?The?Journal?of?Clinical?Investigation http://www.jci.org Volume 116 Number 3 March 2006
Sorting out the roles of PPARα in energy
metabolism and vascular homeostasis
Philippe Lefebvre, Giulia Chinetti, Jean-Charles Fruchart, and Bart Staels
Département d’Athérosclérose, Institut Pasteur de Lille, INSERM U545, and Université de Lille 2, Lille, France.
Nutrient metabolism and energy homeostasis are tightly regulat-
ed by endocrine, paracrine, and autocrine signals that control the
expression and activity of key metabolic enzymes and transport
proteins by transcriptional and posttranscriptional mechanisms.
Lipid mediators play a critical role in metabolic control, and the
PPARs (NR1Cs), a class of ligand-activated transcription factors,
have emerged as master transcriptional regulators of lipid and
carbohydrate metabolism. Saturated and unsaturated long-chain
fatty acids (FAs) and their eicosanoid derivatives are natural activa-
tors of this subclass of nuclear receptors. Increased recognition of
a role for PPARs in metabolic regulation came following the dis-
covery that the hypolipidemic fibrates and the insulin sensitizers
thiazolidinediones were synthetic ligands for PPARα (NR1C1; refs.
1, 2) and PPARγ (NR1C3; ref. 3), respectively. PPARδ (NR1C3), also
known as PPARβ, is the third PPAR isotype.
Accumulating evidence supports a link between the 3 PPARs and
diabetes, obesity, dyslipidemia, and inflammation. PPARα controls
liver and skeletal muscle lipid metabolism, and glucose homeosta-
sis. PPARα influences intracellular lipid and carbohydrate metab-
olism through direct transcriptional control of genes involved in
peroxisomal and mitochondrial β-oxidation pathways, FA uptake,
and triglyceride (TG) catabolism. Moreover, preclinical data sug-
gest a role for PPARα in body weight control, supporting the use
of PPARα agonists to treat obesity (4). Mice deficient in PPARα
exhibit a delayed response to inflammatory stimuli (5). Several
clinical trials demonstrate the efficiency of fibrates at decreasing
circulatory inflammatory markers and reducing the progression of
coronary atherosclerotic lesions. The ability of PPARα to improve
symptoms of the metabolic syndrome (visceral obesity, insulin
resistance, atherogenic dyslipidemia, and inflammation) suggests
that PPARα may be beneficial in the prevention or treatment of
type 2 diabetes mellitus and associated complications.
Structure of PPARα
PPARα has a functional domain structure analogous to those of
other nuclear receptor (NR) superfamily members. Like steroid
receptors, PPARα interacts with hsp90 (6). The central DNA-
binding domain (DBD) of PPARα is flanked by an N-terminal
region called activating function–1 (AF-1) (7) that is activated
by phosphorylation, as shown by insulin-stimulated AF-1 phos-
phorylation (S1). The DBD confers to PPARα the ability to bind
to PPAR response elements (PPREs) in the promoter of target
genes as an obligate heterodimer with retinoid X receptor (RXR)
isotypes (8). PPREs typically are organized as direct repeats of the
core sequence AGGTCA separated by 1 or 2 nucleotides (DR1
and DR2), flanked upstream by A/T–rich sequences (S2). While
PPRE geometry ensures specificity for PPAR/RXR heterodimers,
DR1 and DR2 PPREs are also recognized by RXR homodimers
or retinoic acid receptor (RAR)/RXR heterodimers, suggesting
cross-talk with RARs and RXRs that may influence metabolic
control (9). The C-terminus of PPARα, whose 3D structure has
been solved (10, 11), contains the ligand-regulated E domain or
AF-2 or ligand-binding domain (LBD), which harbors a large
T-shaped ligand-binding pocket (1,300 Å3) to accommodate vari-
ous natural and synthetic ligands.
Transcriptional activation by PPARα
The transactivation process by NRs relies on 5 major steps: ligand
binding; stable binding of liganded NR to DNA; corepressor dis-
missal and coactivator recruitment; activation of transcription;
and dissociation of the transcriptional complex, followed by
either shut-down or reinitiation of transcription. Crystallograph-
ic studies suggest that ligand binding to PPARα induces a global
stabilization of the receptor conformation (11), without major
structural reorganization, unlike the prototypical retinoic acid
receptor LBD that undergoes major structural transitions upon
Nonstandard?abbreviations?used: ABCA1, ABC transporter A1; AF, activating func-
tion; CE, cholesteryl ester; CPT-1, carnitine palmitoyl transferase 1; CRP, C-reactive
protein; FA, fatty acid; FAO, FA oxidation; FIELD, Fenofibrate Intervention and Event
Lowering in Diabetes; LBD, ligand-binding domain; LPL, lipoprotein lipase; MCP-1,
monocyte chemoattractant protein-1; NR, nuclear receptor; PPRE, PPAR response
element; RCT, reverse cholesterol transport; RXR, retinoid X receptor; sdLDL, small
dense LDL; SR, scavenger receptor; TG, triglyceride.
Conflict?of?interest: The authors have declared that no conflict of interest exists.
Citation?for?this?article: J. Clin. Invest. 116:571–580 (2006). doi:10.1172/JCI27989.
572?The?Journal?of?Clinical?Investigation http://www.jci.org Volume 116 Number 3 March 2006
agonist binding (S3). This suggests that the major contribution of
the PPARα ligand is the stabilization of a predefined structure able
to engage protein-protein interactions with coactivators (agonist-
bound PPARα) or corepressors (antagonist-bound PPARα) (11).
This feature is common to PPARα, PPARδ, and PPARγ (S4, S5),
but a recent refinement of the structure of the LBD of PPARδ
showed that this polypeptide is able to trap endogenous bacterial
FAs prior to crystallization (S6). Therefore, the possibility arises
that PPARα, and other isotypes, might shift from an inactive to
an active conformation, similarly to other NRs. However, it is not
known whether PPARα is, in a biological context, constitutively
bound to endogenous FAs.
Coactivator and corepressor complexes possess distinct
enzymatic activities (such as acetylase, deacetylase, methyl-
ase, demethylase, and kinase activities) targeting chromatin,
components of the basal transcriptional machinery, and other
coactivators and corepressors. The orchestrated recruitment and
dismissal of coactivators and corepressors leads to chromatin
decompaction and preinitiation complex assembly on promot-
ers. The transcriptional response is also strongly influenced by
the chemical structure of the ligand, the nature of the PPRE (12),
the structure of the promoter, and the expression of coactivators
and corepressors in a given cell type. The direct interaction of
coactivators and corepressors with PPARα requires 1 or more
cores of a degenerated LXXLL motif on the coregulator protein,
and several proteins have features of a bona fide coactivator or
corepressor for PPARα (S7–S13). However, none has been prov-
en essential for PPARα-induced transcription, including the
prototypical SRC1 molecule (13), reflecting a likely functional
redundancy between coactivators, or the lack of appropriate
models to study such mechanisms. This general mechanism for
transcriptional activation by PPARα is likely similar for other
PPARα target genes.
Gene repression by PPARα
PPARα also interferes negatively with other nuclear signaling path-
ways such as the AP1 (14) and NF-κB pathways. Indeed, PPARα
inhibits genes induced by NF-κB, such as VCAM-1, COX-2, and
IL-6 (15, 16), providing a molecular basis for the antiinflamma-
tory effects of PPARα ligands in vivo. PPARα upregulates expres-
sion of the NF-κB repressor IκBα (17) by increasing occupancy
of the NF-κB binding site present in the IκBα promoter, thereby
potentiating a negative feedback loop. This occurs independently
of PPARα binding to DNA and thus could involve direct protein-
protein interaction of PPARα with the NF-κB complex (18). A
similar mechanism has been described for the fibrate-mediated
inhibition of IL-1–induced expression of C-reactive protein (CRP)
(19). Interference of PPARα with the CAATT/enhancer binding
protein (C/EBP) signaling pathway is the molecular basis for the
inhibition of IL-6–induced fibrinogen-α and -β and of serum amy-
loid A expression (20). PPARα also decreases the expression of IL-6
receptor components as well as that of C/EBPs (21).
Metabolic actions of PPARα and potential pathophysiological consequences. The main effects of PPARα overexpression or of PPARα ligands
in mice (denoted by a single asterisk) and in humans (denoted by a double asterisk) are shown. GSIS, glucose-stimulated insulin secretion.
? The?Journal?of?Clinical?Investigation http://www.jci.org Volume 116 Number 3 March 2006
The biological and therapeutic activities of PPARα are there-
fore the result of the combination of both transactivating and
transrepressive properties of this receptor. In addition, post-
translational modifications are important regulatory controls.
SUMOylation and acetylation regulate transrepressive and
transactivating activities of some NRs, and phosphorylation
may inhibit transrepression by PPARα. PKC inhibition increases
repression of the fibrinogen-β gene by PPARα by modulating the
phosphorylation state of the PPARα D domain (22). The ability
of NRs to regulate transcription is also a function of promoter
architecture, ligand structure, cell type, and physiological and
pathological conditions. This raises the possibility of design-
ing ligands with dissociated transactivating and transrepressive
activities, enabling specific targeting of gene subsets. However,
despite extensive knowledge of PPARα molecular biology, the
design of such ligands remains purely empirical.
Mechanisms controlling PPARα activity
There are several levels at which PPARα activity can be con-
trolled. These include the regulation of its expression, the nature
of the ligand, the levels of coactivators and corepressors, and
posttranslational modifications of PPARα and the associated
coactivators and corepressors. Temporal expression of PPARα in
rats is controlled by the circadian clock (23), through the posi-
tive control of PPARα expression by glucocorticoids (24, 25)
and the clock gene Bmal1 (26). PPARα expression is induced
during fasting in Sv129 mice (27, 28), and influenced by hor-
monal signals such as leptin, growth hormone, and insulin
(24, 29, 30). Synthetic PPARα ligands such as Wy14,643,
GW7647, or fibrates increase the half-life of the PPARα poly-
peptide by preventing its ubiquitination and its subsequent deg-
radation via the proteasome (31).
Human PPARα promoter activity is induced by PPARα itself
and by the nuclear receptor HNF4, a major regulator of gluconeo-
genesis (32). Glucose decreases PPARα expression in the pancreas,
leading to diminished fatty acid oxidation (FAO) and TG accumu-
lation, a supposed cause for pancreatic lipotoxicity (33).
Extracellularly regulated signaling pathways impact on PPARα
through phosphorylation. The role of PKC in specifying PPARα
transcriptional activities has been described above, and a phos-
phorylation-dependent increase in PPARα activity by the stress-
activated p38 protein kinase has been shown to favor PPARα-
mediated transactivation (34).
Endogenous PPARα ligands
The quest for “the” endogenous PPARα ligand is still ongoing.
Early reports identified mono- and polyunsaturated FA as well
as eicosanoids as natural PPARα ligands (2, 35). Long-chain
fatty acyl-CoAs and saturated FAs also bind and activate PPARα
with EC50 values in the high-micromolar range (36, 37). Recent-
ly, Chakravarthy and colleagues reported that liver-specific
inactivation of the fatty acid synthase (FAS) gene in mice result-
ed in a phenotype identical to that of fasting PPARα-deficient
mice (38). Defects in FAO, cholesterol metabolism, and gluco-
neogenesis could be corrected by PPARα agonist treatment in
FAS-deficient mice, suggesting that de novo synthesized end
products of FAS, including palmitate, regulate PPARα activ-
ity. The data also suggest that FAs released from adipocytes are
inactive with respect to PPARα and thus exert physiologically
PPARα and intracellular lipid metabolism
PPARα is highly expressed in tissues displaying a high catabolic
rate of FAs, such as the liver, skeletal muscles (mostly in slow-
twitch, oxidative type I fibers [S14]), brown fat, heart, kidneys,
and cells of atherosclerotic lesions (endothelial cells, smooth
muscle cells, monocytes/macrophages). In rodents, PPARα acti-
vation leads to peroxisome proliferation and hepatocarcinoma, a
property intrinsic to mouse PPARα and, fortunately, not observed
in humans (39). Targeted disruption of the PPARα gene in mice
revealed its role in mitochondrial and peroxisomal FA β-oxida-
tion (FAO), FA uptake, and lipoprotein assembly and transport
(27, 28, 40–46). While the phenotype of PPARα-deficient mice
fed ad libitum is mild, fasting or inhibition of mitochondrial FA
import severely impairs FA uptake and FAO, leading to sex-spe-
cific liver steatosis and cardiac lipid accumulation, hypoglycemia,
and hypothermia (28, 43).
PPARα in hepatic lipid metabolism. Short-term adjustment of
mitochondrial FA β-oxidation occurs through regulation of car-
nitine palmitoyl transferase 1 (CPT-1), which controls FA import
into the mitochondria. CPT-1 expression is regulated by PPARα
in liver and myocytes (44), as well as that of major enzymes of
the β-oxidation pathway (acyl-CoA synthetase, very-long- and
medium-chain acyl-CoA dehydrogenases, 3-ketoacyl-CoA thio-
lase). Partial oxidation of very-long-chain and long-chain FAs, as
well as of other lipid derivatives such as eicosanoids or branched
FAs, occurs in peroxisomes to provide substrates for mitochon-
drial oxidation. The expression of key enzymes catalyzing the
degradation of straight-chain FAs (acyl-CoA oxidase, l-bifunc-
tional protein, thiolase) in peroxisomes is regulated by PPARα.
The mitochondrial HMG-CoA synthase, which converts acetyl-
CoA units into ketone bodies during fasting or diabetes, is also
upregulated by PPARα (45). Thus PPARα acts in liver and other
organs to reduce intracellular FA concentrations, likely contrib-
uting to decreased VLDL particle production and plasma TG
levels in patients treated with an agonist. PPARα’s role in energy
homeostasis is thus clearly demonstrated in animal models, but
unclear at present in humans. Moreover, the lower expression of
PPARα in human compared with rodent liver (47), as well the
dominant-negative splice variant of PPARα in human liver (48),
suggests a more modest role of PPARα in humans.
PPARα and cellular FA uptake. PPARα also modulates FA cellu-
lar uptake. Fatty acid translocase, or CD36, is a glycoprotein reg-
ulating FA uptake in multiple cell types, including hepatocytes,
adipocytes, and monocytes, as well as cells in muscle and intes-
tine. PPARα activation upregulates CD36 expression in liver and
intestine, but not in skeletal muscle (49). Similarly, expression
of the fatty acid transport protein, an integral membrane pro-
tein involved in FA uptake, is upregulated by PPARα activation
in hepatocytes (46).
PPARα in cardiac lipid metabolism. The hearts of PPARα-deficient
mice express very low levels of mitochondrial FAO enzymes, rely-
ing almost exclusively on glucose oxidation for energy, similarly to
fetal hearts (42, 50, 51). A PPARα-dependent transcriptional net-
work is activated in the heart during the transition from fetus to
newborn, creating a metabolic switch from glucose to FAO (S15).
Moreover, the metabolic rate of FA is increased in wild-type car-
diomyocytes upon treatment with a synthetic PPARα agonist (52),
and cardiac overexpression of PPARα leads to upregulation of FAO
enzymes, and to downregulation of enzymes controlling glucose
uptake and oxidation (51). The cardiac hypertrophy and dysfunc-
574?The?Journal?of?Clinical?Investigation http://www.jci.org Volume 116 Number 3 March 2006
tion in these PPARα-overexpressing mice thus resemble the car-
diac phenotype of diabetic mice, and cardiac as well as age-related
liver insulin resistance is observed in these mice (53). Thus PPARα
plays a regulatory role in controlling cardiac metabolic switches.
A decreased expression of PPARα in the nondiabetic, hypertrophic
heart alters FAO in cardiomyocytes and may contribute to cardiac
dysfunction (54), whereas a decreased PPARα expression in the
diabetic heart may be a mechanism to protect the heart from fur-
ther oxidative stress–induced damage due to excessive FAO (55).
Extrapolating these findings in mice to human pathology is diffi-
cult. The NR field has provided ample evidence that ligand-mediat-
ed activation of a receptor can trigger biological responses distinct
from those that result from receptor overexpression (see ref. 51, for
example). Similarly, the outcomes of gene inactivation studies are
not always predictable. Moreover, the metabolic response (such as
TG lowering) to agonist-induced systemic PPARα activation may
alter cardiac metabolism. Nevertheless, data in genetic models sug-
gest that chronic activation of PPARα can lead to ventricular dys-
function, and recent evidence shows that treating cardiomyopathic
mice with fenofibrate worsened heart function (56). However, an
important unresolved issue is the contribution of peroxisome pro-
liferation to the cardiac phenotype, which occurs in mice but not
humans (39). Thus, although there is no evidence that such events
occur in humans treated with weak PPARα agonists (i.e., fibrates),
monitoring of cardiac function in diabetic patients appears to be
indicated for potent PPARα agonists.
PPARα and TG and LDL metabolism. The therapeutic benefit of
fibrates is due in part to reduced VLDL production and enhanced
catabolism of TG-rich particles, which indirectly decreases small
dense LDL (sdLDL) particles, enhancing the formation of HDL
particles and hepatic elimination of excess cholesterol. Fibrates
have a marked effect on VLDL and chylomicron TG hydrolysis
mediated by PPARα, which upregulates lipoprotein lipase (LPL)
transcription in liver and muscle (57). LPL is a triacylglycerol
hydrolase in the capillary endothelium of peripheral tissues,
where its inactivation leads to severe hypertriglyceridemia and
decreased HDL formation (S16). Another control of TG catab-
olism is regulation of the ratio of lipolytic versus antilipolytic
apolipoprotein content in TG-rich particles. ApoC-III is an inhib-
itor of both LPL activity and remnant clearance, and apoC-III–
overexpressing mice are severely hypertriglyceridemic (S17).
ApoC-III synthesis is lowered by PPARα agonists in murine and
human hepatocytes, both in vivo and in vitro (42, 58), thereby
favoring VLDL lipolysis and generation of large LDL particles
that are more efficiently cleared via the LDL receptor. Interest-
ingly, expression of the recently identified apoA-V, a potent acti-
vator of lipolysis, is upregulated by PPARα agonists (59).
PPARα and HDL metabolism. HDLs are protective against athero-
sclerotic vascular disease and are the main vehicle of reverse cho-
lesterol transport (RCT). The interaction of HDL or apoA-I with
scavenger receptor BI (SR-BI) and ABC transporter A1 (ABCA1),
G1, or G4 triggers cholesterol efflux from peripheral tissues, and
HDL particles direct cholesterol for hepatic excretion into the
bile (60). Macrophage cholesterol efflux is of paramount impor-
tance for atherosclerosis, although it represents only a small frac-
tion of the whole-body RCT. PPARα agonists induce ABCA1 and
SR-BI expression in macrophages (61, 62), thereby enhancing the
first steps of macrophage RCT. Expression of the major human
HDL apolipoprotein genes apoA-I and apoA-II is activated in
response to fibrate treatment in vitro (63, 64) and in humans
(65, 66) via direct transcriptional control by PPARα. Devoid of
any functional PPRE in its promoter, the murine apoA-I gene
is negatively regulated by PPARα agonists through an indirect
pathway implicating the PPARα-dependent induction of the
orphan NR Rev-erbα, a negative regulator of transcription (67).
This is an example of the major differences between rodent and
human metabolic control by PPARα (see below). Thus PPARα
activation, by virtue of its effects on the transcriptional activi-
ties of genes involved in lipoprotein metabolism, elicits a global
normolipidemic response, by reducing TG-rich particle produc-
tion, increasing their lipolysis, and promoting HDL metabolism
and RCT. These collective effects should enhance transport of
cholesterol from peripheral tissues to the liver.
It is well established that excess fat intake promotes insulin resis-
tance, resulting in increased gluconeogenesis and hepatic glucose
production. In addition, hepatic and peripheral tissue lipotoxicity
is a major causative factor for the development of type 2 diabe-
tes mellitus. TGs provide the gluconeogenesis pathway with the
essential substrate, glycerol, in addition to acetyl-CoA, reducing
equivalents and ATP.
The mild PPARα-deficient phenotype becomes pronounced
upon exposure to thermic, metabolic, or inflammatory stress (28,
43). The severe hypoglycemia observed specifically in PPARα-defi-
cient mice upon fasting, characterized by a 50% drop in blood
glucose concentration after 24 hours of fasting, suggested a role
for PPARα in glucose homeostasis (28). Several mechanisms may
account for this fasting hypoglycemia, including normal glucose-
6-phosphate production in liver accompanied by the shift from
glucose to glycogen production (68). Other authors attribute
the fasting hypoglycemia to decreased production of lactate and
hepatic glucose (69). Fasting induces the conversion of glycerol
into glucose through the induction of several hepatic enzymes
such as glycerol-3-phosphate dehydrogenase (GPDH) and glyc-
erol kinase. The expression of these enzymes, and of the glyc-
erol transporters aquaporins 3 and 9, is PPARα-dependent (70).
GPDH deficiency in mice and humans leads to hypoglycemia,
underlining the important role of glycerol as a substrate for glu-
cose synthesis (S18, S19).
The mammalian ortholog of TRB3, another PPARα-target
gene, is an important link between glucose and lipid metabo-
lism. TRB3 is an inhibitor of Akt/protein kinase B, a positive
regulator of cellular responses to insulin (S20). Upregulation
of TRB3 expression through direct transcriptional control by
PPARα may impact negatively on liver insulin signaling, and
in turn perturb glucose homeostasis (71). Moreover, glucocor-
ticoid-induced diabetes is PPARα-dependent (72), and, accord-
ingly, PPARα-deficient mice are protected from high-fat diet–
induced insulin resistance (73, 74). Thus, PPARα is a key player
in hepatic glucose homeostasis.
The response to fasting is also dependent on the pancreas, and
PPARα-deficient mice inefficiently suppress insulin secretion
upon fasting, resulting in relative hyperinsulinemia (75). How-
ever, treatment of obese mice with PPARα agonists improves
insulin sensitivity and decreases blood glucose and insulin
levels (76). A similar treatment of severely insulin-resistant
lipoatrophic mice decreases blood glucose but does not normal-
?The?Journal?of?Clinical?Investigation http://www.jci.org Volume 116 Number 3 March 2006
ize insulin levels (77). In another model of lipoatrophy, PPARα
treatment improved both blood glucose and insulin levels
(78). In prediabetic monkeys, lipoatrophic rats, or high-fat-fed
rodents, PPARα activation by a high-affinity agonist reversed
insulin resistance, likely because of increased FA clearance from
insulin-sensitive organs (76, 77, 79, 80). Interestingly, PPARα
activation in pancreatic islet β cells also increases pancreatic
FAO and potentiates glucose-induced insulin secretion, sug-
gesting that PPARα activation protects pancreatic islets from
lipotoxicity (81). This raises the exciting yet untested hypothesis
that PPARα activation may prevent progression from a predia-
betic, insulin-resistant state to type 2 diabetes.
While it is clear that PPARα plays an obligatory role in liver
and heart FAO, the importance of PPARα in skeletal muscle FAO
is obliterated by a compensatory role of the ubiquitous PPARδ
(82). However, overexpression of PPARα in skeletal muscle in
vivo impacts on peripheral glucose homeostasis. The increased
FAO in PPARα-overexpressing muscles is accompanied by a
decreased insulin-stimulated glucose uptake. Mice are resistant
to diet-induced obesity but exhibit glucose intolerance, revealing
a link between muscle PPARα-driven FAO and insulin resistance
(83). This suggests that PPARα activation in skeletal muscles
shifts substrate utilization from glucose to FA, a conclusion sup-
ported by loss-of-function experiments (73, 83). However, only a
few clinical trials report an improvement of glucose homeostasis
after fibrate treatment (84–87). Moreover, the recent Fenofibrate
Intervention and Event Lowering in Diabetes (FIELD) study did
not reveal any effect of fenofibrate on glucose parameters in dia-
betic patients (88); this suggests that effects on glucose homeo-
stasis may be species specific. The multiple metabolic actions of
PPARα are summarized in Figure 1.
PPARα and atherosclerosis
The identification of PPARα expression in cell types of the ath-
erosclerotic lesion has led to a thorough investigation of its
modulatory role in this process. The gradual process of athero-
sclerotic lesion formation involves multiple cell types. Initia-
tion occurs when large arteries are exposed to atherogenic stim-
uli, such as bacterial products, dyslipidemia, proinflammatory
cytokines, or vasoconstrictor hormones such as angiotensin II.
At this early stage, VCAM-1, activated through an NF-κB–depen-
dent pathway, is believed to play a role in monocyte recruitment
PPARα and atherosclero-
sis. The effects of PPARα
agonists in atherosclerosis
are depicted for the most
prominent cell type present
in atherosclerotic lesions.
NPC1 and 2, Niemann-Pick
type C proteins 1 and 2;
OxLDL, oxidized LDL; SR-BI,
scavenger receptor BI; TF,
576?The?Journal?of?Clinical?Investigation http://www.jci.org Volume 116 Number 3 March 2006
to nascent atherosclerotic lesions. Transmigration of monocytes
and mast cells into the arterial intima, attracted by chemokines
such as monocyte chemoattractant protein-1 (MCP-1) and IL-8,
perturbs intercellular communications and promotes monocyte
differentiation into macrophages and mast cell degranulation.
Mast cells produce granule remnants rich in heparin proteogly-
cans, which interact with apoB-100, enhancing LDL retention.
In this inflammatory milieu, SMCs migrate and proliferate,
releasing MMPs that disrupt the ECM, exposing proteoglycans.
Enhanced binding of lipoproteins to these proteoglycans favors
their oxidation and glycation, perpetuating the inflammatory
cycle. Macrophages, expressing scavenger receptors of the B class
(CD36) and the A class (SR-A), internalize modified and oxidized
LDL to form foam cells, which produce additional cytokines
and growth factors. Following modified LDL uptake, choles-
teryl esters (CEs) are continuously hydrolyzed by a CE hydro-
lase and re-esterified by acyl-CoA:cholesterol acyltransferase
(ACAT). Eventually calcification occurs, particularly in patients
on renal dialysis. In addition, apoptosis and necrosis of foam
cells increase tissue factor, which can initiate thrombus forma-
tion. Formation of a necrotic core in the atherosclerotic plaque
eventually progresses to plaque erosion and rupture, leading
to clinical manifestations such as unstable angina, stroke, and
myocardial infarction. However, when cholesterol acceptors are
present in the extracellular fluid, RCT is initiated, and choles-
terol flows out of cells, through the ABC transporters ABCA1
and ABCG1/G4, which may reverse the atherosclerotic lesion.
Clinical trials as well as in vitro data provide compelling evi-
dence that PPARα acts as an antiatherogenic factor by interfering
at multiple stages of the atherosclerosis process (Figure 2). Results
from animal models have yielded conflicting results, which may
be due to inherent differences in the models, and the species dif-
ferences found in rodent and human metabolisms (74, 89–92). In
the absence of inflammatory stimuli, PPARα may promote pro-
atherogenic responses. The expression level of MCP-1 and IL-8 in
endothelial cells is upregulated upon PPARα activation (93). In
addition, PPARα ligands exert ROS-generating effects in unac-
tivated macrophages (94). By contrast, fibrates increase Cu-Zn
superoxide dismutase and decrease NADPH oxidase in endothelial
cells, potentially decreasing LDL oxidation (95). This suggests that
PPARα actions are distinct from inflammatory status, as demon-
strated by MCP-1 upregulation in early atherosclerotic lesions and
MCP-1 downregulation in late lesions during PPARα activation
(90). Antiatherogenic effects can be attributed to PPARα-depen-
dent repression of CRP-induced MCP-1 expression (96), inhibition
of the expression of ET-1 (14), inhibition of IL-1–induced IL-6
release (15), and inhibition of LPS-induced VCAM-1 expression
(16, 97, 98). Similarly, high IFN-γ serum levels are observed in ath-
erosclerotic patients, and IFN-γ release by activated T lymphocytes
is blunted by PPARα activators (99).
Furthermore, PPARα has a critical role in controlling the
cholesterol cycle in macrophages. The expression of ABCA1 is
stimulated by PPARα in foam cells in a liver X receptor–depen-
dent manner, promoting apoA-I–mediated cholesterol efflux
(62). The expression of Niemann-Pick type C proteins 1 and 2,
transporters of cholesterol from lysosomes to the plasma mem-
brane, is also regulated by PPARα, which promotes cholesterol
availability for efflux (100). SR-BI, which plays a role in both
the uptake of HDL-CE by the liver and cholesterol efflux from
macrophages, is upregulated by PPARα ligands in macrophages
(61), favoring cholesterol removal. Another parameter control-
ling macrophage cholesterol uptake is the availability and activ-
ity of released LPL. PPARα reduces LPL secretion and decreases
macrophage uptake of glycated LDL (101). FAO is also induced
in macrophages, as in liver. CPT-1 expression is upregulated by
PPARα ligands, decreasing the FA pool available for cholesterol
Some of the later steps of atherosclerosis are also regulated by
PPARα. Activation of SMC proliferation is a key event in ath-
erosclerosis development and its complications. Upon vascular
injury, SMCs migrate from the media into the neointimal layer
of the vascular wall, where they proliferate and synthesize pro-
teoglycans, leading to intimal hyperplasia. SMC proliferation
is also one of the primary mechanisms underlying restenosis,
an occlusive complication of corrective angioplasty procedures.
PPARα inhibits SMC proliferation by blocking G1/S cell cycle
transition, through the induction of the cyclin-dependent
kinase inhibitor p16. This results in SMC growth inhibition and
reduced neointima formation in a mouse model of carotid artery
injury (103). The migration of SMCs requires the degradation of
the extracellular matrix by MMPs. Among them, MMP-9 con-
tributes significantly to SMC migration, and its expression is
reduced by PPARα (104). Furthermore, by inhibiting the expres-
sion of tissue factor, a major procoagulant, PPARα may block
atherothrombosis (105, 106).
PPARα modulates hepatic inflammation
Fibrates decrease the level of CRP, a major acute-phase protein
stimulated by IL-1 and IL-6 and a risk factor for cardiovascular
disease. Synthesized in the liver, PPARα ligands suppress CRP
expression through an indirect transcriptional mechanism (19).
The expression of fibrinogen-α and -β and of serum amyloid A
is repressed in a similar fashion (107). Thus PPARα acts as an
antiatherogenic factor by modulating local and systemic inflam-
matory responses, as well as lipid homeostasis in cell types that
constitute the atherosclerotic plaque.
Animal models of PPARα action in atherosclerosis
Despite a wealth of evidence documenting antiatherogenic prop-
erties of PPARα ligands in vitro, mouse models have yielded con-
tradictory results, which are furthermore difficult to extrapolate
to human disease. First, mice are notoriously resistant to ath-
erosclerosis, and only an aggressive diet rich in fat, cholesterol,
and cholate and/or genetic manipulation, such as knockout of
apoE or LDL receptor genes or knock-in of human apoE2, yields
models that mimic some features of human dyslipidemia and
atherosclerosis. Here again, the literature points to inconsisten-
cies between effects of PPARα agonists and the phenotype of
PPARα-deficient mice. In the apoE–/– background, PPARα defi-
ciency was shown to protect mice from atherosclerosis, hinting
at a proatherogenic role of PPARα (74). However, apoE–/– mice fed
a Western diet developed atherosclerotic lesions that regressed
moderately upon fenofibrate treatment, an effect accentuated
in the apoE–/– strain expressing a human apoA-I transgene (89).
In LDL receptor–deficient mice, another model of hypercho-
lesterolemia, GW7647, a highly active PPARα agonist, strongly
decreases lesion formation (90). Similarly, in the apoE2 knock-in
mouse, a model of mixed dyslipidemia, fenofibrates also lower
lesion size (92). While these few examples highlight the inequi-
ties of knockout studies and agonist treatment, they also allude
?The?Journal?of?Clinical?Investigation http://www.jci.org Volume 116 Number 3 March 2006
to the distinct pharmacokinetic properties of PPARα ligands.
Fibrates are known to act preferentially in the liver and are low-
affinity ligands for PPARα, whereas high-affinity ligands such as
Wy14,643 and GW7647 are suspected of acting more efficiently
in peripheral tissues. These discrepancies may also arise from dif-
ferences in mouse and human lipid metabolism. In mice, HDL is
the main transporter of cholesterol, whereas LDL is the principal
carrier in humans. In addition, interspecies variation of the mode
of regulation of metabolic genes may be considerable, as men-
tioned for the apoA-I gene. It is also worth noting that PPARα
has species-specific functional (39) and ligand-binding proper-
ties (108–110), so caution must be used in extrapolating data
from the murine to the human situation.
Animal models are also used to identify PPARα-regulated
pathologies other than atherosclerosis. For example, pretreat-
ment of rats or mice with PPARα agonists protects the heart
from reperfusion injury induced by coronary occlusion (111,
112). Cerebral ischemia is also a major cause of stroke, and pre-
ventive treatment by fibrates reduces the susceptibility of mice to
stroke and decreases cerebral infarct size (113, 114). These studies
point to a potential preventive application of PPARα ligands in
such pathologies and, interestingly, expand the biological roles
of PPARα to other organs.
Clinical consequences of PPARα activation
The actions of fibrates in humans have been tested in several clini-
cal studies. Treatment with fibrates, such as fenofibrate, improves
endothelial dysfunction in patients with type 2 diabetes (115). Evi-
dence that PPARα signaling is critical in the progression of athero-
sclerotic lesion formation in humans is provided by coronary angi-
ography in both nondiabetic and diabetic patients. A decreased
atherosclerosis progression was observed with gemfibrozil in
the Lopid Coronary Angiography Trial, with bezafibrate in the
Bezafibrate Coronary Atherosclerosis Intervention Trial, and with
fenofibrate in the Diabetes Atherosclerosis Intervention Study
(116–118). More importantly, the influence of fibrate treatment
on cardiovascular morbidity and mortality was studied in primary
(Helsinki Heart Study; FIELD) and secondary (Bezafibrate Infarc-
tion Prevention; Veterans Affairs High-Density Lipoprotein Choles-
terol Intervention Trial; FIELD) prevention studies (88, 119–121).
In the Helsinki Heart Study, cardiovascular disease risk reduction
upon gemfibrozil treatment was most pronounced in overweight
patients with metabolic syndrome or diabetes and atherogenic dys-
lipidemia (122, 123). In the Bezafibrate Infarction Prevention trial,
reduction in coronary events with bezafibrate was observed only
in patients with serum TG concentrations greater than 200 mg/dl
(119), whereas the Veterans Affairs High-Density Lipoprotein Cho-
lesterol Intervention Trial showed the most significant benefits of
gemfibrozil in diabetics or in nondiabetics with high insulin levels
(124). Altogether, these observations indicate that fibrates are par-
ticularly useful to treat the cardiovascular risk in insulin-resistant
prediabetic individuals, and in diabetic patients with dyslipidemia.
The most recent results come from the FIELD study (88), a com-
bined primary and secondary prevention study testing the effects
of fenofibrate on coronary heart disease in 9,795 type 2 diabetes
patients who had no indication for lipid-lowering therapy. The
primary endpoints, death from coronary heart disease or nonfatal
myocardial infarction, were decreased, although not significantly,
by 11% (mean follow-up, 5 years). However, during the course of
the study, there was a gradual increase in statin use, which was
greater in the placebo group than in the fenofibrate group. Since
statins can decrease cardiovascular risk in type 2 diabetic patients
(125), the actual benefit of fenofibrate thus may be underestimat-
ed because of the higher use of statins in the placebo arm. After
correction for the statin effect, it was estimated that fenofibrate
treatment resulted in a 19% reduction of relative risk of the pri-
mary endpoints. The benefits of fenofibrate were mainly due to
reductions in nonfatal myocardial infarction and coronary revas-
cularization. Moreover, fenofibrate treatment reduced microvascu-
lar complications (such as progression to microalbuminuria and
intervention for retinopathy); this was not explained by changes
in blood glucose control. Finally, the FIELD trial does not sug-
gest that there are safety issues associated with fenofibrate-statin
combination therapy. The major unanswered question is whether
fenofibrate treatment confers additional benefit when given on
top of a statin. This issue will be addressed in the ongoing Action
to Control Cardiovascular Risk in Diabetes (ACCORD) study, the
results of which are expected in early 2010 (S21).
The use of the PPARα agonists, fibrates, as hypolipidemic agents
for several decades has demonstrated their safety and efficacy
for lipid lowering, an important parameter in the prevention of
cardiovascular diseases. Moreover, increasing evidence attribut-
ing antiinflammatory activities to PPARα emerges, documented
largely in in vitro and animal studies. Prediabetic metabolic syn-
drome patients with atherogenic dyslipidemia (inflammation, low
HDL, high TG, and sdLDL) are highly susceptible to cardiovascu-
lar morbidity and respond extremely well to fibrate treatment. In
type 2 diabetics, fibrate treatment was recently demonstrated to
reduce nonfatal myocardial infarction and coronary revasculariza-
tion, suggesting beneficial effects of these drugs in these patients.
Whether activation of PPARα has detrimental effects in the hearts
of diabetic patients, as observed after PPARα overexpression
in mouse cardiomyocytes, is unclear. However, at present, there
is no indication that fibrate treatment would increase chronic
heart insufficiency in humans; this points to possibly distinct
responses of humans versus mice to chronic stimulation of car-
diac metabolism by PPARα activators. This view is strengthened
by the fact that PPARα activators exert species-specific activities
and may induce peroxisome proliferation in mouse hearts, which
could increase oxidative stress. Additionally, these species-specific
responses are illustrated by the observation that fibrate treatment
does not perturb glucose homeostasis in humans, although a
negative effect could have been predicted from mouse data show-
ing that PPARα overexpression in skeletal muscle provokes insulin
resistance. PPARα activators appear to be particularly indicated to
treat dyslipidemia of the metabolic syndrome and type 2 diabetes,
although adverse effects on cardiac and skeletal muscle should
be monitored in the development of novel, more potent PPARα
activators. Promising future developments undoubtedly lie in the
field of selective PPARα modulators (SPPARMs).
Note: References S1–S21 are available online with this article;
Address correspondence to: Bart Staels, U.R. 545 INSERM–Insti-
tut Pasteur de Lille, 1 rue du Professeur Calmette, BP245, 59019
Lille, France. Phone: 33-320-87-73-88; Fax: 33-320-87-71-98;
578? The?Journal?of?Clinical?Investigation http://www.jci.org Volume 116 Number 3 March 2006
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