content. Proc. Natl Acad. Sci. USA 100,
1226–1231 (2003).
172. Park S-Y, Cho Y-R, Fink BN et al.: Cardiac-
specific overexpression of peroxisome
proliferator-activated receptor- causes
insulin resistance in heart and liver. Diabetes
54, 2514–2524 (2005).
• Suggests that heart-specific overexpression
of PPAR as it occurs in diabetic hearts,
leads to cardiac insulin-resistance along
with defects in insulin signaling and STAT5
activity and reduced cardiac function.
173. Barger PM, Brandt JM, Leone TC,
Weinheimer CJ, Kelly DP: Deactivation of
peroxisome proliferator-activated receptor-
during cardiac hypertrophic growth. J. Clin.
Invest. 105, 1723–1730 (2000).
174. Young ME, Laws FA, Goodwin GW,
Taegtmeyer H: Reactivation of peroxisome
proliferator-activated receptor  is associated
with contractile dysfunction in
hypertrophied rat heart. J. Biol. Chem. 276,
44390–44395 (2001).
175. Huss JM, Levy FH, Kelly DP: Hypoxia
inhibits the PPAR/RXR gene regulatory
pathway in cardiac myocytes. J. Biol. Chem.
276, 44390–44395 (2001).
176. Razeghi P, Young ME, Abbasi S,
Taegtmeyer H: Hypoxia in vivo decreases
peroxisome proliferator-activated receptor
-regulated gene expression in rat heart.
Biochem. Biophys. Res. Commun. 287, 5–10
(2001).
www.futuremedicine.com
REPOR T
177. Kelley DP: PPARs of the heart: there is a
crowd. Circ. Res. 92, 482–484 (2003).
178. Motojima K, Passilly P, Peters JM,
Gonzalez FJ, Latruffe N: Expression of
putative fatty acid transport genes are
regulated by peroxisome proliferator-
activated receptor  and  activators in a
tissue- and inducer-specific manner. J. Biol.
Chem. 273, 16710–16714 (1998).
179. van der Vliet HN, Schaap FG, Levels JH
et al.: Adenoviral overexpression of
apolipoprotein A-V reduces serum levels of
triglycerides and cholesterol in mice.
Biochem. Biophys. Res. Commun. 295,
1156–1159 (2002).
180. Schultze A, Alborn WE, Mewton RK,
Konrad RJ: Administration of PPAR
agonist increases serum apolipoprotein
A-V levels and the apolipoprotein
A-V/apolipoprotein C-III ratio. J. Lipid Res.
46, 1591–1595 (2005).
• Demonstrates that PPAR agonist exerts
its hypotriglyceridemic effect by
modulating levels of apolipoprotein
(Apo)A-V and ApoA-V/ApoC-III
(lipoprotein lipase inhibitor).
181. Prieur X, Schapp FG, Coste H, Rodríguez JC:
Hepatocyte nuclear factor-4 regulates the
human apolipoprotein AV gene: identification
of a novel response element and involvement
in the control by peroxisome proliferator-
activated receptor- coactivator-1a, AMP-
activated protein kinase, and mitogen-
activated protein kinase pathway. Mol.
Endocrinol. 19, 3107–3125 (2005).
182. Prieur X, Huby T, Coste H, Schaap FG,
Chapman MJ, Rodríguez JC: Thyroid
hormone regulates the hypotriglyceridemic
gene APOA5. J. Biol. Chem. 260,
27533–27543 (2005).
183. Dobbins RL, Chester MW, Stevenson BE,
Daniels MB, Stein DT, McGarry JD: A fatty
acid-dependent step is critically important
for both glucose- and non-glucose-
stimulated insulin secretion. J. Clin. Invest.
101, 2370–2376 (1998).
184. Wollheim CB, Maechler P: -cell
mitochondria and insulin secretion:
messenger role of nucleotides and
metabolites. Diabetes 51(Suppl. 1),
S37–S42 (2002).
185. Yaney GC, Corkey BE: Fatty acid
metabolism and insulin secretion in
pancreatic  cells. Diabetologia 46,
1297–1312 (2003).
186. Sugden MC, Holmes MJ: Potential role of
peroxisome proliferator-activated receptor-
in the modulation of glucose-stimulated
insulin secretion. Diabetes 53(Suppl. 1),
S71–S81 (2004).
51
SPECIAL REPOR T – Azhar & Kelley
187. Zhou Y-T, Shimabukuro M, Wang M-Y
et al.: Role of peroxisome proliferator-
activated receptor  in disease of pancreatic
-cells. Proc. Natl Acad. Sci. USA 95,
8898–8903 (1998).
188. Roduit R, Morin J, Massé F et al.:
Glucose down-regulates the expression
of the peroxisome proliferator-activated
receptor-1 gene in the pancreatic -cell.
J. Biol. Chem. 275, 35799–35806
(2000).
• Suggests that hyperglycemia
downregulates PPAR gene expression
in pancreatic -cells.
189. Gremlich S, Nolan C, Roduit R
et al.: Pancreatic islet adaptation to
fasting is dependent on peroxisome
proliferator-activated receptor 
transcription up-regulation of fatty acid
oxidation. Endocrinology 146, 375–382
(2005).
190. Ravnskjaer K, Boergesen M, Rubi B et al.:
Peroxisome proliferator-activated receptor 
(PPAR) potentiates, whereas PPAR
attenuates, glucose-stimulated insulin
secretion in pancreatic -cells.
Endocrinology 146, 3266–3276 (2005).
191. Guerre-Millo M, Gervois P, Raspe E et al.:
Peroxisome proliferator-activated receptor 
activators improve insulin sensitivity and
reduce adiposity. J. Biol. Chem. 275,
16638–16642 (2000).
192. Sugden MC, Bulmer K, Gibbons GF,
Knight BL, Holness MJ: Peroxiosme-
proliferator-activated receptor- (PPAR)
deficiency leads to dysregulation of hepatic
lipid and carbohydrate metabolism by fatty
acids and insulin. Biochem. J. 364, 361–368
(2002).
193. Ye J-M, Doyle PJ, Iglesias MA, Watson DG,
Cooney GJ, Kraegen EW: Peroxisome
proliferator-activated receptor (PPAR)
activation lowers muscle lipids and improves
insulin sensitivity in high fat-fed rats:
comparison with PPAR  activation.
Diabetes 50, 411–417 (2001).
194. Chou CJ, Haluzik M, Gregory C et al.:
WY14,643, a peroxisome proliferator-
activated receptor  (PPAR) agonist,
improves hepatic and muscle steatosis and
reverses insulin resistance in lipoatropic
A-ZIP/F-1 mice. J. Biol. Chem. 277,
24484–24489 (2002).
• Experimental evidence is presented
to suggest that administration of
PPAR agonist improves hepatic and
muscle steatosis and causes a reversal
of insulin resistance in lipoatropic
A-ZIP/F-1 mice.
52
195. Koh EH, Kim MS, Park JY et al.:
Peroxisome proliferator-activated receptor
(PPAR)- activation prevents diabetes in
OLETF rats: comparison with PPAR-
activation. Diabetes 52, 2331–2337 (2003).
196. Guan Y: Peroxisome proliferator-activated
receptor family and its relationship to renal
complications of the metabolic syndrome.
J. Am. Soc. Nephrol. 15, 2801–2815 (2004).
197. Li AC, Binder C, Gutierrez A et al.:
Differential inhibition of macrophage foam-
cell formation and atherosclerosis in mice by
PPAR, /, and . J. Clin. Invest. 114,
1564–1576 (2004).
• Provides evidence that administration of
PPAR agonists to male lwo-density
lipoprotein receptor-deficient mice
markedly attenuates atherosclerosis.
This treatment also inhibits macrophage
foam-cell formation.
198. Srivastava RA, Jahagirdar R, Azhar S,
Sharma S, Bisgaier CL: Peroxisome
proliferator-activated receptor- selective
ligand reduces adiposity, improves insulin
sensitivity and inhibits atherosclerosis in
LDL receptor-deficient mice. Mol. Cell.
Biochem. 285, 35–50 (2006).
199. Sugden MC, Greenwood GK, Smith ND,
Holness MJ: Peroxisome
proliferator-activated receptor-
activation during pregnancy attenuates
glucose-stimulated insulin hypersecretion
in vivo by increasing insulin sensitivity,
without impairing pregnancy-induced
increases in -cell glucose sensing and
responsiveness. Endocrinology 144, 146–153
(2003).
200. Plutzky J: The potential role of peroxisome
proliferator-activated receptors on
inflammation in Type 2 diabetes mellitus
and atherosclerosis. Am. J. Cardiol. 92,
34–41 (2003).
201. Bloomgarden ZT: Inflammation,
atherosclerosis, and aspects of insulin
action. Diabetes Care 28, 2312–2319
(2005).
202. Lusis AJ: Atherosclerosis. Nature 407,
233–241 (2000).
203. Hansson GK: Inflammation, atherosclerosis,
and coronary artery disease. N. Engl. J. Med.
352, 1685–1695 (2005).
204. Beaven SW, Tontonoz P: Nuclear receptors
in lipid metabolism: targeting the heart of
dyslipidemia. Annu. Rev. Med. 57, 313–329
(2006).
205. Blaschke F, Takata Y, Caglayan E et al.:
Obesity, peroxisome proliferator activated
receptor, and atherosclerosis in Type 2
diabetes. Arterioscler. Thromb. Vasc. Biol. 26,
28–40 (2005).
Future Lipidol. (2007) 2(1)
206. Skalen K, Gustafsson M, Rydberg EK et al.:
Subendothelial retention of atherogenic
lipoproteins in early atherosclerosis. Nature
417, 750–754 (2002).
207. Inoue I, Shino K, Awata T, Katayama S:
Expression of peroxisome proliferator-
activated receptor  (PPAR) in primary
cultures of human vascular endothelial cells.
Biochem. Biophys. Res. Commun. 246,
370–374 (1998).
208. Staels B, Koening W, Habib A, Merval R,
Lebret M, Torra IP: Activation of human
aortic smooth-muscle cells is inhibited by
PPAR but not by PPAR activators. Nature
393, 790–793 (1998).
209. Chinetti G, Griglio S, Antonucci M,
Torra IP, Delerive P, Majd Z: Activation of
proliferator-activated receptor  and 
induces apoptosis of human
monocyte-derived macrophages. J. Biol.
Chem. 273, 25573–25580 (1998).
210. Chinetti G, Gbaguidi FG, Griglio S,
Mallat Z, Antonucci M, Poulain P:
CLA-1/SR-BI is expressed in atherosclerotic
lesion macrophages and regulated by
activators of peroxisome proliferator-
activated receptors. Circulation 101,
2411–2417 (2000).
211. Zhu L, Bisgaier CL, Aviram M, Newton RS:
9-Cis retinoic acid induces monocyte
chemoattractant protein-1 secretion
in human monocytic THP-1 cells.
Arterioscler. Thromb. Vasc. Biol. 19,
2105–2111 (1999).
212. Delerive P, Martin-Nizard F, Chinetti G
et al.: Peroxisome proliferator-activated
receptor activators inhibit thrombin-
induced endothelin-1 production in human
vascular endothelial cells by inhibiting the
activator protein-1 signaling pathway. Circ.
Res. 85, 394–402 (1999).
213. Jackson SM, Parhami F, Xi XP et al.:
Peroxisome proliferator-activated receptor
activators target human endothelial cells to
inhibit leukocyte-endothelial cell
interaction. Arterioscler. Thromb. Vasc. Biol.
19, 2094–2104 (1999).
214. Marx N, Sukhova GK, Collins T, Libby P,
Plutzky J: PPAR activators inhibit
cytokine-induced vascular cell adhesion
molecule-1 expression in human
endothelial cells. Circulation 99, 3125–3131
(1999).
215. Shu H, Wong B, Zhou G et al.: Activation
of PPAR or  reduces secretion of matrix
metalloproteinase 9 but not interleukin 8
from human monocytic THP-1 cells.
Biochem. Biophys. Res. Commun. 267,
345–349 (2000).
future science group

216. Chinetti G, Lestavel S, Bocher V et al.:
PPAR- and PPAR- activators induce
cholesterol removal from human
macrophage foam cells through stimulation
of the ABCA1 pathway. Nat. Med. 7, 53–58
(2001).
217. Neve BP, Corseaux D, Chinetti G et al.:
PPAR agonists inhibit tissue factor
expression in human monocytes and
macrophages. Circulation 103, 207–212
(2001).
218. Marx N, Mackman N, Schonbeck U et al.:
PPAR activators inhibit tissue factor
expression and activity in human
monocytes. Circulation 103, 213–219
(2001).
219. Delerive P, De Bosscher K,
Vanden-Berghe W, Fruchart JC,
Haegeman G, Staels B: DNA
binding-independent induction of IB
gene transcription by PPAR. Mol.
Endocrinol. 16, 1029–1039 (2002).
220. Delerive P, De Bosscher K, Besnard S,
Vanden-Berghe W, Peters JM, Gonzalez FJ:
Peroxisome proliferator-activated receptor 
negatively regulates the vascular
inflammatory gene response by negative
cross-talk with transcription factors NF-B
and AP-1. J. Biol. Chem. 274, 32048–32054
(1999).
221. Poynter ME, Daynes RA: Peroxisome
proliferator-activated receptor  activation
modulates cellular redox status, represses
nuclear factor-B signaling, and reduces
inflammatory cytokine production in aging.
J. Biol. Chem. 273, 32833–32841 (1998).
222. Madej A, Okopien B, Kowalski J,
Zielinski M, Wysocki J, Szygula B: Effects
of fenofibrate on plasma cytokine
concentrations in patients with
atherosclerosis and hyperlipoproteinemia
IIB. Int. J. Clin. Pharmacol. Ther. 36,
345–349 (1998).
future science group
PPAR and the metabolic syndrome – SPECIAL
223. Goya K, Sumitani S, Xu X, Kitamura T,
Yamamoto H, Kurebayashi S: Peroxisome
proliferator-activated receptor  agonists
increase nitric oxide synthase expression in
vascular endothelial cells. Arterioscler.
Thromb. Vasc. Biol. 24, 658–663 (2004).
224. Loscalzo J: Nitric oxide and vascular tone.
N. Engl. J. Med. 333, 251–253 (1995).
225. De Caterina R, Libby P, Peng HB et al.:
Nitric oxide decreases cytokine-induced
endothelial activation. Nitric oxide
selectively reduces endothelial expression of
adhesion molecules and proinflammatory
cytokines. J. Clin. Invest. 96, 60–68 (1995).
226. Li AC, Glass CG: PPAR- and LXR-
dependent pathways controlling lipid
metabolism and the development of
atherosclerosis. J. Lipid Res. 45, 2161–2173
(2004).
227. Devchand PR, Keller H, Peters JM, Vasquez
M, Gonzalez FJ, Wahli W: The PPAR-
leukotriene B4 pathway to inflammation.
Nature 384, 23–24 (1996).
• Provides evidence that leukotriene B4 is an
activating ligand of PPAR and proposes a
feedback mechanism between the duration
of the inflammatory response and hepatic
clearance of leukotriene B4 via PPAR-
controlled mechanisms.
228. Cuzzocrea S, Mazzon E, Di Paola R et al.:
The role of the peroxisome proliferators-
activated receptor- (PPAR-) in the
regulation of acute inflammation. J. Leukoc.
Biol. 79, 999–1010 (2006).
229. Tordjman K, Bernal-Mizrachi C, Zemany L
et al.: PPAR deficiency reduces insulin
resistance and atherosclerosis in apoE-null
mice. J. Clin. Invest. 107, 1025–1034
(2001).
• Suggests that PPAR may contribute to the
pathogenesis of diet-induced insulin
resistance and atherosclerosis.
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REPOR T
230. Fu T, Kashireddy P, Borensztajn J: The
peroxisome proliferator-activated receptor 
agonist ciprofibrate severely aggravates
hypercholesterolaemia and accelerates the
development of atherosclerosis in mice
lacking apolipoprotein E. Biochem. J. 373,
941–947 (2003).
• Demonstrates the hypercholesterolemic
and proatherogenic actions of the
PPAR agonist ciprofibrate in a mouse
model of atherosclerosis.
231. Claudel T, Leibowitz MD, Fievet C et al.:
Reduction of atherosclerosis in
apolipoprotein E knockout mice by
activation of the retinoid X receptor. Proc.
Natl Acad. Sci. USA 98, 2610–2615 (2001).
232. Duez H, Chao YS, Hernandez G et al.:
Reduction of atherosclerosis by the
peroxisome proliferator-activated receptor 
agonist fenofibrate in mice. J. Biol. Chem.
277, 48051–48057 (2002).
• Provides evidence that the PPAR
agonist fenofibrate is highly effective in
reducing atherosclerotic plaques in animal
models of atherosclerosis.
Affiliations
• Salman Azhar, PhD
GRECC-182BVA Palo Alto Health Care System,
Division of Gastroenterology and Hepatology,
Department of Medicine, Stanford University
School of Medicine, 3801 Miranda Avenue,
Palo Alto, CA 94304, USA
Tel.: +1 650 858 3933;
+1 650 493 5000 ext. 65365;
Fax: +1 650 496 2505; +1 650 849 0484;
salman.azhar@va.gov
• Glen Kelley, BSc
Insmed, Inc., 8720 Stony Point Parkway,
Suite 200, Richmond, VA 23235, USA
Tel.: +1 804 565 3033;
Fax: +1 804 565 3500;
gkelley@insmed.com
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