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(Received for publication, May 12, 1997, and in revised form, August 1, 1997)
From the ABSTRACT The peroxisome proliferator-activated
receptor- INTRODUCTION Peroxisome proliferator-activated receptors
(PPARs)1 are a subfamily of
the nuclear hormone receptor gene family. There are three distinct
PPARs, termed PPAR In addition to its role in Given the effects of treatment with PPAR EXPERIMENTAL PROCEDURES (4-chloro-6-(2,3-xylidine)-pyrimidinylthio)acetic
acid (Wy 14,643), a powerful PPAR For all experiments, we used male mice, 10-16
weeks of age, 20-35 g, F4 C57BL/6N X Sv/129 homozygous wild-type (+/+)
or knockout ( Serum
lipids (cholesterol and triglycerides) and HDL cholesterol were
determined by enzymatic assay adapted to microtiter plates using
commercially available reagents (Boehringer Mannheim). Serum HDL
cholesterol content was determined after precipitation of
apoB-containing lipoproteins with phosphotungstic acid/mg (Boehringer Mannheim). Serum levels of mouse apoA-I and apoA-II were measured by an
immunonephelometric assay using specific polyclonal antibodies.
The distribution of lipoproteins in serum from mice was analyzed by
nondenaturing discontinuous gradient polyacrylamide gel electrophoresis
(Lipofilm kit, Sebia, Issy-les-Moulineaux, France) according to the
manufacturer's instructions.
HDL lipoprotein fraction (d = 1.063-1.21 g/ml) was
isolated by sequential ultracentrifugation as described (15). The HDL fraction was assayed for its protein (16) and lipid (cholesterol, triglyceride, and phospholipid) content. HDL size was determined on
polyacrylamide gradient gels (4-20%, Novex, San Diego, CA). 10 µg
of HDL protein were loaded, and the electrophoresis was performed in a
Novex apparatus at 125 V for 13 h in 0.025 M Tris, 0.192 M glycine, pH 8.3. Gels were stained with Coomassie
Brilliant Blue R-250. Proteins in the high molecular mass calibration
mixture (Pharmacia Biotech Inc.) were used as calibrating proteins on these gels.
Lipoprotein cholesterol profiles were obtained by fast protein liquid
chromatography as described (17). This system allows separation of the
three major lipoprotein classes; VLDL, low density lipoproteins, and
HDL. Cholesterol concentrations were determined in the eluted
fractions. Accumulated data were analyzed by the Millenium 20/0 program
(Waters).
RNA was isolated from liver by the acid
guanidinium thiocyanate/phenol/chloroform method (18). Northern and dot
blot analysis of total cellular RNA was performed as described (19).
Rat apoA-I, apoA-II, apoA-IV, and apoC-III cDNAs were used as
probes (20, 21). GAPDH and 36B4 (22, 23) (encoding the human acidic ribosomal phosphoprotein PO (23)) were used as control probes. All
probes were labeled by random primed labeling (Boehringer Mannheim).
Filters were hybridized with 1.5 × 106 cpm/ml of each
probe as described (21). Autoradiograms were analyzed by quantitative
scanning densitometry (Bio-Rad GS670 Densitometer) as described (21).
RNA expression data of the various apolipoproteins were corrected for
the expression of a control probe. An arbitrary value of 100 was
assigned to the average of the wild-type (+/+) untreated animals for
each experiment.
RESULTS Compared with control (+/+) mice, serum total and HDL
cholesterol concentrations were significantly higher in PPAR Table I.
Serum lipid concentrations in PPAR
Volume 272, Number 43,
Issue of October 24, 1997
pp. 27307-27312
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.
Alterations in Lipoprotein Metabolism in Peroxisome
Proliferator-activated Receptor
-deficient Mice*
,
, and
Laboratory of Metabolism, NCI, National
Institutes of Health, Bethesda, Maryland 20892 and § U.325
INSERM, Département d'Athérosclérose, Institut
Pasteur, 59019 Lille, France
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
FOOTNOTES
ACKNOWLEDGEMENTS
REFERENCES
(PPAR) controls gene expression in response to a
diverse class of compounds collectively referred to as peroxisome
proliferators. Whereas most known peroxisome proliferators are of
exogenous origin and include hypolipidemic drugs and other industrial
chemicals, several endogenous PPAR activators have been identified
such as fatty acids and steroids. The latter finding and the fact that
PPAR modulates target genes encoding enzymes involved in lipid
metabolism suggest a role for PPAR in lipid metabolism. This was
investigated in the PPAR-deficient mouse model. Basal levels of
total serum cholesterol, high density lipoprotein cholesterol, hepatic
apolipoprotein A-I mRNA, and serum apolipoprotein A-I in
PPAR-deficient mice are significantly higher compared with wild-type
controls. Treatment with the fibrate Wy 14,643 decreased apoA-I serum
levels and hepatic mRNA levels in wild-type mice, whereas no effect
was detected in the PPAR-deficient mice. Administration of the
fibrate Wy 14,643 to wild-type mice results in marked depression of
hepatic apolipoprotein C-III mRNA and serum triglycerides compared
with untreated controls. In contrast, PPAR-deficient mice were
unaffected by Wy 14,643 treatment. These studies demonstrate that
PPAR modulates basal levels of serum cholesterol, in particular high
density lipoprotein cholesterol, and establish that fibrate-induced
modulation in hepatic apolipoprotein A-I, C-III mRNA, and serum
triglycerides observed in wild-type mice is mediated by PPAR.
, 
(also called 
, NUC-1), and 
, each encoded
by a separate gene and showing a distinct tissue distribution (for
review, see Refs. 1-5). Activated PPARs heterodimerize with another
nuclear receptor, RXR and alter transcription of target genes after
binding to specific response elements or PPREs. PPREs consist of a
direct repeat of the nuclear receptor hexameric DNA recognition motif
spaced by one nucleotide. Numerous PPAR target genes have been
identified (for review, see Ref. 4). Since they are activated by
various fatty acid metabolites as well as several drugs used in the
treatment of metabolic disorders, PPARs can be considered as key
messengers that modulate nutritional, pharmacological, and metabolic
stimuli into changes in gene expression. PPARs were initially
considered orphan receptors, since no direct binding of the various
activators to the receptors could be demonstrated. However, PPAR has
recently been shown to bind and be activated by leukotriene B4 and
fibrates (6). In addition, prostaglandin J2 derivatives and the
antidiabetic thiazolidinediones have been shown to be natural and
synthetic ligands for PPAR, respectively (7-9).
was the first PPAR to be identified (10), and it is expressed
primarily in tissues that have a high level of fatty acid catabolism
such as liver (11). In the liver, PPAR modulates oxidation of fatty
acids and detoxification of several xenobiotic compounds. Numerous
studies have demonstrated that several genes encoding enzymes involved
in metabolic pathways, such as - and 
-oxidation, contain a PPRE
in their promoter region and are under transcriptional control of
PPAR (reviewed in Ref. 4). Consistent with this observation, PPAR
knockout mice, which are apparently healthy under basal conditions, are
not able to induce genes involved in - and -oxidation when
treated with compounds that activate PPAR (12). Fatty acid oxidation
pathways have diverse roles in physiology, extending from a role in
lipid metabolism strictu sensu to a role in the metabolism
of various lipid mediators and signaling factors (6).
- and -oxidation pathways, PPAR was
suggested to be important in the control of extracellular lipid
metabolism (for review, see Refs. 1-5). For example, PPAR activators such as fibrates have an important role in the control of
HDL cholesterol levels. Gene expression of apoA-I and apoA-II, the
major apolipoproteins in HDL, is controlled by PPAR. Thus, these
protagonists of reverse cholesterol transport (13), a protective
pathway against coronary artery disease (14), can be modulated by
PPAR (reviewed in Refs. 3-5). Besides the role of PPARs in HDL
metabolism, they also affect metabolism of triglyceride-rich lipoprotein particles (reviewed in Refs. 3-5). In fact, activation of
either PPAR and/or PPAR has pronounced triglyceride-lowering effects in animals and man due to effects on both clearance and production rates of triglyceride-rich lipoproteins.
activators on lipoprotein
metabolism, the goal of this study was to analyze in a more direct
fashion whether PPAR is involved in the regulation of lipoprotein
metabolism. Thus, we examined lipoprotein metabolism in
PPAR-deficient mice. These data unequivocally demonstrate that
PPAR has an important regulatory role in lipid metabolism.
activator and ligand (6), was
purchased commercially (ChemSyn Science Laboratories, Lenexa, KS).
Pelleted mouse chow was commercially prepared containing either 0.0 (control) or 0.1% Wy 14,643 (Bioserv, Frenchtown, NJ).
/) for PPAR (12). Mice from both genotypes were fed
either the control or Wy 14,643 diet ad libitum for 14 days.
At the end of the experiments, animals were weighed and euthanized by
overexposure to carbon dioxide. Blood was collected, and serum was
separated and used within 1 week for analysis of lipids, lipoproteins,
and apolipoproteins. The liver was removed immediately, weighed, and frozen in liquid nitrogen and stored at 80 °C until further
analysis.
(/) Mice Have Elevated Levels of HDL
Particles
(/) mice (Table I). Total serum cholesterol
and serum HDL cholesterol levels in the PPAR (/) mice were 64 and 63% higher, respectively, than values in control PPAR (+/+)
mice. Plasma triglyceride values were not significantly different
between the two groups.
(/) and (+/+) mice
n
Total cholesterol
Triglycerides
HDL
cholesterol
mg/dl
PPAR
(+/+)32
85 ± 15
145
± 41
59 ± 10
PPAR
(/)24
139
± 27a
157 ± 36
96 ± 24a
a
p < 0.0001 by Mann-Whitney test.
Separation of the different lipoprotein fractions by electrophoresis of
lipostained samples from PPAR (/) and (+/+) mice confirmed a
robust increase in HDL concentrations in PPAR (/) serum (data
not shown). When staining intensity of 100% was arbitrarily attributed
to the HDL band of the PPAR (+/+) animals, the relative staining
intensity of the HDL from the PPAR (/) animals was 197%.
(/) Mice
To analyze in more
detail the distribution of lipoproteins in plasma from the PPAR
(/) and (+/+) mice, aliquots from pooled serum from these animals
were subjected to gel filtration chromatography. The cholesterol
profiles showed a striking increase in HDL levels as depicted in Fig.
1. This increase is consistent with the
increase in HDL cholesterol levels measured by the phosphotungstic
acid/mg precipitation technique (Table I) and by lipofilm
electrophoresis. Cholesterol concentrations from each of the
lipoprotein fractions were further measured. As expected, almost all of
the cholesterol was distributed in HDL in both genotypes of mice
(85.9 ± 3.5% versus 88.9 ± 0.6% in PPAR
(+/+) and (/), respectively). In addition, the data confirmed a
large increase in HDL cholesterol concentrations in PPAR (/)
mice compared with PPAR (+/+) mice (137.1 ± 9.7 versus 78.9 ± 10.2 mg/dl, respectively).
Fig. 1. Representative profile of the serum cholesterol distribution between lipoproteins from PPAR
(+/+) and
PPAR (/) mice after gel filtration chromatography. Serum
lipoproteins were separated by gel filtration chromatography using a
superose 6HR 10/30 column at a flow rate of 0.35 ml min
1.
Cholesterol concentrations were measured in the eluted fractions at 490 nm.
[View Larger Version of this Image (14K GIF file)]
HDL from pooled serum samples from PPAR (/) and (+/+) mice was
isolated by density equilibrium ultracentrifugation, and the
composition was determined. HDL particles from PPAR (+/+) were not
different in their composition compared with PPAR (/) mice
(Table II). Since the particle size
distribution of HDL was comparable and showed a homogeneous population
of HDL particles in both groups of animals (Fig.
2), we can conclude that the increase in
HDL cholesterol is essentially due to an increase in the amount of
circulating HDL lipoproteins.
|
||||||||||||||||||||||||||||||
Fig. 2. Size distribution of HDL particles in PPAR
(+/+) and PPAR (/) mice. HDL particles were isolated by
density equilibrium ultracentrifugation and electrophoresed in a
gradient polyacrylamide gel. The gel was stained for protein with
Coomassie Brilliant Blue R-250. Lane 1 contains molecular
weight markers. Lanes 2 and 3 represent HDL
profiles from PPAR (/) and PPAR (+/+) mice,
respectively.
[View Larger Version of this Image (57K GIF file)]
The Increase in HDL Is Due to an Increase in the HDL Apolipoprotein apoA-I
To verify whether the observed increase in HDL particle
number and HDL cholesterol was associated with a concomittant increase in the major HDL apolipoproteins, we determined serum apoA-I and apoA-II concentrations in PPAR (/) and (+/+) mice by a
nephelometric assay (Fig. 3, A
and B). Serum apoA-I was significantly greater in the
PPAR (/) mice compared with (+/+) mice (136 ± 46 versus 96 ± 19 mg/dl; p < 0.01). The
increase in serum apoA-I levels was due to an increase in hepatic
apoA-I mRNA levels observed in PPAR (/) mice compared with
control (+/+) mice (Figs. 3A and
4). ApoA-II concentrations tended also to
be higher in PPAR (/) mice relative to the (+/+) controls, but
the difference was not statistically significant (64 ± 27 versus 54 ± 15 mg/dl) (Fig. 3B). Similarly,
hepatic apoA-II mRNA had a tendency to be more elevated in the
(/) animals (Figs. 3B and 4).
Fig. 3. Liver apoA-I and apoA-II mRNA levels and serum apoA-I and apoA-II concentrations before and after after Wy 14,643 treatment in PPAR
(+/+) and (/) mice. Bar graphs
showing apoA-I (A) and apoA-II (B) data before
and after Wy 14,643 treatment in PPAR (+/+) and (/) mice. 
,
values before treatment with Wy 14,643; 
, values after treatment
with Wy 14,463. Each value represents the mean ± S.D. of the
indicated number of animals. When existent, statistically significant
differences between treated and untreated animals of the same genotype,
as well as between wild-type and deficient mice are indicated by
asterisks (Mann-Whitney test, * p < 0.05;
** p < 0.01; *** p < 0.001).
[View Larger Version of this Image (45K GIF file)]
Fig. 4. Liver apoA-I and apoA-II mRNA levels before and after after Wy 14,643 treatment in PPAR
(+/+) and (/)
mice. Representative Northern blot showing the differences
in apoA-I and apoA-II mRNA levels in PPAR (+/+) and (/)
mice. As a control for loading efficiency, the Northern blots were
rehybridized with a GAPDH probe.
[View Larger Version of this Image (102K GIF file)]
ApoA-I Levels Are Not Controlled by Fibrates in PPAR
(/)
mice
Previous work from our laboratories and others has shown
that rodent serum apoA-I and hepatic mRNA levels are down-regulated by treatment with fibrate hypolipidemic drugs. Since fibrates are
potent activators and ligands of PPAR, we examined this regulation in PPAR (/) mice. A significant decrease in both hepatic apoA-I mRNA levels (p < 0.05) and serum apoA-I
(p < 0.01) was observed in (+/+) mice after treatment
with Wy 14,643. However, administration of Wy 14,643 to PPAR (/)
animals resulted in no significant change in hepatic apolipoprotein A-I
mRNA and serum apoA-I levels (Figs. 3A and 4). Absence
of a regulatory effect of fibrates on apoA-I protein and mRNA
levels in Wy 14,643 fed PPAR (/) mice suggests and implies
PPAR unequivocally as a major determinant of HDL metabolism. ApoA-II
serum levels increased after fibrate treatment in PPAR (+/+) mice
(p < 0.01) whereas they decreased in PPAR (/)
mice (p < 0.01) (Fig. 3B). The increase in
apoA-II levels was accompanied by an increase in hepatic apoA-II mRNA levels in PPAR (+/+) mice (Figs. 3B and 4). No change in
hepatic apoA-II mRNA levels was present in PPAR (/) mice
(Figs. 3B and 4).
(/) Mice
Although no major
difference in basal serum triglyceride levels between PPAR (+/+) and
(/) mice was detected (Table I), previous studies have shown that
administration of fibrates to both rodents and humans results in lower
triglyceride concentrations and lower hepatic apoC-III mRNA (21,
24, 25). In addition, the apoC-III gene has a PPRE and plays a critical
role in the control of triglyceride metabolism. Combined, these
observations suggest that fibrate regulation of triglyceride metabolism
occurs through a PPAR-dependent pathway. Consistent with
this idea, PPAR (+/+) mice fed the Wy 14,643 diet had significantly
lower serum triglyceride concentration compared with untreated control (+/+) mice (p < 0.001) (Fig.
5A). In contrast, the
characteristic lowering of triglyceride levels in response to fibrate
administration was not observed in the PPAR (/) mice fed the Wy
14,643 diet compared with controls (Fig. 5A).
Fig. 5. Triglycerides and apolipoprotein C-III mRNA levels after Wy 14,643 treatment in PPAR
(+/+) and (/)
mice. A, bar graph showing serum triglyceride concentrations
and apoC-III mRNA levels before () and after () Wy 14,643 treatment in PPAR (+/+) and (/) mice. Each value represents the
mean ± S.D. of the indicated number of animals. When existent,
statistically significant differences between treated and untreated
animals of the same genotype, as well as between wild-type and
deficient mice are indicated by asterisks (Mann-Whitney
test, * p < 0.05; ** p < 0.01; ***
p < 0.001). B, representative Northern blot
showing the differences in apoC-III and acyl-CoA oxidase mRNA
levels in PPAR (+/+) and (/) mice. As a control for loading
efficiency, the Northern blots were rehybridized with a GAPDH
probe.
[View Larger Version of this Image (54K GIF file)]
Consistent with the hypothesis that PPAR has a major role in
regulating apoC-III levels accompanying major changes in triglyceride metabolism, we observed a decrease in liver apoC-III mRNA levels in
PPAR (+/+) mice fed the Wy 14,643 diet (p < 0.001)
(Fig. 5, A and B). In contrast, liver apoC-III
mRNA levels were not affected in the PPAR (/) mice fed the
Wy 14,643 diet compared with untreated controls (Fig. 5, A
and B).
DISCUSSION
Since peroxisome proliferators induce altered expression of genes
encoding peroxisomal -oxidation enzymes, microsomal -oxidation enzymes, and apolipoproteins, a role in lipid homeostasis for these
compounds can be hypothesized. This idea is further supported by the
known triglyceride-lowering effects of fibrates, a commonly used class
of hypolipidemic agents. Recently it was shown that several peroxisome
proliferators including fibrates and a fatty acid derivative are
capable of activating PPAR. To better delineate a role for PPAR
in lipid homeostasis, we examined lipid and lipoprotein metabolism in
PPAR-deficient mice.
Serum lipid and lipoprotein parameters were markedly altered in PPAR
(/) mice compared with PPAR (+/+) mice. Most striking was the
consistent increase in total and HDL cholesterol levels in the PPAR
(/) mice. This increase in HDL cholesterol levels was associated
with a parallel elevation in serum apoA-I levels, which was associated
with higher levels of hepatic apoA-I mRNA levels. Despite the
higher level of serum HDL cholesterol, the composition and the size
distribution of HDL particles was not different between the two
genotypes. This suggests that the increase in serum HDL cholesterol in
the PPAR (/) mice was essentially due to an increase in the
amount of circulating HDL lipoproteins. Another strong argument
supporting an active role of PPAR in the control of HDL metabolism
was provided by the absence of a similar regulatory effect of fibrate
lipid-lowering drugs on liver apoA-I and apoA-II mRNA and serum
apoA-I and apoA-II levels in PPAR (/) animals. In fact, apoA-I
mRNA levels were, as reported previously (20, 26), decreased after
fibrate treatment in PPAR (+/+) animals, whereas no regulation was
observed in the (/) mice. Similar to previous work in humans (27),
apoA-II mRNA and serum levels were only increased by fibrates in
PPAR (+/+), but not in (/) mice. Combined, these observations
clearly establish PPAR as a key regulatory factor in HDL
metabolism.
The pathways through which PPAR and its activators/ligands alter
apolipoprotein expression and HDL metabolism is an active area of
research. There is some confusion in this area that stems from
differences between human and rodent apoA-I gene regulation by
fibrates. In rats, serum HDL cholesterol and hepatic apoA-I mRNA
levels are typically down-regulated by fibrates (20, 26, 28), whereas
these parameters increase to a variable extent in humans (26, 29, 30).
The mechanisms by which fibrates exert an overall negative effect on
the minimal promoter of the mouse apoA-I gene are as of yet not
defined.The present results, which demonstrate an increase in liver
apoA-I mRNA levels under basal conditions in PPAR (/) mice
and show no regulatory effect of fibrates in these mice, are consistent
with a negative regulatory effect of PPAR activators on rodent apoA-I
expression (20, 26). This indicates that PPAR is one of the key
players in determining liver apoA-I expression.
Human liver apoA-II expression is stimulated by PPAR. In fact, PPAR
induces apoA-II expression through interaction with a PPRE located in
the apoA-II J site (27). The absence in PPAR (/) mice of
increased apoA-II mRNA and serum levels, typically observed in
PPAR (+/+) mice after fibrate treatment, indicates that regulatory
mechanisms similar to those for the human apoA-II gene must exist in
mice. The regulatory function of PPAR on gene expression of these
two major HDL apolipoproteins may have important clinical implications
in man. Since apoA-I and apoA-II are major determinants of HDL
metabolism, alterations in their gene expression could significantly
affect reverse cholesterol transport pathway, which seems to protect
against coronary atherosclerosis.
PPAR (+/+) mice fed the 0.1% Wy 14,643 diet have significantly
lower hepatic apoC-III mRNA levels and triglyceride concentration compared with control untreated (+/+) mice. This is consistent with
previous reports showing a similar reduction in apoC-III levels in rats
after treatment with hypolipidemic fibrates (21, 24, 25). In contrast,
PPAR (/) mice fed Wy 14,643 did not exhibit the prototypical
response to a peroxisome proliferator since hepatic apoC-III mRNA
and triglyceride levels were not different compared with control (+/+)
mice. These observations demonstrate that Wy 14,643-induced reductions
in hepatic apoC-III mRNA and triglyceride metabolism are mediated
by PPAR and hence establish a role for PPAR in the control of
VLDL and triglyceride metabolism in addition to its role in HDL
metabolism described above.
Our observations are also consistent with previous studies, which
suggested that activation of PPAR results in lower serum triglyceride levels in animals and man. Steady state triglyceride levels are dependent on two pathways, endogenous synthesis and tissue
clearance. Production of triglycerides in the liver is controlled in
large part by substrate (fatty acids) availability, whereas tissue
clearance of triglycerides is dependent on lipoprotein lipase activity
and apolipoprotein C-III. Fibrates can affect both of these processes
(reviewed in Ref. 4). For example, fibrates have been shown to
stimulate lipolysis and clearance of triglycerides due to decreased
transcription and production of apoC-III (21, 24, 25), an
apolipoprotein that limits tissue clearance of triglyceride. The effect
of peroxisome proliferators on apoC-III expression may involve
competition by PPAR for binding to a cis-acting sequence on
the apoC-III promoter as well as a direct repression of hepatic nuclear
factor-4 expression (25). In addition to apoC-III-mediated effects on
the clearance of triglyceride-rich lipoproteins induced by PPAR,
this receptor also influences production rates of these particles.
Fibrate activation of PPAR in the liver stimulates fatty acid uptake
and conversion to acyl-CoA derivatives by the induction of the genes
coding for the fatty acid transporter protein2 and acyl-CoA synthase (31-33). The resulting
acyl-CoA derivatives in hepatocytes are then more efficiently
oxidized by induction of fatty acid -oxidation pathways in
peroxisomes and mitochondria (see above). Besides modulating
-oxidation of fatty acids, PPAR activation can also inhibit
de novo fatty acid synthesis that contributes to decreased
triglyceride synthesis and VLDL production (reviewed in Ref. 4). Hence,
both enhanced catabolism of triglyceride-rich particles as well as
reduced secretion of VLDL particles are mechanisms that contribute to
the hypolipidemic effect of PPAR activation.
Our results clearly show that PPAR modulates lipid metabolism in a
homeostatic mechanism since mice lacking functional PPAR have higher
levels of serum HDL. In addition, PPAR has an important role in
mediating the effects of fibrates on apolipoprotein, HDL, and
triglyceride metabolism. Our observations in the PPAR-deficient mouse warrant further studies to delineate the role of normal and
abnormal PPAR activity in man. It may be especially interesting to
evaluate genetic linkage in the PPAR gene from patients with abnormalities in lipid metabolism such as hypoalphalipoproteinemia, hypertriglyceridemia, or combined hyperlipidemia.
FOOTNOTES
¶ Research associate from CNRS.
Research director from INSERM.
** Research director from CNRS. To whom correspondence should be addressed: U.325 INSERM, Institut Pasteur, 1 Rue Calmette, 59019 Lille Cédex, France. Fax: 33-3-2087-7360; E-mail: Johan.Auwerx{at}pasteur-lille.fr.
1 The abbreviations used are: PPAR, peroxisome proliferator-activated receptor; PPRE, peroxisome proliferator-response element; HDL, high density lipoprotein; VLDL, very low density lipoprotein.
2 Martin, G., Schoonjans, K., Lefebvre, A., Staels, B., and Auwerx, J. (1997) J. Biol. Chem., manuscript in press.
ACKNOWLEDGEMENTS
Excellent technical help from Delphine Cayet, Bruno Derudas, and Odille Vidal are acknowledged.
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 G. P. Collett, A. M. Betts, M. I. Johnson, A. B. Pulimood, S. Cook, D. E. Neal, and C. N. Robson Peroxisome Proliferator-activated Receptor {{alpha}} Is an Androgen-responsive Gene in Human Prostate and Is Highly Expressed in Prostatic Adenocarcinoma Clin. Cancer Res., August 1, 2000; 6(8): 3241 - 3248. [Abstract] [Full Text]
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 J. M. Peters, S. S. T. Lee, W. Li, J. M. Ward, O. Gavrilova, C. Everett, M. L. Reitman, L. D. Hudson, and F. J. Gonzalez Growth, Adipose, Brain, and Skin Alterations Resulting from Targeted Disruption of the Mouse Peroxisome Proliferator-Activated Receptor beta (delta ) Mol. Cell. Biol., July 15, 2000; 20(14): 5119 - 5128. [Abstract] [Full Text]
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C. Rodríguez, V. Noé, A. Cabrero, C. J. Ciudad, and J. C. Laguna Differences in the Formation of PPARalpha -RXR/acoPPRE Complexes between Responsive and Nonresponsive Species upon Fibrate Administration Mol. Pharmacol., July 1, 2000; 58(1): 185 - 193. [Abstract] [Full Text]
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Y.-J. Y. Wan, D. An, Y. Cai, J. J. Repa, T. Hung-Po Chen, M. Flores, C. Postic, M. A. Magnuson, J. Chen, K. R. Chien, et al. Hepatocyte-Specific Mutation Establishes Retinoid X Receptor alpha as a Heterodimeric Integrator of Multiple Physiological Processes in the Liver Mol. Cell. Biol., June 15, 2000; 20(12): 4436 - 4444. [Abstract] [Full Text]
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M.-C. Vohl, P. Lepage, D. Gaudet, C. G. Brewer, C. Bétard, P. Perron, G. Houde, C. Cellier, J. M. Faith, J.-P. Després, et al. Molecular scanning of the human PPARa gene: association of the L162V mutation with hyperapobetalipoproteinemia J. Lipid Res., June 1, 2000; 41(6): 945 - 952. [Abstract] [Full Text]
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M. Marrapodi and J. Y. L. Chiang Peroxisome proliferator-activated receptor {alpha} (PPAR{alpha}) and agonist inhibit cholesterol 7{alpha}-hydroxylase gene (CYP7A1) transcription J. Lipid Res., March 1, 2000; 41(3): 514 - 520. [Abstract] [Full Text]
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M. Marrapodi and J. Y. L. Chiang Peroxisome proliferator-activated receptor {alpha} (PPAR{alpha}) and agonist inhibit cholesterol 7{alpha}-hydroxylase gene (CYP7A1) transcription J. Lipid Res., March 1, 2000; 41(4): 514 - 520. [Abstract] [Full Text]
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 R. B. Clark, D. Bishop-Bailey, T. Estrada-Hernandez, T. Hla, L. Puddington, and S. J. Padula The Nuclear Receptor PPAR{gamma} and Immunoregulation: PPAR{gamma} Mediates Inhibition of Helper T Cell Responses J. Immunol., February 1, 2000; 164(3): 1364 - 1371. [Abstract] [Full Text] [PDF]
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M. C. Hunt, S. E. B. Nousiainen, M. K. Huttunen, K. E. Orii, L. T. Svensson, and S. E. H. Alexson Peroxisome Proliferator-induced Long Chain Acyl-CoA Thioesterases Comprise a Highly Conserved Novel Multi-gene Family Involved in Lipid Metabolism J. Biol. Chem., November 26, 1999; 274(48): 34317 - 34326. [Abstract] [Full Text] [PDF]
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E. Raspé, L. Madsen, A-M. Lefebvre, I. Leitersdorf, L. Gelman, J. Peinado-Onsurbe, J. Dallongeville, J-C. Fruchart, R. Berge, and B. Staels Modulation of rat liver apolipoprotein gene expression and serum lipid levels by tetradecylthioacetic acid (TTA) via PPAR{alpha} activation J. Lipid Res., November 1, 1999; 40(11): 2099 - 2110. [Abstract] [Full Text]
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 B. Desvergne and W. Wahli Peroxisome Proliferator-Activated Receptors: Nuclear Control of Metabolism Endocr. Rev., October 1, 1999; 20(5): 649 - 688. [Abstract] [Full Text]
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 P. Gervois, I. P. Torra, G. Chinetti, T. Grötzinger, G. Dubois, J.-C. Fruchart, J. Fruchart-Najib, E. Leitersdorf, and B. Staels A Truncated Human Peroxisome Proliferator-Activated Receptor {alpha} Splice Variant with Dominant Negative Activity Mol. Endocrinol., September 1, 1999; 13(9): 1535 - 1549. [Abstract] [Full Text]
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 T. B. Barclay, J. M. Peters, M. B. Sewer, L. Ferrari, F. J. Gonzalez, and E. T. Morgan Modulation of Cytochrome P-450 Gene Expression in Endotoxemic Mice Is Tissue Specific and Peroxisome Proliferator-Activated Receptor-alpha Dependent J. Pharmacol. Exp. Ther., September 1, 1999; 290(3): 1250 - 1257. [Abstract] [Full Text]
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P. R. Devchand, A. K. Hihi, M. Perroud, W.-D. D. Schleuning, B. M. Spiegelman, and W. Wahli Chemical Probes That Differentially Modulate Peroxisome Proliferator-activated Receptor alpha and BLTR, Nuclear and Cell Surface Receptors for Leukotriene B4 J. Biol. Chem., August 13, 1999; 274(33): 23341 - 23348. [Abstract] [Full Text] [PDF]
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H. M. Guardiola-Diaz, S. Rehnmark, N. Usuda, T. Albrektsen, D. Feltkamp, J.-A. Gustafsson, and S. E. H. Alexson Rat Peroxisome Proliferator-activated Receptors and Brown Adipose Tissue Function during Cold Acclimatization J. Biol. Chem., August 13, 1999; 274(33): 23368 - 23377. [Abstract] [Full Text] [PDF]
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 M. R. Hill, S. Clarke, K. Rodgers, B. Thornhill, J. M. Peters, F. J. Gonzalez, and J. M. Gimble Effect of Peroxisome Proliferator-Activated Receptor Alpha Activators on Tumor Necrosis Factor Expression in Mice during Endotoxemia Infect. Immun., July 1, 1999; 67(7): 3488 - 3493. [Abstract] [Full Text] [PDF]
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 M. Kockx, P. P. Gervois, P. Poulain, B. Derudas, J. M. Peters, F. J. Gonzalez, H. M.G. Princen, T. Kooistra, and B. Staels Fibrates Suppress Fibrinogen Gene Expression in Rodents Via Activation of the Peroxisome Proliferator-Activated Receptor-alpha Blood, May 1, 1999; 93(9): 2991 - 2998. [Abstract] [Full Text] [PDF]
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 S. A. Kliewer, J. M. Lehmann, and T. M. Willson Orphan Nuclear Receptors: Shifting Endocrinology into Reverse Science, April 30, 1999; 284(5415): 757 - 760. [Abstract] [Full Text]
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P. Gervois, S. Chopin-Delannoy, A. Fadel, G. Dubois, V. Kosykh, J.-C. Fruchart, J. Najïb, V. Laudet, and B. Staels Fibrates Increase Human REV-ERB{alpha} Expression in Liver via a Novel Peroxisome Proliferator-Activated Receptor Response Element Mol. Endocrinol., March 1, 1999; 13(3): 400 - 409. [Abstract] [Full Text]
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J. P. Vanden Heuvel Peroxisome Proliferator–Activated Receptors: A Critical Link among Fatty Acids, Gene Expression and Carcinogenesis J. Nutr., February 1, 1999; 129(2): 575 - 575. [Abstract] [Full Text] [PDF]
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B. Staels, J. Dallongeville, J. Auwerx, K. Schoonjans, E. Leitersdorf, and J.-C. Fruchart Mechanism of Action of Fibrates on Lipid and Lipoprotein Metabolism Circulation, November 10, 1998; 98(19): 2088 - 2093. [Abstract] [Full Text] [PDF]
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P. Costet, C. Legendre, J. More, A. Edgar, P. Galtier, and T. Pineau Peroxisome Proliferator-activated Receptor alpha -Isoform Deficiency Leads to Progressive Dyslipidemia with Sexually Dimorphic Obesity and Steatosis J. Biol. Chem., November 6, 1998; 273(45): 29577 - 29585. [Abstract] [Full Text] [PDF]
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N. Vu-Dac, S. Chopin-Delannoy, P. Gervois, E. Bonnelye, G. Martin, J.-C. Fruchart, V. Laudet, and B. Staels The Nuclear Receptors Peroxisome Proliferator-activated Receptor alpha and Rev-erbalpha Mediate the Species-specific Regulation of Apolipoprotein A-I Expression by Fibrates J. Biol. Chem., October 2, 1998; 273(40): 25713 - 25720. [Abstract] [Full Text] [PDF]
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K. Motojima, P. Passilly, J. M. Peters, F. J. Gonzalez, and N. Latruffe Expression of Putative Fatty Acid Transporter Genes Are Regulated by Peroxisome Proliferator-activated Receptor alpha and gamma Activators in a Tissue- and Inducer-specific Manner J. Biol. Chem., July 3, 1998; 273(27): 16710 - 16714. [Abstract] [Full Text] [PDF]
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T. Aoyama, J. M. Peters, N. Iritani, T. Nakajima, K. Furihata, T. Hashimoto, and F. J. Gonzalez Altered Constitutive Expression of Fatty Acid-metabolizing Enzymes in Mice Lacking the Peroxisome Proliferator-activated Receptor alpha (PPARalpha ) J. Biol. Chem., March 6, 1998; 273(10): 5678 - 5684. [Abstract] [Full Text] [PDF]
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Y.-J. Y. Wan, Y. Cai, W. Lungo, P. Fu, J. Locker, S. French, and H. M. Sucov Peroxisome Proliferator-activated Receptor alpha -mediated Pathways Are Altered in Hepatocyte-specific Retinoid X Receptor alpha -deficient Mice J. Biol. Chem., September 1, 2000; 275(36): 28285 - 28290. [Abstract] [Full Text] [PDF]
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S. Kersten, S. Mandard, N. S. Tan, P. Escher, D. Metzger, P. Chambon, F. J. Gonzalez, B. Desvergne, and W. Wahli Characterization of the Fasting-induced Adipose Factor FIAF, a Novel Peroxisome Proliferator-activated Receptor Target Gene J. Biol. Chem., September 8, 2000; 275(37): 28488 - 28493. [Abstract] [Full Text] [PDF]
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J. Dallongeville, E. Bauge, A. Tailleux, J. M. Peters, F. J. Gonzalez, J.-C. Fruchart, and B. Staels Peroxisome Proliferator-activated Receptor alpha Is Not Rate-limiting for the Lipoprotein-lowering Action of Fish Oil J. Biol. Chem., February 9, 2001; 276(7): 4634 - 4639. [Abstract] [Full Text] [PDF]
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M. Bouly, D. Masson, B. Gross, X.-c. Jiang, C. Fievet, G. Castro, A. R. Tall, J.-C. Fruchart, B. Staels, L. Lagrost, et al. Induction of the Phospholipid Transfer Protein Gene Accounts for the High Density Lipoprotein Enlargement in Mice Treated with Fenofibrate J. Biol. Chem., July 6, 2001; 276(28): 25841 - 25847. [Abstract] [Full Text] [PDF]
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N. M. Morton, M. C. Holmes, C. Fievet, B. Staels, A. Tailleux, J. J. Mullins, and J. R. Seckl Improved Lipid and Lipoprotein Profile, Hepatic Insulin Sensitivity, and Glucose Tolerance in 11beta -Hydroxysteroid Dehydrogenase Type 1 Null Mice J. Biol. Chem., October 26, 2001; 276(44): 41293 - 41300. [Abstract] [Full Text] [PDF]
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M. Guerre-Millo, P. Gervois, E. Raspe, L. Madsen, P. Poulain, B. Derudas, J.-M. Herbert, D. A. Winegar, T. M. Willson, J.-C. Fruchart, et al. Peroxisome Proliferator-activated Receptor alpha Activators Improve Insulin Sensitivity and Reduce Adiposity J. Biol. Chem., May 26, 2000; 275(22): 16638 - 16642. [Abstract] [Full Text] [PDF]
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T. Imai, M. Jiang, P. Chambon, and D. Metzger Impaired adipogenesis and lipolysis in the mouse upon selective ablation of the retinoid X receptor alpha mediated by a tamoxifen-inducible chimeric Cre recombinase (Cre-ERT2) in adipocytes PNAS, January 2, 2001; 98(1): 224 - 228. [Abstract] [Full Text] [PDF]
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T. Claudel, M. D. Leibowitz, C. Fievet, A. Tailleux, B. Wagner, J. J. Repa, G. Torpier, J.-M. Lobaccaro, J. R. Paterniti, D. J. Mangelsdorf, et al. Reduction of atherosclerosis in apolipoprotein E knockout mice by activation of the retinoid X receptor PNAS, February 27, 2001; 98(5): 2610 - 2615. [Abstract] [Full Text] [PDF]
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T. Imai, M. Jiang, P. Kastner, P. Chambon, and D. Metzger Selective ablation of retinoid X receptor alpha in hepatocytes impairs their lifespan and regenerative capacity PNAS, April 10, 2001; 98(8): 4581 - 4586. [Abstract] [Full Text] [PDF]
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F. M. Gregoire, Q. Zhang, S. J. Smith, C. Tong, D. Ross, H. Lopez, and D. B. West Diet-induced obesity and hepatic gene expression alterations in C57BL/6J and ICAM-1-deficient mice Am J Physiol Endocrinol Metab, March 1, 2002; 282(3): E703 - E713. [Abstract] [Full Text] [PDF]
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