Clin Chem Lab Med 2000; 38(1):3–11 © 2000 by Walter de Gruyter · Berlin · New York
Review
Regulation of Lipid and Lipoprotein Metabolism by PPAR Activators
Philippe Gervois, Inés Pineda Torra, Jean-Charles
Fruchart and Bart Staels
Département d’Athérosclérose, INSERM U.325, Institut
Pasteur de Lille et Faculté de Pharmacie, Université de
Lille II, Lille, France
The peroxisome proliferator-activated receptors
(PPARs) are ligand-activated transcription factors be-
longing to the nuclear hormone receptor superfamily.
PPARa, the first identified PPAR family member, is
principally expressed in tissues exhibiting high rates of
b-oxidation such as liver, kidney, heart and muscle.
PPARg, on the other hand, is expressed at high levels
in adipose tissue. PPARs are activated by dietary fatty
acids and eicosanoids, as well as by pharmacological
drugs, such as fibrates for PPARa and glitazones for
PPARg. PPARa mediates the hypolipidemic action of fi-
brates in the treatment of hypertriglyceridemia and
hypoalphalipoproteinemia. PPARa is considered a ma-
jor regulator of intra- and extracellular lipid metabo-
lism. Upon fibrate activation, PPARa down-regulates
hepatic apolipoprotein C-III and increases lipoprotein
lipase gene expression, key players in triglyceride me-
tabolism. In addition, PPARa activation increases
plasma HDL cholesterol via the induction of hepatic
apolipoprotein A-I and apolipoprotein A-II expression
in humans. Glitazones exert a hypotriglyceridemic ac-
tion via PPARg-mediated induction of lipoprotein li-
pase expression in adipose tissue. PPARs play also a
role in intracellular lipid metabolism by up-regulating
the expression of enzymes involved in conversion of
fatty acids in acyl-coenzyme A esters, fatty acid entry
into mitochondria and peroxisomal and mitochondrial
fatty acid catabolism. These observations have pro-
vided the molecular basis leading to a better under-
standing of the mechanism of action of fibrates and
glitazones on lipid and lipoprotein metabolism and
identify PPARs as attractive targets for the rational de-
sign of more potent lipid-lowering drugs.
Key words: Nuclear receptors; Fibrates; Lipoprotein
metabolism.
Abbreviations: ACO acyl-CoA oxidase; ACS acyl-CoA
synthetase; apo apolipoprotein; CAD coronary artery
disease; FA fatty acid; FAS fatty acid synthase; FATP
fatty acid transport protein; HDL high density lipopro-
tein; LCAT lecithin:cholesterol acyltransferase; LDL
low density lipoprotein; LPL lipoprotein lipase; oxLDL
oxidized low density lipoprotein; PPARs peroxisome
proliferator-activated receptors; PPRE peroxisome
proliferator response element; RXR retinoic X recep-
tor; SR-BI scavenger receptor BI; TG triglycerides;
Brought to you by | University of Arizona
Authenticated
Download Date | 5/28/15 10:38 AM
UCPs uncoupling proteins; VLDL very low density
lipoprotein.
Introduction
Numerous epidemiological and intervention studies
have firmly established the causative relationship be-
tween dyslipidemia and coronary artery disease (CAD).
Hypercholesterolemia (high LDL-cholesterol levels) is
considered a major risk factor for CAD (1, 2). Hypoal-
phalipoproteinemia (low plasma HDL), alone or com-
bined with hypertriglyceridemia, constitutes another
important risk factor as well (3). Furthermore, elevated
plasma triglyceride levels have been recently identified
as an independent factor associated with increased
mortality in patients with established CAD (4). Fibrates
are hypolipidemic drugs currently used in the treat-
ment of dyslipidemia (5). Coronary angiography trials
have demonstrated that administration of fibrates re-
duces the progression of CAD (6, 7). Results from the
recently published Veterans Affairs High-Density
Lipoprotein Cholesterol Intervention Trial, a secondary
prevention trial with the fibrate derivative gemfibrozil,
demonstrated a highly significant reduction in cardio-
vascular events in patients with low baseline HDL-C
concentrations treated with gemfibrozil (8).
Although fibrates have been widely used in clinical
practice as hypolipidemic drugs, their mechanism of
action was only recently elucidated. Fibrates also be-
long to a class of compounds termed peroxisome pro-
liferators which are able to induce peroxisome prolifer-
ation and hepatomegaly resulting, after long-term
treatment, in hepatocarcinogenesis in rodents (9). This
effect is accompanied by the transcriptional induction
of genes implicated in peroxisomal β-oxidation and oc-
curs through activation of specific transcription factors
named peroxisome proliferator-activated receptors
(PPARs) (10, 11). Although the induction of peroxisome
proliferation by fibrates in rodents requires PPARα (12),
activation of PPARα by fibrates does not lead to perox-
isome proliferation in humans. By contrast, PPARα ac-
tivators exert potent lipid lowering activities. Results
from studies conducted over the past five years have
identified PPARs as key regulators of lipid and lipopro-
tein metabolism and as mediators of lipid effects of fi-
brate and glitazone action (13). In this report, we will re-
view recent advances on the role of PPARs in lipid and
lipoprotein metabolism.
4 Gervois et al.: Role of PPARs in lipid and lipoprotein metabolism
PPARs: Transcription Factors and Nuclear Receptors
PPARs are members of the nuclear hormone receptor
superfamily and are ligand-activated transcription fac-
tors (13) involved in translating the effects of lipid solu-
ble factors such as hormones, vitamins, fatty acids (FA)
and various drugs into the gene expression level.
Three distinct PPARs, α, β(δ) and γ, each encoded by a
separate gene and displaying different tissue (14–17)
and developmental (18) expression patterns, have
been identified. PPARα is preferentially expressed in
liver, heart and kidney while PPARγ is expressed at high
levels in adipose tissue. All PPARs are furthermore also
expressed, to variable extents, in a wide variety of
other cells and tissues. Whereas PPARα modulates the
transcription of genes implicated in lipid and lipopro-
tein metabolism in liver (5), PPARγ mediates adipogen-
esis (19). Recent findings suggest that PPARγ activation
induces the terminal differentiation of human breast
cancer cells (20) and may modulate the development of
colorectal cancer (21–23). PPARs are activated by nat-
ural ligands derived from FAs such as 8(S) hydroxye-
icosatetraenoic acid, 8(S) hydroxyeicosapentaenoic
acid and leukotriene B4 for PPARα (24) and
prostaglandin-J2 and components of oxidized low-
density lipoprotein (oxLDL) for PPARγ (24, 25). More-
over, hypolipidemic drugs of the fibrate class and an-
tidiabetic glitazones constitute synthetic ligands for
PPARα and PPARγ respectively (24). Natural and syn-
thetic ligands have also been identified for PPARδ (26,
27). Following ligand binding, PPAR interacts with the
retinoic X receptor (RXR) to form a PPAR/RXR het-
erodimeric complex which binds to a specific response
element, termed peroxisome proliferator response ele-
ment (PPRE), located in the regulatory region of target
genes (Figure 1). Although the majority of PPREs iden-
tified so far consist of a direct repeat of the canonical
AGGTCA sequence spaced by 1 nucleotide (DR-1) (13),
DR-2 elements may also function as PPRE (28). PPARs
positively regulate target genes through this DNA bind-
ing dependent mechanism. In addition, PPARs have
been shown to repress gene transcription in a DNA
binding independent manner. PPARs interfere with the
NF-κB, STAT and AP-1 transcription pathways, proba-
bly due to protein-protein interaction between the tran-
scription factors leading to the formation of inactive
complexes (29–34) (Figure 1). The interactions between
PPARα with Jun and p65, partners of the AP-1 and NF-
κB transcription factor complexes respectively, result
in the inhibition of AP-1 and NF-κB protein binding to
their respective response elements (33, 34).
PPAR activity may be regulated at the transcrip-
tional, post-transcriptional and at the protein level. In
rats, PPARα expression is regulated by hormones, such
as glucocorticoids, insulin and leptin, by physiological
stimuli such as stress and fasting and follows a diurnal
rhythm (35–40). Although little is known about factors
regulating PPARα expression in humans, the observa-
tion that PPARα expression in liver varies significantly
among individuals (41, 42) suggests that PPARα is also
strongly regulated at the gene level in humans by ge-
Brought to you by | University of Arizona
Authenticated
Download Date | 5/28/15 10:38 AM
Fig. 1 Mechanism of transcriptional gene regulation by
PPARs.
Activated PPARs form a heterodimeric complex with the
retinoic X receptor (RXR) which subsequently binds to a PPRE
located within the regulatory sequence of target genes and
therefore inducing gene transcription. PPARs negatively regu-
late gene transcription through protein-protein interaction
leading to interference with the STAT (not represented for the
clarity of the figure), NF-ΚB and Fos/Jun pathways.
netic and environmental factors. The transcriptional
regulation of PPARγ occurs at least in part, through the
use of alternative promoters, which results, both in ro-
dents and humans (43, 44), in the production of two
distinct proteins, PPARγ1 and PPARγ2, with distinct ac-
tivation capacities (45). In addition, glucocorticoids are
implicated in the regulation of PPARγ expression dur-
ing differentiation of 3T3-L1 preadipocytes (46).
Finally, PPAR activity may be modulated at the pro-
tein level. Protein phosphorylation constitutes a com-
mon post-translational mechanism of regulation. Both
PPARα and PPARγ are regulated by physiological phos-
phorylation, thus affecting their transactivation poten-
tial, and modulating their biological functions (47–52).
The production of isoforms with repressive activity on
the wild type receptor represents another mechanism
of regulation of PPAR signalling occurring at the pro-
tein level. Such an isoform, resulting from alternative
splicing and giving rise to a truncated protein, has been
identified for PPARα (41, 42). This variant acts in a lig-
and independent manner and alters PPARα wild type
transcriptional capacity.
Regulation of Intracellular Lipid Metabolism by PPARs
PPARα plays a key role in intracellular FA metabolism
(Figure 2). High level of PPARα expression is observed
in tissues with elevated FA catabolism. PPARα regu-
lates the expression of genes coding for enzymes im-
plicated in the peroxisomal β-oxidation pathway such
as acyl-CoA oxidase (ACO), multi-functional enzyme
and 3 ketoacyl-CoA thiolase (13). Moreover, these en-
zymes have been shown to influence PPARα ligand me-
tabolism (53, 54). PPARα also modulates genes in-
volved in FA uptake, activation to acyl-CoA esters,
mitochondrial β-oxidation and ketone body synthesis
(13, 55). Intracellular FA concentrations are controlled,
in part, by the activity of the FA transport protein
 Gervois et al.: Role of PPARs in lipid and lipoprotein metabolism 5

FA flux from peripheral tissues, such as adipose tissue,

Fig. 2 PPARα enhances FA catabolism by inducing genes
(bold) involved in FA uptake (FATP), esterification (ACS) and β-
oxidation (β-ox). PPARα activation enhances FA β-oxidation
and therefore diminishes the FA pool to be incorporated into
TG-rich lipoproteins. Consequently, PPARα stimulates lipid
flux by controlling the FA flux from peripheral tissues such as
adipose tissue to the liver.
Bold arrows indicate pathways enhanced by PPARα activa-
tors. FA, fatty acid; TG, triglycerides; LPL, lipoprotein lipase;
FAS, FA synthase.
to the liver (Figure 2). Interestingly, it is likely that
PPARα plays also a role in adipose tissue as a mediator
of leptin-induced lipolysis (37). Indeed, hyperleptine-
mia in rodents depletes adipocyte fat, while it up-regu-
lates FA oxidation enzymes, UCPs and PPARα, which is
normally low in adipocytes.
Whereas PPARα is involved in hepatic lipid metabo-
lism, PPARγ modulates lipid homeostasis through its
function in adipose tissue. Several key genes for
adipocyte differentiation and lipid storage contain a
PPRE. Gene expression of aP2 (66), phosphoenol pyru-
vate carboxykinase (67), ACS (68, 69), FATP (56) and
LPL (70) is regulated by PPARγ. The induction of LPL
promotes FA delivery to adipocytes while induction of
FATP and ACS results in enhanced FA uptake by the
adipocyte. These actions contribute to enhanced TG
synthesis and accumulation in adipose tissue suggest-
ing that PPARγ activation maintains the mature
adipocyte phenotype and participates in lipid home-
ostasis.
Regulation of Lipoprotein Metabolism by PPARs

Metabolic effects of PPAR activators

(FATP), which controls the entry of FA through the cell
Studies carried out both in rodents and humans led to
membrane, and by acyl-CoA synthetase (ACS) which
the establishment of four major metabolic pathways
traps FA inside the cells by their conversion to ester de-
affected by fibrates and explaining their effects on
rivatives. PPARα activation mediates the induction of
lipoprotein metabolism (Figure 3). These are: (1) Induc-
FATP expression in liver and intestine and the up-regu-
tion of lipoprotein lipolysis as a result of either an in-
lation of ACS expression in liver and kidney (56). The
crease in intrinsic lipoprotein lipase activity or an in-
implication of PPARα in FA transport was further
creased accessibility of TG-rich lipoprotein particles for
demonstrated by the lack of induction of FATP and FA
lipolysis due to reduced TG-rich lipoprotein apo C-III
translocase mRNA in liver by PPARα activators in
content (71, 72). (2) Limitation of hepatic TG synthesis
PPARα-null mice (57).
and VLDL production due to increased FA uptake, en-
FA metabolism is regulated by the rate of mitochon-
hanced FA catabolism and reduced FA synthesis (56,
drial FA uptake. PPAR α has been demonstrated to af-
68, 73). (3) Increase in LDL particle removal as a result
fect FA import into mitochondria by up-regulating the
of changes in plasma LDL composition and subsequent
expression of muscle- (58–60) and liver-type α-carni-
increase in LDL affinity for its receptor leading to en-
tine palmitoyltransferase I genes (39). Interestingly,
hanced LDL catabolism (74). (4) Increase in HDL pro-
specific inhibition of mitochondrial FA import in
duction and stimulation of reverse cholesterol trans-
PPARα-null mice causes hepatic and cardiac lipid accu-
port.
mulation, hypoglycemia and death in 100% of males
Fibrates increase the production of apolipoprotein
and 25% of females (61). Furthermore, PPARα-deficient
A-I and A-II in human liver (13, 75–77), which leads to
mice fed a high fat diet showed a massive accumula-
tion of lipids in liver (39, 62) highlighting the crucial role
PPARα plays in lipid metabolism. A concordant pheno-
type was observed in PPARα-deficient mice fasted for
24 hours who displayed hypoglycemia, hypoketone-
mia, and elevated plasma FA levels (39). Recent studies
revealed that PPARα might increase energy expendi-
ture by up-regulating the expression of uncoupling
proteins (UCPs) (63–65). These data strongly argue in
favour of a critical role for PPARα in the regulation of
lipid metabolism. Through their effect on the expres-
sion of FA transporter and FA oxidation genes, PPARα
activators direct the FA flux to the β-oxidation pathway
and therefore diminish the FA pool to be incorporated
to triglyceride (TG)-rich lipoproteins. Consequently, Fig. 3 Metabolic effects of fibrates on lipid and lipoprotein
PPARα maintains lipid homeostasis by controlling the metabolism.

Brought to you by | University of Arizona

Authenticated
Download Date | 5/28/15 10:38 AM
6 Gervois et al.: Role of PPARs in lipid and lipoprotein metabolism
increased plasma HDL concentrations and enhanced
reverse cholesterol transport.
Glitazones, antidiabetic agents, are primarily studied
for their effect on glucose homeostasis. Nevertheless,
these drugs exert hypotriglyceridemic action both in
rodents and in humans by increasing lipolysis and
clearance of TG-rich lipoproteins (78–83). This effect
may be attributed, at least in part, to the induction of
adipose tissue LPL expression (70, 84).
PPARs and TG metabolism
The role of PPARs in TG metabolism is convincingly es-
tablished (13). The hypotriglyceridemic effect of PPARα
activators is the result of increased lipoprotein lipolysis
and enhanced FA oxidation. The process of TG clear-
ance is directly under the control of LPL and apo C-III.
PPARα activators repress apo C-III expression (85, 86)
and induce LPL in liver (70) (Figure 4). Moreover,
PPARα enhances FA catabolic rate, which subsequently
affects TG synthesis and VLDL production (13).
PPARα plays a central role in hepatic apo C-III gene
regulation as demonstrated using PPARα-deficient
mice (87). Hepatic apo C-III gene transcription is con-
trolled by numerous nuclear receptors, such as HNF-4,
ARP-I, Ear/COUP-TF (88) and RXRα (88, 89). HNF-4,
RXRα and PPARα can activate apo C-III transcription
through a common DNA binding site of the upstream
regulatory region of the apo C-III gene, whereas ARP-1
and Ear/COUP-TF function as repressors of transcrip-
tion. Several mechanisms may be involved to explain
the effects of fibrates on apo C-III gene regulation. First,
the repression of apo C-III gene expression by fibrates
might be the result of a competition between transcrip-
tion factors. Substitution of the strong activator HNF-4
by a less active PPAR/RXR complex may explain a re-
duction of apo C-III transcriptional activity. The fine-
tuning of apo C-III regulation will then depend on the
relative abundance of PPARα and HNF-4. Against this
hypothesis is the observation that the RXR homodimer
Fig. 4 Implication of PPARα in the transcriptional regulation
of human genes involved in lipoprotein metabolism. A-I, A-II
and C-III, apolipoproteins; LPL, lipoprotein lipase; HDL, high-
density lipoprotein; TG, triglycerides; PPRE, peroxisome pro-
liferator response element. (+), activation of transcription; (–)
repression of transcription.
Brought to you by | University of Arizona
Authenticated
Download Date | 5/28/15 10:38 AM
is also able to increase apo C-III expression (89). Sec-
ond, apo C-III repression by fibrates might occur via
PPARα-dependent enhanced expression of a negative
regulator of transcription. Fibrates induce the hepatic
expression of human and rat Rev-erbα, a nuclear or-
phan receptor which is a strong repressor of transcrip-
tion (28, 90). The induction of Rev-erbα is mediated by
PPARα which interacts with a PPRE located within the
human Rev-erbα promoter (28). Such a mechanism is
consistent with the observation that Rev-erbα-deficient
mice exhibit increased plasma TG and apo C-III con-
centrations and elevated hepatic apo C-III mRNA levels
(91). Finally, as already shown for other target genes
(29, 32, 92, 93), PPARα might repress transcription of
apo C-III by interacting with other transcription factors
leading to the formation of inactive complexes thereby
limiting the induction of apo C-III expression. Further
studies are required to elucidate the exact role of
PPARα in the regulation of apo C-III gene expression.
The induction by glitazones of LPL gene expression
in adipocytes (70) is mediated by PPARγ, which inter-
acts with a PPRE present both in the rodent and human
LPL promoter (70). The increase in LPL production will
enhance clearance of plasma TGs and FA delivery to
the adipose tissue. This mechanism of action likely
constitutes the basis for the hypotriglyceridemic action
of PPARγ activators.
PPARs and HDL metabolism
Both apo A-I and HDL are inversely correlated with the
incidence of CAD (94). There is evidence supporting the
protective role of HDL through the removal and the re-
cycling of cholesterol excess from peripheral tissues to
liver. PPARα appears to be the major isoform impli-
cated in HDL metabolism. PPARα activators affect HDL
metabolism in an opposite manner in rodents and hu-
mans. Whereas fibrate treatment of rats lowers plasma
HDL, an increase is generally observed in humans
(95–97). Such an increase in HDL plasma levels is re-
lated, at least in part, to changes in apo A-I and apo A-II
gene expression in liver (Figure 4). Apo A-I and apo A-
II gene transcription is up-regulated in humans by
PPARα activators (75–77). By contrast, these genes are
repressed in rodents (77, 98). Recent studies in trans-
genic mice lacking PPARα univocally confirmed the im-
plication of PPARα in the regulation of apo A-I and HDL
metabolism in rodent species (87, 99). Basal plasma
HDL cholesterol, hepatic apo A-I mRNA and apo A-I
plasma levels are higher in PPARα-deficient mice, com-
pared to wild type control mice. Treatment with fibrates
lowered both hepatic apo A-I mRNA levels and apo A-I
plasma levels in wild type mice, whereas no effect was
observed in PPARα-deficient mice. Studies on the reg-
ulation of hepatic apo A-I gene expression, carried out
in human apo A-I transgenic mice, demonstrated an in-
duction of plasma HDL and human apo A-I concentra-
tions by fibrates (77). It was shown that the effects on
human apo A-I mRNA levels are due to an enhanced
transcription rate. Moreover, treatment of human pri-
mary hepatocytes with fibrates increases mRNA levels
 Gervois et al.: Role of PPARs in lipid and lipoprotein metabolism
and secretion of apo A-I, supporting the hypothesis
that a direct action of fibrates on liver human apo A-I
expression results in an increase in plasma apo A-I and
HDL-cholesterol. To determine whether fibrates in-
crease HDL and apo A-I concentrations without induc-
ing hepatomegaly and peroxisome proliferation, their
effects were tested in rabbits, an animal model more
resistant to peroxisome proliferation than rodents
(100). In normal rabbits, plasma A-I levels remain un-
changed upon fibrate treatment. By contrast, adminis-
tration of fibrates to transgenic human apo A-I rabbits
results in increased plasma HDL and human apo A-I
concentrations due to the induction of human apo A-I
gene expression in liver (100). These actions occured
independently of alterations in TG concentrations and
without affecting liver weight or peroxisomal acyl-CoA
oxidase activity. These data demonstrate a direct ac-
tion of PPARα activators on apo A-I expression result-
ing in increased human apo A-I concentrations and
HDL plasma levels and decreased plasma apo A-I and
HDL-cholesterol in rodents. The beneficial effects of fi-
brates on plasma lipoprotein homeostasis can thus oc-
cur dissociated from potentially deleterious peroxi-
some proliferation.
The molecular mechanism underlying the gene reg-
ulation of apo A-I by fibrates was elucidated by VuDac
et al. (76). The authors demonstrated a direct involve-
ment of PPARα in the control of apo A-I gene transcrip-
tion since PPARα binds to a PPRE located in the A site
of the human apo A-I gene promoter (Figure 5). In ro-
dents, the mechanism of negative regulation of apo A-
I gene expression by fibrates appears to be more com-
plex. The lack of rat apo A-I transcriptional induction is
due to 3 nucleotide differences between the rat and the
human apo A-I promoter A sites which prevent PPARα
from binding to the rodent A site (90). By contrast, Rev-
erbα binds to a negative response element adjacent to
the TATA box present only in the rat apo A-I promoter,
but which is lacking in the human apo A-I promoter
(90). Since fibrates induce rev-erbα expression, rodent
apo A-I expression may be repressed via this mecha-
nism. The results from these studies allowed the eluci-
dation of the mechanisms explaining the opposite reg-
ulation of human vs. rodent apo A-I in response to
fibrate through the implication of Rev-erbα and PPARα.
These data provide new insight into the negative regu-
Fig. 5 Scheme summarizing our current understanding of
the species-specific regulation of apo A-I gene transcription
by fibrates.
Brought to you by | University of Arizona
Authenticated
Download Date | 5/28/15 10:38 AM
7
lation of gene expression by fibrates, namely the in-
duction of expression of a negative regulator of gene
transcription.
Fibrates also influence the expression of human apo
A-II, the other major protein constituent of HDL (75).
Administration of fenofibrate to patients with CAD re-
sults in a marked increase in plasma apo A-II concen-
trations. This increase in plasma apo A-II is due to a di-
rect effect on hepatic apo A-II production, since fibrates
induce apo A-II mRNA levels both in primary cultures
of human hepatocytes and in human hepatoblastoma
HepG2 cells (75). The induction of apo A-II mRNA levels
is followed by an increase in apo A-II secretion in both
cell culture systems. PPARα binds with high affinity to
a DR-1-type PPRE located in the human apo A-II pro-
moter, thereby activating apo A-II gene transcription.
These data demonstrate that fibrates increase human
apo A-II plasma levels by stimulating transcription of
its gene through the interaction of activated PPARα
with the apo A-II-PPRE.
In addition to influencing the transcription of HDL
apolipoproteins, fibrates also affect the expression of
enzymes and receptors regulating HDL metabolism. In
rats, fibrates decrease the production of both the major
HDL apolipoproteins as well as of HDL-remodelling en-
zymes, such as hepatic lipase and lecithin:cholesterol
acyltransferase (LCAT) (101–103). Furthermore, PPAR
agonists regulate the expression of HDL receptors.
Murine scavenger receptor BI (SR-BI) and its human
homologue CLA-1 have been identified as HDL recep-
tors, which bind HDL with high affinity and mediate the
selective uptake of cholesteryl esters in liver and
steroidogenic tissues (104, 105). In addition, studies
demonstrating that the rate of cholesterol efflux medi-
ated by HDL or serum is correlated with cellular SR-BI
expression levels (106) suggest that SR-BI may pro-
mote cholesterol removal from peripheral cells includ-
ing macrophages. Therefore, SR-BI/CLA-1 may play a
role in the transport of cholesterol by HDL from periph-
eral tissues to the liver, which is known as the reverse
cholesterol transport pathway (107). Interestingly,
since PPARs are expressed in human macrophages
(108), the regulation of CLA-1/SR-BI by PPAR activators
was recently investigated (109). Treatment of differen-
tiated human macrophages with PPAR activators re-
sulted in the induction of CLA-1 expression. Further-
more, SR-BI is induced in aortas of apo E-deficient mice
upon treatment with PPAR activators. Together this
data point to a major role of PPARs in the regulation of
HDL metabolism.
Conclusion
Investigations over the last five years have consider-
ably improved our knowledge on the metabolic conse-
quences of the activation of the PPAR signalling path-
ways. The important role of PPARs in regulating lipid
and lipoprotein metabolism and in mediating the ac-
tions of pharmacological compounds is becoming
more precisely understood, even though the mecha-
8 Gervois et al.: Role of PPARs in lipid and lipoprotein metabolism
nism of negative regulation of certain genes such as
apo C-III by PPARs requires further mechanistic stud-
ies. Taking into account the effects that currently clini-
cally used PPAR activators have on energy and lipid
homeostasis, PPARs can be considered as promising
pharmacological targets for the rational development
of novel compounds useful in the treatment of dyslipi-
demia and related disorders.
References
1. Randomised trial of cholesterol lowering in 4444 patients
with coronary heart disease: the Scandinavian Simvas-
tatin Survival Study (4S). Lancet 1994; 344:1383–9.
2. Shepherd J, Cobbe SM, Ford I, Isles C, Lorimer A, Mac-
Farlane P, et al.Prevention of coronary heart disease with
pravastatin in men with hypercholesterolemia. West
Scotland Coronary Prevention Study Group. N Engl J
Med 1995; 333:1301–7.
3. Saku K, Zhang B, Ohta T, and Arakawa K. Quantity and
function of high density lipoprotein as an indicator of
coronary atherosclerosis. J Am Coll Cardiol 1999;
33:436–43.
4. Haim M, Benderly M, Brunner D, Behar S, Graff E, Re-
icher-Reiss H, et al. Elevated serum triglyceride levels and
long-term mortality in patients with coronary heart dis-
ease: the Bezafibrate Infarction Prevention (BIP) Registry.
Circulation 1999; 100:475–82.
5. Staels B, Dallongeville J, Auwerx J, Schoonjans K, Leit-
ersdorf E, and Fruchart JC. Mechanism of action of fi-
brates on lipid and lipoprotein metabolism. Circulation
1998; 98:2088–93.
6. Ericsson CG, Hamsten A, Nilsson J, Grip L, Svane B, and
de Faire U. Angiographic assessment of effects of bezafi-
brate on progression of coronary artery disease in young
male postinfarction patients. Lancet 1996; 347:849–53.
7. Frick MH, Syvanne M, Nieminen MS, Kauma H, Majahalme
S, Virtanen V, et al. Prevention of the angiographic pro-
gression of coronary and vein-graft atherosclerosis by
gemfibrozil after coronary bypass surgery in men with low
levels of HDL cholesterol. Lopid Coronary Angiography
Trial (LOCAT) Study Group. Circulation 1997; 96:2137–43.
8. Rubins HB, Robins SJ, Collins D, Fye CL, Anderson JW,
Elam MB, et al. Gemfibrozil for the secondary prevention
of coronary heart disease in men with low levels of high-
density lipoprotein cholesterol. Veterans Affairs High-
Density Lipoprotein Cholesterol Intervention Trial Study
Group. N Engl J Med 1999; 341:410–8.
9. Reddy J, and Qureshi S. Tumorigenicity of the hypolipi-
daemic peroxisome proliferator ethyl-alpha-p-chlorophe-
noxyisobutyrate (clofibrate) in rats. Br J Cancer 1979;
40:476–82.
10. Issemann I, and Green S. Activation of a member of the
steroid hormone receptor superfamily by peroxisome
proliferators. Nature 1990; 347:645–50.
11. Vanden Heuvel JP. Peroxisome proliferator-activated re-
ceptors: a critical link among fatty acids, gene expression
and carcinogenesis. J Nutr 1999; 129:575S-80S.
12. Lee SS, Pineau T, Drago J, Lee EJ, Owens JW, Kroetz DL,
et al. Targeted disruption of the alpha isoform of the per-
oxisome proliferator-activated receptor gene in mice re-
sults in abolishment of the pleiotropic effects of peroxi-
some proliferators. Mol Cell Biol 1995; 15:3012–22.
13. Schoonjans K, Staels B, and Auwerx J. The peroxisome
proliferator activated receptors (PPARs) and their effects
Brought to you by | University of Arizona
Authenticated
Download Date | 5/28/15 10:38 AM
on lipid metabolism and adipocyte differentiation.
Biochim Biophys Acta 1996; 1302:93–109.
14. Cullingford TE, Bhakoo K, Peuchen S, Dolphin CT, Patel R,
and Clark JB. Distribution of mRNAs encoding the perox-
isome proliferator-activated receptor alpha, beta, and
gamma and the retinoid X receptor alpha, beta, and
gamma in rat central nervous system. J Neurochem
1998; 70:1366–75.
15. Braissant O, Foufelle F, Scotto C, Dauca M, and Wahli W.
Differential expression of peroxisome proliferator-acti-
vated receptors (PPARs): tissue distribution of PPAR-al-
pha, -beta, and -gamma in the adult rat. Endocrinology
1996; 137:354–66.
16. Auboeuf D, Rieusset J, Fajas L, Vallier P, Frering V, Riou
JP, et al. Tissue distribution and quantification of the ex-
pression of mRNAs of peroxisome proliferator-activated
receptors and liver X receptor-alpha in humans: no alter-
ation in adipose tissue of obese and NIDDM patients. Di-
abetes 1997; 46:1319–27.
17. Dreyer C, Krey G, Keller H, Givel F, Helftenbein G, and
Wahli W. Control of the peroxisomal beta-oxidation path-
way by a novel family of nuclear hormone receptors. Cell
1992; 68:879–87.
18. Braissant O, and Wahli W. Differential expression of per-
oxisome proliferator-activated receptor- alpha, -beta, and
-gamma during rat embryonic development. Endocrinol-
ogy 1998; 139:2748–54.
19. Spiegelman BM. PPAR-gamma: adipogenic regulator and
thiazolidinedione receptor. Diabetes 1998; 47:507–14.
20. Mueller E, Sarraf P, Tontonoz P, Evans RM, Martin KJ,
Zhang M, et al. Terminal differentiation of human breast
cancer through PPAR gamma. Mol Cell 1998; 1:465–70.
21. Lefebvre AM, Chen I, Desreumaux P, Najib J, Fruchart JC,
Geboes K, et al. Activation of the peroxisome proliferator-
activated receptor gamma promotes the development of
colon tumors in C57BL/6J-APCMin/+ mice. Nature Med
1998; 4:1053–7.
22. Saez E, Tontonoz P, Nelson MC, Alvarez JG, Ming UT,
Baird SM, et al. Activators of the nuclear receptor
PPARgamma enhance colon polyp formation. Nature
Med 1998; 4:1058–61.
23. Sarraf P, Mueller E, Jones D, King FJ, DeAngelo DJ, Par-
tridge JB, et al. Differentiation and reversal of malignant
changes in colon cancer through PPARgamma. Nature
Med 1998; 4:1046–52.
24. Willson TM, and Wahli W. Peroxisome proliferator-acti-
vated receptor agonists. Curr Opin Chem Biol 1997;
1:235–41.
25. Nagy L, Tontonoz P, Alvarez JG, Chen H, and Evans RM.
Oxidized LDL regulates macrophage gene expression
through ligand activation of PPARγ. Cell 1998; 93:229–40.
26. Xu HE, Lambert MH, Montana VG, Parks DJ, Blanchard
SG, Brown PJ, et al. Molecular recognition of fatty acids
by peroxisome proliferator-activated receptors. Mol Cell
1999; 3:397–403.
27. Berger J, Leibowitz MD, Doebber TW, Elbrecht A, Zhang
B, Zhou G, et al. Novel peroxisome proliferator-activated
receptor (PPAR) gamma and PPARdelta ligands pro-
duce distinct biological effects. J Biol Chem 1999;
274:6718–25.
28. Gervois P, Chopin-Delannoy S, Fadel A, Dubois G, Kosykh
V, Fruchart JC, et al. Fibrates increase human REV-ERBal-
pha expression in liver via a novel peroxisome prolifera-
tor-activated receptor response element. Mol Endocrinol
1999; 13:400–9.
29. Staels B, Koenig W, Habib A, Merval R, Lebret M, Pineda
Torra I, et al. Activation of human aortic smooth-muscle
 Gervois et al.: Role of PPARs in lipid and lipoprotein metabolism
cells is inhibited by PPARalpha but not by PPARgamma
activators. Nature 1998; 393:790–3.
30. Ricote M, Li AC, Willson TM, Kelly CJ, and Glass CK. The
peroxisome proliferator-activated receptor-gamma is a
negative regulator of macrophage activation. Nature
1998; 391:79–82.
31. Jiang C, Ting AT, and Seed B. PPAR-gamma agonists in-
hibit production of monocyte inflammatory cytokines.
Nature 1998; 391:82–6.
32. Sakai M, Matsushima-Hibiya Y, Nishizawa M, and Nishi S.
Suppression of rat gluthatione transferase P expression
by peroxisome proliferators:interaction between Jun and
peroxisome proliferator-activated receptor α. Cancer Res
1995; 53:5370–6.
33. Delerive P, Martin F, Chinetti G, Trottein F, Fruchart JC, Na-
jib J, et al. PPAR activators inhibit thrombin-induced en-
dothelin-1 production in human vascular endothelial cells
by inhibiting the AP-1 signalling pathways. Circ Res 1999;
85:394–402.
34. Delerive P, De Bosscher K, Besnard S, Vanden Berghe W,
Peters JM, Gonzalez FJ, et al. PPARα negatively regulates
the vascular wall inflammatory gene response by nega-
tive cross-talk with transcription factors NF−κB and AP-1.
J Biol Chem 1999; 274:32048–54.
35. Lemberger T, Staels B, Saladin R, Desvergne B, Auwerx J,
and Wahli W. Regulation of the peroxisome proliferator-
activated receptor alpha gene by glucocorticoids. J Biol
Chem 1994; 269:24527–30.
36. Steineger HH, Sorensen HN, Tugwood JD, Skrede S, Spy-
devold O, and Gautvik KM. Dexamethasone and insulin
demonstrate marked and opposite regulation of the
steady-state mRNA level of the peroxisomal proliferator-
activated receptor (PPAR) in hepatic cells. Hormonal
modulation of fatty acid-induced transcription. Eur J
Biochem 1994; 225:967–74.
37. Wang MY, and Unger RH. Novel form of lipolysis induced
by leptin. J Biol Chem 1999; 274:17541–4.
38. Zhou YT, Wang ZW, Higa M, Newgard CB, and Unger RH.
Reversing adipocyte differentiation: implications for
treatment of obesity. Proc Natl Acad Sci USA 1999;
96:2391–5.
39. Kersten S, Seydoux J, Peters JM, Gonzalez FJ, Desvergne
B, and Wahli W. Peroxisome proliferator-activated recep-
tor alpha mediates the adaptive response to fasting. J
Clin Invest 1999; 103:1489–98.
40. Lemberger T, Saladin R, Vazquez M, Assimacopoulos F,
Staels B, Desvergne B, et al. Expression of the peroxi-
some proliferator-activated receptor α gene is stimulated
by stress and follows a diurnal rhythm. J Biol Chem 1996;
271:1764–9.
41. Gervois P, Pineda Torra I, Chinetti G, Dubois G, Grötzinger
T, Fruchart JC, et al. A truncated human PPARα splice
variant with dominant negative activity. Mol Endocrinol
1999; 13:1535–49.
42. Palmer CN, Hsu MH, Griffin KJ, Raucy JL, and Johnson
EF. Peroxisome proliferator activated receptor-alpha ex-
pression in human liver. Mol Pharmacol 1998; 53:14–22.
43. Zhu Y, Qi C, Korenberg JR, Chen XN, Noya D, Rao MS, et
al. Structural organization of mouse peroxisome prolifer-
ator-activated receptor gamma (mPPAR gamma) gene:
alternative promoter use and different splicing yield two
mPPAR gamma isoforms. Proc Natl Acad Sci USA 1995;
92:7921–5.
44. Fajas L, Auboeuf D, Raspe E, Schoonjans K, Lefebvre AM,
Saladin R, et al. The organization, promoter analysis, and
expression of the human PPARgamma gene. J Biol Chem
1997; 272:18779–89.
Brought to you by | University of Arizona
Authenticated
Download Date | 5/28/15 10:38 AM
9
45. Werman A, Hollenberg A, Solanes G, Bjorbaek C, Vidal-
Puig AJ, and Flier JS. Ligand-independent activation do-
main in the N terminus of peroxisome proliferator-acti-
vated receptor gamma (PPARgamma). Differential
activity of PPARgamma1 and -2 isoforms and influence of
insulin. J Biol Chem 1997; 272:20230–5.
46. Wu Z, Bucher NL, and Farmer SR. Induction of peroxi-
some proliferator-activated receptor gamma during the
conversion of 3T3 fibroblasts into adipocytes is mediated
by C/EBPbeta, C/EBPdelta, and glucocorticoids. Mol Cell
Biol 1996; 16:4128–36.
47. Juge-Aubry CE, Hammar E, Siegrist-Kaiser C, Pernin A,
Takeshita A, Chin WW, et al. Regulation of the transcrip-
tional activity of the peroxisome proliferator-activated
receptor alpha by phosphorylation of a ligand-indepen-
dent trans-activating domain. J Biol Chem 1999;
274:10505–10.
48. Shao D, Rangwala SM, Bailey ST, Krakow SL, Reginato
MJ, and Lazar MA. Interdomain communication regulat-
ing ligand binding by PPAR-gamma. Nature 1998;
396:377–80.
49. Shalev A, Siegrist-Kaiser CA, Yen PM, Wahli W, Burger
AG, Chin WW, et al. The peroxisome proliferator-acti-
vated receptor alpha is a phosphoprotein: regulation by
insulin. Endocrinology 1996; 137:4499–502.
50. Adams M, Reginato MJ, Shao D, Lazar MA, and Chatter-
jee VK. Transcriptional activation by peroxisome prolifer-
ator-activated receptor gamma is inhibited by phospho-
rylation at a consensus mitogen- activated protein kinase
site. J Biol Chem 1997; 272:5128–32.
51. Hu E, Kim JB, Sarraf P, and Spiegelman BM. Inhibition of
adipogenesis through MAP kinase-mediated phosphory-
lation of PPARgamma. Science 1996; 274:2100–3.
52. Camp HS, Tafuri SR, and Leff T. c-Jun N-terminal kinase
phosphorylates peroxisome proliferator-activated recep-
tor-γ1 and negatively regulates its transcriptional activity.
Endocrinology 1999; 140:392–7.
53. Hashimoto T, Fujita T, Usuda N, Cook W, Qi C, Peters JM,
et al. Peroxisomal and mitochondrial fatty acid beta-oxi-
dation in mice nullizygous for both peroxisome prolifera-
tor-activated receptor alpha and peroxisomal fatty Acyl-
CoA oxidase. Genotype correlation with fatty liver
phenotype. J Biol Chem 1999; 274:19228–36.
54. Qi C, Zhu Y, Pan J, Usuda N, Maeda N, Yeldandi AV, et al.
Absence of spontaneous peroxisome proliferation in
enoyl-CoA Hydratase/L-3-hydroxyacyl-CoA dehydroge-
nase-deficient mouse liver. Further support for the role of
fatty acyl-CoA oxidase in PPAR alpha ligand metabolism.
J Biol Chem 1999; 274:15775–80.
55. Aoyama T, Peters JM, Iritani N, Nakajima T, Furihata K,
Hashimoto T, et al. Altered constitutive expression of
fatty acid-metabolizing enzymes in mice lacking the per-
oxisome proliferator-activated receptor alpha (PPARal-
pha). J Biol Chem 1997; 273:5678–84.
56. Martin G, Schoonjans K, Lefebvre AM, Staels B, and Auw-
erx J. Coordinate regulation of the expression of the fatty
acid transport protein and acyl-CoA synthetase genes by
PPARalpha and PPARgamma activators. J Biol Chem
1997; 272:28210–7.
57. Motojima K, Passilly P, Peters JM, Gonzalez FJ, and
Latruffe N. Expression of putative fatty acid transporter
genes are regulated by peroxisome proliferator-acti-
vated receptor alpha and gamma activators in a tissue-
and inducer-specific manner. J Biol Chem 1998;
273:16710–4.
58. Mascaro C, Acosta E, Ortiz JA, Marrero PF, Hegardt FG,
and Haro D. Control of human muscle-type carnitine
10 Gervois et al.: Role of PPARs in lipid and lipoprotein metabolism
palmitoyltransferase I gene transcription by peroxisome
proliferator-activated receptor. J Biol Chem 1998;
273:8560–73.
59. Brandt JM, Djouadi F, and Kelly DP. Fatty acids activate
transcription of the muscle carnitine palmitoyltrans-
ferase I gene in cardiac myocytes via the peroxisome
proliferator-activated receptor alpha. J Biol Chem 1998;
273:23786–92.
60. Yu GS, Lu YC, and Gulick T. Co-regulation of tissue-spe-
cific alternative human carnitine palmitoyltransferase
Ibeta gene promoters by fatty acid enzyme substrate. J
Biol Chem 1998; 273:32901–9.
61. Djouadi F, Weinheimer CJ, Saffitz JE, Pitchford C, Bastin
J, Gonzalez FJ, et al. A gender-related defect in lipid me-
tabolism and glucose homeostasis in peroxisome prolif-
erator- activated receptor alpha- deficient mice. J Clin In-
vest 1998; 102:1083–91.
62. Leone TC, Weinheimer CJ, and Kelly DP. A critical role for
the peroxisome proliferator-activated receptor alpha
(PPARalpha) in the cellular fasting response: The PPARal-
pha-null mouse as a model of fatty acid oxidation disor-
ders. Proc Natl Acad Sci USA 1999; 96:7473–8.
63. Kelly LJ, Vicario PP, Thompson GM, Candelore MR, Doeb-
ber TW, Ventre J, et al. Peroxisome proliferator-activated
receptors gamma and alpha mediate in vivo regulation of
uncoupling protein (UCP-1, UCP-2, UCP-3) gene expres-
sion. Endocrinology 1998; 139:4920–7.
64. Brun S, Carmona MC, Mampel T, Vinas O, Giralt M, Igle-
sias R, et al. Activators of peroxisome proliferator-acti-
vated receptor-alpha induce the expression of the uncou-
pling protein-3 gene in skeletal muscle: a potential
mechanism for the lipid intake-dependent activation of
uncoupling protein-3 gene expression at birth. Diabetes
1999; 48:1217–22.
65. Tsuboyama-Kasaoka N, Takahashi M, Kim H, and Ezaki O.
Up-regulation of liver uncoupling protein-2 mRNA by ei-
ther fish oil feeding or fibrate administration in mice.
Biochem Biophys Res Commun 1999; 257:879–85.
66. Tontonoz P, Hu E, Graves RA, Budavari AI, and Spiegel-
man BM. mPPAR gamma 2: tissue-specific regulator of an
adipocyte enhancer. Genes Dev 1994; 8:1224–34.
67. Tontonoz P, Hu E, Devine J, Beale EG, and Spiegelman
BM. PPAR gamma 2 regulates adipose expression of the
phosphoenolpyruvate carboxykinase gene. Mol Cell Biol
1995; 15:351–7.
68. Schoonjans K, Watanabe M, Suzuki H, Mahfoudi A, Krey
G, Wahli W, et al. Induction of the acyl-coenzyme A syn-
thetase gene by fibrates and fatty acids is mediated by a
peroxisome proliferator response element in the C pro-
moter. J Biol Chem 1995; 270:19269–76.
69. Schoonjans K, Staels B, Grimaldi P, and Auwerx J. Acyl-
CoA synthetase mRNA expression is controlled by fibric-
acid derivatives, feeding and liver proliferation. Eur J
Biochem 1993; 216:615–22.
70. Schoonjans K, Peinado-Onsurbe J, Lefebvre AM, Hey-
man RA, Briggs M, Deeb S, et al. PPARalpha and
PPARgamma activators direct a distinct tissue-specific
transcriptional response via a PPRE in the lipoprotein li-
pase gene. EMBO J 1996; 15:5336–48.
71. Heller F, and Harvengt C. Effects of clofibrate, bezafibrate,
fenofibrate and probucol on plasma lipolytic enzymes in
normolipaemic subjects. Eur J Clin Pharmacol 1983;
25:57–63.
72. Malmendier CL, Lontie JF, Delcroix C, Dubois DY, Magot
T, and De Roy L. Apolipoproteins C-II and C-III metabolism
in hypertriglyceridemic patients. Effect of a drastic
triglyceride reduction by combined diet restriction and
Brought to you by | University of Arizona
Authenticated
Download Date | 5/28/15 10:38 AM
fenofibrate administration. Atherosclerosis 1989;
77:139–49.
73. D’Costa MA, and Angel A. Inhibition of hormone-stimu-
lated lipolysis by clofibrate. A possible mechanism for its
hypolipidemic action. J Clin Invest 1975; 55:138–48.
74. Caslake MJ, Packard CJ, Gaw A, Murray E, Griffin BA, Val-
lance BD, et al. Fenofibrate and LDL metabolic hetero-
geneity in hypercholesterolemia. Arterioscler Thromb
1993; 13:702–11.
75. Vu-Dac N, Schoonjans K, Kosykh V, Dallongeville J,
Fruchart JC, Staels B, et al. Fibrates increase human
apolipoprotein A-II expression through activation of the
peroxisome proliferator-activated receptor. J Clin Invest
1995; 96:741–50.
76. Vu-Dac N, Schoonjans K, Laine B, Fruchart JC, Auwerx J,
and Staels B. Negative regulation of the human
apolipoprotein A-I promoter by fibrates can be attenu-
ated by the interaction of the peroxisome proliferator-ac-
tivated receptor with its response element. J Biol Chem
1994; 269:31012–8.
77. Berthou L, Duverger N, Emmanuel F, Langouet S, Auwerx
J, Guillouzo A, et al. Opposite regulation of human versus
mouse apolipoprotein A-I by fibrates in human
apolipoprotein A-I transgenic mice. J Clin Invest 1996;
97:2408–16.
78. Stevenson RW, Hutson NJ, Krupp MN, Volkmann RA, Hol-
land GF, Eggler JF, et al. Actions of novel antidiabetic
agent englitazone in hyperglycemic hyperinsulinemic
ob/ob mice. Diabetes 1990; 39:1218–27.
79. Sohda T, Mizuno K, Momose Y, Ikeda H, Fujita T, and Me-
guro K. Studies on antidiabetic agents. 11. Novel thiazo-
lidinedione derivatives as potent hypoglycemic and hy-
polipidemic agents. J Med Chem 1992; 35:2617–26.
80. Kemnitz JW, Elson DF, Roecker EB, Baum ST, Bergman
RN, and Meglasson MD. Pioglitazone increases insulin
sensitivity, reduces blood glucose, insulin, and lipid lev-
els, and lowers blood pressure, in obese, insulin- resis-
tant rhesus monkeys. Diabetes 1994; 43:204–11.
81. Young PW, Cawthorne MA, Coyle PJ, Holder JC, Holman
GD, Kozka IJ, et al. Repeat treatment of obese mice with
BRL 49653, a new potent insulin sensitizer, enhances in-
sulin action in white adipocytes. Association with in-
creased insulin binding and cell-surface GLUT4 as mea-
sured by photoaffinity labeling. Diabetes 1995;
44:1087–92.
82. Lohray BB, Bhushan V, Rao BP, Madhavan GR, Murali N,
Rao KN, et al. Novel euglycemic and hypolipidemic
agents. 1. J Med Chem 1998; 41:1619–30.
83. Reddy KA, Lohray BB, Bhushan V, Reddy AS, Mamidi NV,
Reddy PP, et al. Novel antidiabetic and hypolipidemic
agents. 5. Hydroxyl versus benzyloxy containing chro-
man derivatives. J Med Chem 1999; 42:3265–78.
84. Lefebvre AM, Peinado-Onsurbe J, Leitersdorf I, Briggs
MR, Paterniti JR, Fruchart JC, et al. Regulation of lipopro-
tein metabolism by thiazolidinediones occurs through a
distinct but complementary mechanism relative to fi-
brates. Arterioscler Thromb Vasc Biol 1997; 17:1756–64.
85. Hertz R, Bishara-Shieban J, and Bar-Tana J. Mode of ac-
tion of peroxisome proliferators as hypolipidemic drugs.
Suppression of apolipoprotein C-III. J Biol Chem 1995;
270:13470–5.
86. Staels B, Vu-Dac N, Kosykh V, Saladin R, Fruchart JC, Dal-
longeville J, et al. Fibrates down-regulate apolipoprotein
C-III expression independent of induction of peroxisomal
Acyl co-enzyme A oxidase. J Clin Invest 1995; 95:705–12.
87. Peters JM, Hennuyer N, Staels B, Fruchart JC, Fievet C,
Gonzalez FJ, et al. Alterations in lipoprotein metabolism
 Gervois et al.: Role of PPARs in lipid and lipoprotein metabolism
in peroxisome proliferator-activated receptor alpha-defi-
cient mice. J Biol Chem 1997; 272:27307–12.
88. Ladias JA, Hadzopoulou-Cladaras M, Kardassis D, Cardot
P, Cheng J, Zannis V, et al. Transcriptional regulation of
human apolipoprotein genes ApoB, ApoCIII, and ApoAII
by members of the steroid hormone receptor superfamily
HNF- 4, ARP-1, EAR-2, and EAR-3. J Biol Chem 1992;
267:15849–60.
89. Vu-Dac N, Gervois P, Pineda Torra I, Fruchart JC, Kosykh
V, Kooistra T, et al. Retinoids increase human apo C-III ex-
pression at the transcriptional level via the retinoid X re -
ceptor. Contribution to the hypertriglyceridemic action of
retinoids. J Clin Invest 1998; 102:625–32.
90. Vu-Dac N, Chopin-Delannoy S, Gervois P, Bonnelye E,
Martin G, Fruchart JC, et al. The nuclear receptors perox-
isome proliferator-activated receptorα and Rev-erbα me-
diate the species-specific regulation of apolipoprotein A-I
expression by fibrates. J Biol Chem 1998; 273:25713–20.
91. Duez H, Mansen A, Fruchart JC, Vennstrom B, Fievet C,
and Staels B. Rev-erbα : a nuclear receptor with a role in
lipoprotein metabolism. Circulation 1998; 98:17,I-
449:2363.
92. Poynter ME, and Daynes RA. Peroxisome proliferator-ac-
tivated receptor alpha activation modulates cellular re-
dox status, represses nuclear factor-kappaB signaling,
and reduces inflammatory cytokine production in aging.
J Biol Chem 1998; 273:32833–41.
93. Zhou YC, and Waxman DJ. Cross-talk between janus ki-
nase-signal transducer and activator of transcription
(JAK-STAT) and peroxisome proliferator-activated recep-
tor-alpha (PPARα) signalling pathways. Growth hormone
inhibition of PPARα transcriptional activity mediated by
STAT5b. J Biol Chem 1999; 274:2672–81.
94. Miller GJ, and Miller NE. Plasma-high-density-lipoprotein
concentration and development of ischaemic heart-dis-
ease. Lancet 1975; 1:16–9.
95. Balfour JA, McTavish D, and Heel RC. Fenofibrate. A re-
view of its pharmacodynamic and pharmacokinetic prop-
erties and therapeutic use in dyslipidaemia. Drugs 1990;
40:260–90.
96. Malmendier CL, and Delcroix C. Effects of fenofibrate on
high and low density lipoprotein metabolism in heterozy-
gous familial hypercholesterolemia. Arteriosclerosis
1985; 55:161–9.
97. Bard JM, Parra HJ, Camare R, Luc G, Ziegler O, Dachet C,
et al. A multicenter comparison of the effects of simvas-
tatin and fenofibrate therapy in severe primary hypercho-
lesterolemia, with particular emphasis on lipoproteins
defined by their apolipoprotein composition. Metabolism
1992; 41:498–503.
98. Berthou L, Saladin R, Yaqoob P, Branellec D, Calder P,
Fruchart JC, et al. Regulation of rat liver apolipoprotein A-
I, apolipoprotein A-II and acyl-coenzyme A oxidase gene
expression by fibrates and dietary fatty acids. Eur J
Biochem 1995; 232:179–87.
99. Costet P, Legendre C, More J, Edgar A, Galtier P, and
Pineau T. Peroxisome proliferator-activated receptor al-
Brought to you by | University of Arizona
Authenticated
Download Date | 5/28/15 10:38 AM
11
pha-isoform deficiency leads to progressive dyslipidemia
with sexually dimorphic obesity and steatosis. J Biol
Chem 1998; 273:29577–85.
100. Hennuyer N, Poulain P, Madsen L, Berge RK, Houdebine
LM, Branellec D, et al. Beneficial effects of fibrates on
apolipoprotein A-I metabolism occur independently of
any peroxisome proliferative response. Circulation 1999;
99:2445–51.
101. Staels B, van Tol A, Andreu T, and Auwerx J. Fibrates in-
fluence the expression of genes involved in lipoprotein
metabolism in a tissue-selective manner in the rat. Arte-
rioscler Thromb 1992; 12:286–94.
102. Staels B, Peinado-Onsurbe J, and Auwerx J. Down-regu-
lation of hepatic lipase gene expression and activity by
fenofibrate. Biochim Biophys Acta 1992; 1123:227–30.
103. Staels B, van Tol A, Skretting G, and Auwerx J.
Lecithin:cholesterol acyltransferase gene expression is
regulated in a tissue-selective manner by fibrates. J Lipid
Res 1992; 33:727–35.
104. Acton S, Rigotti A, Landschulz KT, Xu S, Hobbs HH, and
Krieger M. Identification of scavenger receptor SR-BI as a
high density lipoprotein receptor. Science 1996;
271:518–20.
105. Calvo D, Gomez-Coronado D, Lasuncion MA, and Vega
MA. CLA-1 is an 85-kD plasma membrane glycoprotein
that acts as a high- affinity receptor for both native (HDL,
LDL, and VLDL) and modified (OxLDL and AcLDL)
lipoproteins. Arterioscler Thromb Vasc Biol 1997;
17:2341–9.
106. Ji Y, Jian B, Wang N, Sun Y, Moya ML, Phillips MC, et al.
Scavenger receptor BI promotes high density lipopro-
tein-mediated cellular cholesterol efflux. J Biol Chem
1997; 272:20982–5.
107. Trigatti B, Rayburn H, Vinals M, Braun A, Miettinen H,
Penman M, et al. Influence of the high density lipoprotein
receptor SR-BI on reproductive and cardiovascular
pathophysiology. Proc Natl Acad Sci USA 1999;
96:9322–7.
108. Chinetti G, Griglio S, Antonucci M, Pineda Torra I,
Delerive P, Majd Z, et al. Activation of proliferator-acti-
vated receptors alpha and gamma induces apoptosis of
human monocyte-derived macrophages. J Biol Chem
1998; 273:25573–80.
109. Gbaguidi F, Chinetti G, Griglio S, Antonucci M, Fruchart
JC, Chapman J, et al. Regulation of CLA-1 (CD36 and
LIMP II analogous I) by activators of peroxisome prolifer-
ator activated receptors (PPARs). Atherosclerosis 1999;
144: Suppl 1:112.
Received 18 October 1999; accepted in present form
4 January 2000
Corresponding author: Bart Staels, INSERM U.325,
Département d’Athérosclérose, Institut Pasteur de Lille 1,
rue du Professeur Calmette, BP245, 59019 Lille Cedex, France
Tel:+33-3-20-87-73-88, Fax: +33-3-20-87-73-60
Email: Bart.Staels@pasteur-lille.fr