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J Biol Chem, Vol. 273, Issue 10, 5678-5684, March 6, 1998
From the Peroxisome
proliferator-activated receptor Peroxisomes are single membrane-bound subcellular organelles that
contain a variety of enzymes involved in a number of metabolic processes (1). The most well characterized reactions carried out by
peroxisomes are those that catalyze in fatty acid In addition to fatty acid oxidation, peroxisomes also carry out
The number of peroxisomes is increased in rodents by treatment with
high fat diets, cold temperature, starvation, ACTH, and certain
chemicals generically termed peroxisome proliferators (1). Peroxisome
proliferators include a structurally diverse group of chemicals that
include 1) hypolipidemic drugs (clofibrate, gemfibrozil, fenofibrate,
benzofibrate, etofibrate, and Wy-14,643), 2) the azole antifungal
compounds such as bifenazole, 3) leukotriene D4
antagonists, 4) herbicides, 5) pesticides, 6) phthalate esters used in
the plastics industry (di-[2-ethylhexyl] phthalate), 7) simple
solvents including trichloroethylene, and 8) natural chemicals such as
phenyl acetate and the steroid dehydroepiandrosterone sulfate. Among
them, the most potent peroxisome proliferator is Wy-14,643.
Peroxisome proliferation is most pronounced in liver, kidney, and
heart. In liver, the number of peroxisomes increases from about
500-600/cell to >5,000/cell after exposure to peroxisome proliferators (1). This is accompanied by an increase in cell volume
and cell number, resulting in hepatomegaly. Coincident with an increase
in the number of peroxisomes, several peroxisomal enzymes are induced
by transcriptional activation (4). Transcription of genes encoding the
key To determine the function of PPAR Materials--
Sodium
2-[5-(4-chlorophenyl)pentyl]-oxirane-2-carboxylate (POCA) was
purchased from Byk Gulden Pharmazeutika (Konstanz, Germany). [1-14C]lauric acid (55 mCi/mmol),
[1-14C]palmitic acid (54 mCi/mmol), and
[1-14C]lignoceric acid (47 mCi/mmol) were from American
Radiolabeled Chemicals (St. Louis, MO).
Animals and Wy-14,643 Treatment--
PPAR Fatty Acid Analysis of Fatty Acid Synthesizing Enzymes--
Fatty acid
synthetase (15), malic enzyme (ME) (16), ATP-citrate lyase (17),
acetyl-CoA carboxylase (18), and glucose-6-phosphate dehydrogenase (19)
were measured as described previously.
Analysis of Fatty Acid mRNA Analysis--
mRNA analysis was performed by
Northern blotting. Total liver RNA was extracted, electrophoresed on
1.1 M formaldehyde-containing 1% agarose gels, and
transferred to nylon membranes (23). The membranes were incubated with
32P-labeled cDNA probes and analyzed on a Fuji system
analyzer (Fuji Photo Film Co., Tokyo, Japan). The cDNA probes used
were for VLCAD (35), LCAD (36), LACS (37), ME (38), and SCHAD (39).
Analysis of Fatty Acid-metabolizing Enzymes--
To identify
specific fatty acid-metabolizing enzymes that were influenced by
PPAR
Altered Constitutive Expression of Fatty Acid-metabolizing
Enzymes in Mice Lacking the Peroxisome Proliferator-activated Receptor
(PPAR)*
§,
,,, and Department of Biochemistry, Shinshu
University School of Medicine, Matsumoto, Nagano 390, Japan,
¶ Laboratory of Metabolism, NCI, National Institutes of Health,
Bethesda Maryland 20892, Tezukayama Gakuin College, Sakai, Osaka
590, Japan, ** Department of Hygiene and Medical Genetics, Shinshu
University School of Medicine, Matsumoto, Nagano 390, Japan, and
Department of Laboratory Medicine, Shinshu
University School of Medicine, Matsumoto, Nagano 390, Japan
ABSTRACT
Top
Abstract
Introduction
Procedures
Results
Discussion
References
(PPAR) is a member of the
steroid/nuclear receptor superfamily and mediates the biological and
toxicological effects of peroxisome proliferators. To determine the
physiological role of PPAR in fatty acid metabolism, levels of
peroxisomal and mitochondrial fatty acid metabolizing enzymes were
determined in the PPAR null mouse. Constitutive liver 
-oxidation
of the long chain fatty acid, palmitic acid, was lower in the PPAR
null mice as compared with wild type mice, indicating defective
mitochondrial fatty acid catabolism. In contrast, constitutive
oxidation of the very long chain fatty acid, lignoceric acid, was not
different between wild type and PPAR null mice, suggesting that
constitutive expression of enzymes involved in peroxisomal
-oxidation is independent of PPAR. Indeed, the PPAR null mice
had normal levels of the peroxisomal acyl-CoA oxidase, bifunctional
protein (hydratase + 3-hydroxyacyl-CoA dehydrogenase), and thiolase but
lower constitutive expression of the D-type bifunctional protein
(hydratase + 3-hydroxyacyl-CoA dehydrogenase). Several mitochondrial
fatty acid metabolizing enzymes including very long chain acyl-CoA
dehydrogenase, long chain acyl-CoA dehydrogenase, short chain-specific
3-ketoacyl-CoA thiolase, and long chain acyl-CoA synthetase are also
expressed at lower levels in the untreated PPAR null mice, whereas
other fatty acid metabolizing enzymes were not different between the
untreated null mice and wild type mice. A lower constitutive expression
of mRNAs encoding these enzymes was also found, suggesting that the
effect was due to altered gene expression. In wild type mice, both
peroxisomal and mitochondrial enzymes were induced by the peroxisome
proliferator Wy-14,643; induction was not observed in the PPAR null
animals. These data indicate that PPAR modulates constitutive
expression of genes encoding several mitochondrial fatty
acid-catabolizing enzymes in addition to mediating inducible
mitochondrial and peroxisomal fatty acid -oxidation, thus
establishing a role for the receptor in fatty acid homeostasis.
INTRODUCTION
Top
Abstract
Introduction
Procedures
Results
Discussion
References
-oxidation. Since
plants lack mitochondria, peroxisomes are solely responsible for their
fatty acid -oxidation. The peroxisomal fatty acid -oxidation pathway produces hydrogen peroxide through the activity of acyl-CoA oxidase, thus historically accounting for the name "peroxisomes." Typically, H2O2 is decomposed to molecular
oxygen and water by catalase and glutathione peroxidase. Human genetic
deficiencies in peroxisome biogenesis and individual peroxisomal
enzymes have been described that result in accumulation of long chain
fatty acids (2). The most severe of the peroxisome deficiencies causes neurological and anatomical abnormalities.
-oxidation of the cholesterol side chain during the synthesis of
bile acids and participate in the biosynthesis of cholesterol (3),
ether glycolipids, and dolichols. Catabolism of purines, polyamines,
glyoxylate and certain amino acids have been attributed to
peroxisome-localized enzymes. Thus, peroxisomes are essential organelles for maintaining cellular and organismal homeostasis.
-oxidation enzymes acyl-CoA oxidase, enoyl-CoA
hydratase/3-hydroxyacyl-CoA dehydrogenase (bifunctional enzyme), and
thiolase are markedly elevated as a result of treatment with peroxisome
proliferators (5). Genes encoding the microsomal cytochrome P450 in the
CYP4A family are also activated by these agents (6). Changes in
peroxisomal and microsomal gene expression induced by peroxisome
proliferators are mediated by the peroxisome proliferator-activated
receptor (PPAR),1 a member of
the nuclear receptor superfamily. Three distinct PPARs have been found,
designated PPAR, 
(also called NUC-1 and ), and 
. Tissue
distribution of each receptor is different, suggesting that each has
unique functions. In rodents, PPAR is abundant in the liver, kidney,
and heart, all of which display peroxisome proliferation in response to
PPAR activators and have high rates of lipid metabolism (7).
Expression of PPAR is ubiquitous and is highly expressed in the
central nervous system (7). The role of PPAR is not known. PPAR
and PPAR2, resulting from differential mRNA splicing, are
present predominantly in adipose tissue and spleen. PPAR is
responsible in part for adipocyte differentiation and regulation of
adipocyte-specific genes (8). It is also the target for the
thiazolidinedione drugs that increase insulin sensitivity of target
tissues (9).
and its role in peroxisome
proliferation and hepatocarcinogenesis, a PPAR null mouse was generated (10). These animals exhibit a normal phenotype and normal
basal levels of hepatic peroxisomes. However, the PPAR null mouse is
nonresponsive to peroxisome proliferation. Compared with wild type
mice, administration of peroxisome proliferators to PPAR null mice
does not cause an increase in the number of peroxisomes, hepatomegaly,
nor increases in mRNA encoded by target genes. Furthermore, these
mice do not display physiological, toxicological, or carcinogenic
responses induced by peroxisome proliferators (11-13). Interestingly,
abnormal hepatic lipid accumulation was initially reported in the
PPAR null mice, suggesting an alteration in lipid metabolism (10).
To investigate the biochemical basis for altered lipid metabolism,
constitutive levels of peroxisomal and mitochondrial fatty
acid-metabolizing enzymes were examined in the PPAR null mouse.
EXPERIMENTAL PROCEDURES
Top
Abstract
Introduction
Procedures
Results
Discussion
References
null mice on an
Sv/129 genetic background were produced as described (10). Wild type
Sv/129 were used as controls in all experiments. Mice were fed either a
control diet or one containing 0.1% Wy-14,643 for 2 weeks.
-Oxidation Activity--
Fatty acid -oxidation
activity was measured by the method of Shindo et al., (14).
Briefly, unfrozen livers were homogenized in four volumes of 0.25 M sucrose containing 1 mM EDTA in a
Potter-Elvehjem homogenizer using a tight-fitting teflon pestle.
Approximately 500 µg of homogenate was incubated with the assay
medium in 0.2 ml of 150 mM potassium chloride, 10 mM HEPES, pH 7.2, 0.1 mM EDTA, 1 mM
potassium phosphate buffer, pH 7.2, 5 mM Tris malonate, 10 mM magnesium chloride, 1 mM carnitine, 0.15%
bovine serum albumin, 5 mM ATP, and 50 µM
each fatty acid (5.0 × 104 cpm of radioactive
substrate). The reaction was run for 30 min at 25 °C and stopped by
the addition of 0.2 ml of 0.6 N perchloric acid. The
mixture was centrifuged at 2,000 × g for 10 min, and the unreacted fatty acid in the supernatant was removed with 2 ml of
n-hexane using three extractions. Radioactive degradation products in the water phase were counted. In some experiments, 20 µM POCA or 2 mM potassium cyanide was added
to the incubation mixture to inhibit mitochondrial -oxidation
activity. Fatty acid -oxidation activity was expressed as
nmol/min/liver.
-Oxidizing Enzymes--
Liver extracts
were subjected to 10% SDS-polyacrylamide gel electrophoresis and
transferred to nitrocellulose membranes. The membranes were incubated
with the primary antibody followed by alkaline phosphatase-conjugated
goat anti-rabbit IgG. Immunoblotting was performed using rabbit
polyclonal antibodies against rat acyl-CoA oxidase (AOX) (20), short
chain-specific 3-ketoacyl-CoA thiolase (T1) (21), acetoacetyl-CoA
thiolase (T2) (22, 23), cytosolic thioesterase (CTE II) (24), short
chain acyl-CoA dehydrogenase (SCAD) (25), medium chain acyl-CoA
dehydrogenase (MCAD) (25), long chain acyl-CoA dehydrogenase (LCAD)
(25), very long chain acyl-CoA dehydrogenase (VLCAD) (26), long chain
acyl-CoA synthetase (LACS) (27), very long chain acyl-CoA synthetase
(VLACS) (28), peroxisomal thiolase (PT) (21), carnitine palmitoyl-CoA
transferase (CPT II) (29), short chain 3-hydroxyacyl-CoA dehydrogenase
(SCHAD) (30), peroxisomal bifunctional protein (PH) (30), mitochondrial short chain specific hydratase (MH) (31), mitochondrial trifunctional protein and subunit (TP and TP) (32), mitochondrial
thioesterase I (MTEI) (33), and peroxisomal D-type bifunctional protein
(DBF) (34).
RESULTS
Top
Abstract
Introduction
Procedures
Results
Discussion
References
, antibodies were used to measure protein levels on immunoblots
(Fig. 1, Table
I). Constitutive expression of several
enzymes (VLCAD, LCAD, LACS, and T1) were lower by 30-60% in untreated
PPAR null mice as compared with untreated wild type mice. Curiously,
constitutive expression of the SCHAD was higher by about 4-fold in the
PPAR null mouse liver as compared with wild type mice. Other
mitochondrial enzymes examined were expressed at similar levels in
untreated PPAR null and wild type mice. The expression of all
mitochondrial, microsomal, and cytosolic fatty acid-metabolizing
enzymes except for MH were increased in wild type mice fed Wy-14,643
compared with controls, with levels of induction ranging from 1.7-fold
for T2 to 4.7-fold for SCHAD. The expression of CTE II was totally
dependent on Wy-14,643 treatment in wild type mice. In the PPAR null
animals, there was no increase in expression of these enzymes after
feeding Wy-14,643 for 2 weeks (Fig. 1, Table I).
View larger version (51K):
[in a new window]
Fig. 1.
Immunoblot analysis of selected fatty
acid-metabolizing enzymes. Three lanes form a group of mice.
Diet, age, and genotype are indicated. Liver cell lysate (8 µg) was
subjected to electrophoresis and Western immunoblotting. The blots were
stained with antibodies against VLCAD (panel A), LCAD
(panel B), SCHAD (panel C), T1 (panel D), LACS (panel E), DBF (panel F), and CTE
II (panel G).
Western immunoblot quantitation of hepatic fatty acid-metabolizing
enzymes in wild type (+/+) and PPAR-null (
/) mice
-oxidation
enzyme expression of AOX, PH, PT, and VLACS was not significantly different between wild type and PPAR null mice (Fig. 1, Table I),
although DBF was 36% lower in the PPAR null animals. All of the
peroxisomal enzymes were induced from 3-7-fold in the wild type mice,
and this effect was not observed in the PPAR null mice.
Basal activities of cytosolic enzymes involved in fatty acid synthesis
including fatty acid synthetase, acetyl-CoA carboxylase, glucose-6-phosphate dehydrogenase, and ATP-citrate lyase were similar
in the untreated wild type and PPAR null mice except for ME, which
was present at only 50% of the level in the PPAR null mouse (Table
II). ME and glucose-6-phosphate
dehydrogenase were marginally induced (4-fold and 2-fold, respectively)
by Wy-14,643 feeding in the wild type mice, and these effects were not
observed in the PPAR null mouse treated with Wy-14,643.
|
Expression of mRNAs--
To determine whether the lower
expression of fatty acid-metabolizing enzymes and ME is due to altered
gene expression, hepatic mRNA levels were analyzed by Northern
blots (Fig. 2). Constitutive levels of
VLCAD, LCAD, ME, and LACS mRNA were lower in the PPAR null mice
compared with controls, consistent with the protein measurements. It is
noteworthy that hepatic levels of mRNA for SCHAD were not different
between untreated PPAR null and wild type mice even though the
protein levels were increased by 4-fold in the null mouse. Levels of
the mRNAs encoding, LCAD, and ME were significantly induced in wild
type mice by Wy-14,643. These data are also consistent with the Western
blot analysis. In contrast, the mRNAs encoding LACS and SCHAD were
not significantly increased by the drug. In the PPAR null mice,
there was no difference in mRNA levels for any of the enzymes after
treatment with Wy-14,643.
|
Analysis of Overall Fatty Acid -Oxidation Activity--
As
shown in Table I, six enzymes involved in fatty acid -oxidation had
lower constitutive expression in the PPAR null mice. Four of the six
(VLCAD, LCAD, LACS, and DBF) have highest catalytic activities with
long chain fatty acid substrates (25-27, 34), whereas the other two
(SCHAD and T1) are more active with short and medium chain fatty acids
(21, 30). To evaluate the significance of the altered fatty acid
-oxidation enzymes, total hepatic -oxidation was measured using
lauric acid (C-12), palmitic acid (C-16), and lignoceric acid (C-24).
Compared with wild type controls, the PPAR null mice basal levels of
total fatty acid -oxidation was lower with palmitic acid as a
substrate; there was no difference in metabolism of lauric acid and
lignoceric acid (Fig. 3). Wy-14,643 feeding caused a significant increase in metabolism of all three fatty
acids in wild type animals. No induction was observed in PPAR null
mice, consistent with the results found with the enzymes levels (Fig. 1
and Table I). Results were identical whether the data were calculated
per liver protein or per liver. These data provide evidence that the
lower constitutive expression of several long chain-specific fatty acid
-oxidation enzymes in the PPAR null mice compared with wild type
mice (Table I) significantly affects long chain fatty acid oxidation.
The lack of a difference in constitutive oxidation of the very long
chain-specific fatty acid, lignoceric acid, carried out by peroxisomal
enzymes supports the finding of no effect of PPAR on expression of
these enzymes except DBF in untreated null mice (Table I).
|
0.001 between the
two values.
-oxidation was minimal.
|
Time Course of Induction--
The kinetics of VLCAD and ME
mRNA and protein expression were determined after administration of
Wy-14,643. VLCAD mRNA and protein were rapidly induced within 1 day
after Wy-14,643 treatment in wild type mice (Fig.
4A). No induction of VLCAD was
found in PPAR null mice after 14 days of feeding Wy-14,643. Levels
of VLCAD mRNA and protein decreased to about 2-fold after 5 days of
feeding yet remained elevated up to 14 days of feeding. A similar time
course of induction was also observed in protein levels of several
mitochondrial fatty acid -oxidation enzymes (LCAD, SCAD, TP, and
TP). Induction of ME mRNA and enzyme activity reached maximal
levels of 4-fold after 7 days of Wy-14,643 feeding in the wild type
mice; neither mRNA nor activity were induced in the PPAR null
animal (Fig. 4B). Similar time course of induction was
observed in protein levels of several other enzymes (LACS, AOX, PH, PT,
DBF, VLACS, MCAD, and CTE II). Thus, the kinetics of the increase in ME
expression is slower than that of VLCAD. The reason for this
differential induction is not presently known.
|
) and PPAR
) mice. VLCAD or ME mRNA levels in wild type (
) and
PPAR
) mice are shown.
| |
DISCUSSION |
|---|
|
Top
Abstract
Introduction
Procedures
Results
Discussion
References
|
|---|
Constitutive expression of VLCAD, LCAD, SCHAD, T1, LACS, DBF, and
ME is regulated by PPAR since their abundance was significantly altered in the absence of PPAR as compared with wild type controls. With the exception of SCHAD, which was up-regulated in the PPAR null
mice, all of these proteins were found at lower levels in the PPAR
null mice. This shows that PPAR has an important role in regulating
basal levels of these enzymes involved in fatty acid -oxidation and
ME that participates in fatty acid synthesis. Although the mechanism
for this peroxisome proliferator-independent mechanism is not known, it
may be a result of altered gene expression since PPAR is known to
control transcription through interaction with peroxisome proliferator
response elements (4). The down-regulation is selective since
constitutive expression of other enzymes including MCAD, SCAD, TP,
TP, MH, T2, CPT II, and MTE I appear to be unaffected by loss of the
receptor. This is similar to the peroxisomal enzymes AOX, PH, PT, and
VLACS, where there was no difference in expression levels between the
untreated wild type and PPAR null mice. The data on enzyme levels
are supported by the results of total fatty acid metabolism in liver
where oxidation of long chain fatty acid, palmitate, which is
reflective of mitochondrial metabolism, was lower in the PPAR null
mice, whereas oxidation of the very long chain fatty acid, lignocerate,
was not different between the wild type and PPAR null mice. The lack
of difference in metabolism of this very long chain fatty acid is
almost certainly due to similar levels of the peroxisomal enzymes in
the two genotypes. Lower constitutive expression of fatty
acid-metabolizing enzymes and mitochondrial palmitic acid -oxidation
suggests that PPAR controls gene expression in the absence of
exogenous ligands for the receptor, and mice lacking PPAR have an
impaired ability to metabolize lipids.
To further elucidate the role of PPAR in lipid metabolism, the
effect of the prototypical peroxisome proliferator Wy-14,643 in PPAR
null mice was investigated. Indeed, PPAR was shown to transactivate
genes in the presence of peroxisome proliferators (40-42). In addition
to the peroxisomal -oxidation enzymes and microsomal fatty acid
hydroxylase P450, liver fatty acid binding protein and the genes
encoding MCAD (43), 3-hydroxy-3-methylglutaryl-CoA synthase (44), and
ME (45) are also activated by PPAR as indicated by
transactivation assays. The present study extends these observations by
confirming that expression of VLCAD, LCAD, SCAD, TP, TP, MTE I,
CTE II, SCHAD, T1, T2, LACS, and CPT II are all higher as a result of
Wy-14,643 feeding in wild type mice but not in PPAR null mice.
Northern analysis of mRNA encoding some of these enzymes revealed
that induction is most likely due to increases in mRNA. These
observations demonstrate that changes in gene expression of proteins
involved in lipid metabolism are mediated by PPAR after exposure to
peroxisome proliferators. Indeed, peroxisome proliferator response
elements have been found and shown to be functionally active in the
MCAD (43) and LACS (46) genes. A peroxisome proliferator response
element has not been found in the LCAD (47), even though it is induced
in wild type mice by Wy-14,643 feeding. Expression of ME is also
elevated at the mRNA and protein level in agreement with a role of
PPAR in its regulation (45).
The fibrate class of drugs can also lead to suppression of gene
expression of numerous proteins involved in lipid metabolism (4).
Levels of apolipoprotein A-I, apolipoprotein C-III, apolipoprotein A-IV, hepatic lipase, and lecithin cholesterol acyltransferase are all
lowered by treatment of mice with fibrate drugs (4, 48, 49). The
alterations of these proteins in addition to altered gene expression of
peroxisomal fatty acid -oxidizing enzymes are thought to contribute
to the lipid-lowering effects of hypolipidemic drugs (4). In addition,
it was recently shown that the down-regulation of apolipoprotein C-III
mRNA and protein that contributes to the triglyceride-lowering
effect of Wy-14,643 is mediated by PPAR (50). The results presented
here extend these observations by demonstrating that the peroxisome
proliferator Wy-14,643 induces significant changes in many fatty acid
-oxidizing enzymes and total hepatic -oxidation, which in turn
are likely to further contribute to the triglyceride-lowering
effect of the fibrate class of hypolipidemic drugs. Combined, these
results establish that PPAR functions in the control of lipid
homeostasis in mice by regulating constitutive and inducible expression
of fatty acid catabolism. Since nuclear receptors usually require a
ligand for gene activation, the constitutive control of the enzymes
would suggest that an endogenous ligand exists in liver.
The lower expression of mRNAs encoding several fatty
acid-metabolizing enzymes in PPAR null mice suggests either the
presence of an endogenous ligand that preferentially controls genes
encoding fatty acid-metabolizing enzymes and ME or that a
ligand-independent mechanism is involved. Indeed, phosphorylation of a
Ser-112 in PPAR through mitogen-activated protein kinase has been
shown to modulate its activity (51, 52). This kinase recognition site
is conserved between PPAR and PPAR. Irrespective of the mechanism
of PPAR activation, these results suggest that it differentially activates genes in the absence of exogenous ligands.
The identification of endogenous ligands has recently been addressed.
It was shown that PPAR participates in the control of the
inflammatory response involving leukotriene B4 (53). These
studies also established that leukotriene B4 can directly bind to recombinant PPAR. Possible direct binding of peroxisome proliferators was shown by induced conformational changes as detected by protease sensitivity of in vitro translated PPAR (54).
Other indirect transactivation experiments suggest that PPAR may
mediate the action of 8(S)-hydroxyeicosatetraenoic acid
(55). It is likely that other ligands for PPAR exist, including
fatty acid metabolites, as first suggested by the ability of fatty
acids to transactivate the receptor (56, 57). Evidence exists for the
presence of endogenous PPAR activators in cultured cells used for
transactivation studies. High background levels of reporter gene
activation are usually found in these types of studies (41, 58).
Further support for the existence of endogenous ligands was provided by
the demonstration that unsaturated fatty acids can bind to PPAR
(59). Thus, constitutive regulation of genes encoding fatty
acid-metabolizing enzymes and ME may be mediated by levels of one or
more fatty acid metabolites. These metabolites may be important
endogenous ligands that function in the control of fatty acid
metabolism. Support for this idea was provide by the observation that
dietary polyunsaturated fatty acids induce AOX and CYP4A P450 in a
PPAR-dependent mechanism (11). Taken together, these
studies suggest that PPAR may have several endogenous ligands, which
upon binding to the receptor result in the activation of fatty acid
catabolism including the oxidative degradation of leukotrienes,
arachidonic acid epoxides, and other fatty acid derivatives.
Among the important issues that need to be addressed is the species
differences in response to peroxisome proliferators (60). Mice and rats
are highly susceptible to peroxisome proliferation and
hepatocarcinogenesis, whereas nonhuman primates and humans appear to be
resistant. The mechanism of this species differences is not presently
known, but it might be due to lower hepatic levels of PPAR (61, 62).
Despite the lack of demonstratable peroxisome proliferation, the
fibrate drugs are highly effective lipid-lowering agents in humans
(63). Thus, PPAR may differentially regulate expression of genes
that cause peroxisome proliferation and genes encoding enzymes that are
responsible for fatty acid mobilization, transport, and catabolism. For
example, high cellular levels of receptor may activate genes encoding
peroxisomal, mitochondrial, and microsomal fatty acid metabolism in
addition to genes that directly or indirectly control the cell cycle
and peroxisome proliferation.
| |
FOOTNOTES |
|---|
* The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
§ Dept. of Biochemistry, Shinshu University School of Medicine, Asahi, Matsumoto, Nagano, Japan 390. Tel.: 81-263-37-2602; Fax: 81-263-37-2604; E-mail: toshifu{at}gipac.shinshu-u.ac.jp.
1
The abbreviations used are: PPAR, peroxisome
proliferator-activated receptor; VLCAD, very long chain acyl-CoA
dehydrogenase; LCAD, long chain acyl-CoA dehydrogenase; MCAD, medium
chain acyl-CoA dehydrogenase; SCAD, short chain acyl-CoA dehydrogenase;
TP, trifunctional protein subunit (long chain- specific
hydratase + long chain-specific 3-hydroxyacyl-CoA dehydrogenase);
TP, trifunctional protein subunit (long chain- specific
3-ketoacyl-CoA thiolase); MH, mitochondrial (short chain-specific)
hydratase; SCHAD, short chain 3-hydroxyacyl-CoA dehydrogenase; T1,
short chain-specific 3-ketoacyl-CoA thiolase; T2, acetoacetyl-CoA
thiolase; LACS, long chain acyl-CoA synthetase; CPT II, carnitine
palmitoyl-CoA transferase; MTE I, mitochondrial thioesterase I; CTE II,
cytosolic thioesterase II; AOX, acyl-CoA oxidase; PH, peroxisomal
bifunctional protein (hydratase + 3-hydroxyacyl-CoA dehydrogenase);
DBF, D-type (peroxisomal) bifunctional protein (hydratase + 3-hydroxyacyl-CoA dehydrogenase) and key enzyme of bile acid synthesis
from cholesterol; PT, peroxisomal thiolase; VLACS, very long chain
acyl-CoA synthetase; ME, malic enzyme; POCA, sodium
2-[5-(4-chlorophenyl)pentyl]-oxirane-2-carboxylate.
| |
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Abstract
Introduction
Procedures
Results
Discussion
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T. C. McCarthy, P. T. Pollak, E. A. Hanniman, and C. J. Sinal Disruption of Hepatic Lipid Homeostasis in Mice after Amiodarone Treatment Is Associated with Peroxisome Proliferator-Activated Receptor-{alpha}Target Gene Activation J. Pharmacol. Exp. Ther., December 1, 2004; 311(3): 864 - 873. [Abstract] [Full Text] [PDF]
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S. P. Anderson, C. Dunn, A. Laughter, L. Yoon, C. Swanson, T. M. Stulnig, K. R. Steffensen, R. A.S. Chandraratna, J.-A. Gustafsson, and J. C. Corton Overlapping Transcriptional Programs Regulated by the Nuclear Receptors Peroxisome Proliferator-Activated Receptor {alpha}, Retinoid X Receptor, and Liver X Receptor in Mouse Liver Mol. Pharmacol., December 1, 2004; 66(6): 1440 - 1452. [Abstract] [Full Text] [PDF]
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 J. M. Huss and D. P. Kelly Nuclear Receptor Signaling and Cardiac Energetics Circ. Res., September 17, 2004; 95(6): 568 - 578. [Abstract] [Full Text] [PDF]
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P. Howroyd, C. Swanson, C. Dunn, R. C. Cattley, and J. C. Corton Decreased Longevity and Enhancement of Age-Dependent Lesions in Mice Lacking the Nuclear Receptor Peroxisome Proliferator-Activated Receptor {alpha} (PPAR{alpha}) Toxicol Pathol, August 1, 2004; 32(5): 591 - 599. [Abstract] [PDF]
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 M. You and D. W. Crabb Recent Advances in Alcoholic Liver Disease II. Minireview: molecular mechanisms of alcoholic fatty liver Am J Physiol Gastrointest Liver Physiol, July 1, 2004; 287(1): G1 - G6. [Abstract] [Full Text] [PDF]
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 C. Cheung, T. E. Akiyama, J. M. Ward, C. J. Nicol, L. Feigenbaum, C. Vinson, and F. J. Gonzalez Diminished Hepatocellular Proliferation in Mice Humanized for the Nuclear Receptor Peroxisome Proliferator-Activated Receptor {alpha} Cancer Res., June 1, 2004; 64(11): 3849 - 3854. [Abstract] [Full Text] [PDF]
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 J. K. Reddy Peroxisome Proliferators and Peroxisome Proliferator-Activated Receptor {alpha}: Biotic and Xenobiotic Sensing Am. J. Pathol., June 1, 2004; 164(6): 2305 - 2321. [Full Text] [PDF]
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D. J. Kim, T. E. Akiyama, F. S. Harman, A. M. Burns, W. Shan, J. M. Ward, M. J. Kennett, F. J. Gonzalez, and J. M. Peters Peroxisome Proliferator-activated Receptor {beta} ({delta})-dependent Regulation of Ubiquitin C Expression Contributes to Attenuation of Skin Carcinogenesis J. Biol. Chem., May 28, 2004; 279(22): 23719 - 23727. [Abstract] [Full Text] [PDF]
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T. E. Akiyama, G. Lambert, C. J. Nicol, K. Matsusue, J. M. Peters, H. B. Brewer Jr., and F. J. Gonzalez Peroxisome Proliferator-activated Receptor {beta}/{delta} Regulates Very Low Density Lipoprotein Production and Catabolism in Mice on a Western Diet J. Biol. Chem., May 14, 2004; 279(20): 20874 - 20881. [Abstract] [Full Text] [PDF]
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K. Savolainen, T. J. Kotti, W. Schmitz, T. I. Savolainen, R. T. Sormunen, M. Ilves, S. J. Vainio, E. Conzelmann, and J. K. Hiltunen A mouse model for {alpha}-methylacyl-CoA racemase deficiency: adjustment of bile acid synthesis and intolerance to dietary methyl-branched lipids Hum. Mol. Genet., May 1, 2004; 13(9): 955 - 965. [Abstract] [Full Text] [PDF]
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 J. Zhang, D. I. W. Phillips, C. Wang, and C. D. Byrne Human skeletal muscle PPAR{alpha} expression correlates with fat metabolism gene expression but not BMI or insulin sensitivity Am J Physiol Endocrinol Metab, February 1, 2004; 286(2): E168 - E175. [Abstract] [Full Text] [PDF]
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P. Ferre The Biology of Peroxisome Proliferator-Activated Receptors: Relationship With Lipid Metabolism and Insulin Sensitivity Diabetes, February 1, 2004; 53(90001): S43 - 50. [Abstract] [Full Text]
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Y. Jia, C. Qi, Z. Zhang, T. Hashimoto, M. S. Rao, S. Huyghe, Y. Suzuki, P. P. Van Veldhoven, M. Baes, and J. K. Reddy Overexpression of Peroxisome Proliferator-activated Receptor-{alpha} (PPAR{alpha})-regulated Genes in Liver in the Absence of Peroxisome Proliferation in Mice Deficient in both L- and D-Forms of Enoyl-CoA Hydratase/Dehydrogenase Enzymes of Peroxisomal {beta}-Oxidation System J. Biol. Chem., November 21, 2003; 278(47): 47232 - 47239. [Abstract] [Full Text] [PDF]
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B. L. Knight, D. D. Patel, S. M. Humphreys, D. Wiggins, and G. F. Gibbons Inhibition of cholesterol absorption associated with a PPAR{alpha}-dependent increase in ABC binding cassette transporter A1 in mice J. Lipid Res., November 1, 2003; 44(11): 2049 - 2058. [Abstract] [Full Text] [PDF]
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O. Barbier, D. Duran-Sandoval, I. Pineda-Torra, V. Kosykh, J.-C. Fruchart, and B. Staels Peroxisome Proliferator-activated Receptor {alpha} Induces Hepatic Expression of the Human Bile Acid Glucuronidating UDP-glucuronosyltransferase 2B4 Enzyme J. Biol. Chem., August 29, 2003; 278(35): 32852 - 32860. [Abstract] [Full Text] [PDF]
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 R. E Olson Nutrition and genetics: an expanding frontier: Robert H Herman Memorial Award in Clinical Nutrition Lecture, 2002 Am. J. Clinical Nutrition, August 1, 2003; 78(2): 201 - 208. [Abstract] [Full Text] [PDF]
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 C. H. Hurst and D. J. Waxman Activation of PPAR{alpha} and PPAR{gamma} by Environmental Phthalate Monoesters Toxicol. Sci., August 1, 2003; 74(2): 297 - 308. [Abstract] [Full Text] [PDF]
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M. Fischer, M. You, M. Matsumoto, and D. W. Crabb Peroxisome Proliferator-activated Receptor {alpha} (PPAR{alpha}) Agonist Treatment Reverses PPAR{alpha} Dysfunction and Abnormalities in Hepatic Lipid Metabolism in Ethanol-fed Mice J. Biol. Chem., July 18, 2003; 278(30): 27997 - 28004. [Abstract] [Full Text] [PDF]
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T. A. Hopkins, M. C. Sugden, M. J. Holness, R. Kozak, J. R. B. Dyck, and G. D. Lopaschuk Control of cardiac pyruvate dehydrogenase activity in peroxisome proliferator-activated receptor-{alpha} transgenic mice Am J Physiol Heart Circ Physiol, June 5, 2003; 285(1): H270 - H276. [Abstract] [Full Text] [PDF]
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C.-H. Lee, P. Olson, and R. M. Evans Minireview: Lipid Metabolism, Metabolic Diseases, and Peroxisome Proliferator-Activated Receptors Endocrinology, June 1, 2003; 144(6): 2201 - 2207. [Abstract] [Full Text] [PDF]
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Y.-J. Y. Wan, G. Han, Y. Cai, T. Dai, T. Konishi, and A.-S. Leng Hepatocyte Retinoid X Receptor-{alpha}-Deficient Mice Have Reduced Food Intake, Increased Body Weight, and Improved Glucose Tolerance Endocrinology, February 1, 2003; 144(2): 605 - 611. [Abstract] [Full Text] [PDF]
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 L. de las Fuentes, P. Herrero, L. R. Peterson, D. P. Kelly, R. J. Gropler, and V. G. Davila-Roman Myocardial Fatty Acid Metabolism: Independent Predictor of Left Ventricular Mass in Hypertensive Heart Disease Hypertension, January 1, 2003; 41(1): 83 - 87. [Abstract] [Full Text] [PDF]
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M. Iemitsu, T. Miyauchi, S. Maeda, T. Tanabe, M. Takanashi, Y. Irukayama-Tomobe, S. Sakai, H. Ohmori, M. Matsuda, and I. Yamaguchi Aging-induced decrease in the PPAR-alpha level in hearts is improved by exercise training Am J Physiol Heart Circ Physiol, November 1, 2002; 283(5): H1750 - H1760. [Abstract] [Full Text] [PDF]
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H. Huang, O. Starodub, A. McIntosh, A. B. Kier, and F. Schroeder Liver Fatty Acid-binding Protein Targets Fatty Acids to the Nucleus. REAL TIME CONFOCAL AND MULTIPHOTON FLUORESCENCE IMAGING IN LIVING CELLS J. Biol. Chem., August 2, 2002; 277(32): 29139 - 29151. [Abstract] [Full Text] [PDF]
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M. E. Young, P. H. Guthrie, P. Razeghi, B. Leighton, S. Abbasi, S. Patil, K. A. Youker, and H. Taegtmeyer Impaired Long-Chain Fatty Acid Oxidation and Contractile Dysfunction in the Obese Zucker Rat Heart Diabetes, August 1, 2002; 51(8): 2587 - 2595. [Abstract] [Full Text] [PDF]
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 R. A. Coleman, T. M. Lewin, C. G. Van Horn, and M. R. Gonzalez-Baro Do Long-Chain Acyl-CoA Synthetases Regulate Fatty Acid Entry into Synthetic Versus Degradative Pathways? J. Nutr., August 1, 2002; 132(8): 2123 - 2126. [Abstract] [Full Text] [PDF]
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T. Helledie, L. Grontved, S. S. Jensen, P. Kiilerich, L. Rietveld, T. Albrektsen, M. S. Boysen, J. Nohr, L. K. Larsen, J. Fleckner, et al. The Gene Encoding the Acyl-CoA-binding Protein Is Activated by Peroxisome Proliferator-activated Receptor gamma through an Intronic Response Element Functionally Conserved between Humans and Rodents J. Biol. Chem., July 19, 2002; 277(30): 26821 - 26830. [Abstract] [Full Text] [PDF]
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D. M. Muoio, P. S. MacLean, D. B. Lang, S. Li, J. A. Houmard, J. M. Way, D. A. Winegar, J. C. Corton, G. L. Dohm, and W. E. Kraus Fatty Acid Homeostasis and Induction of Lipid Regulatory Genes in Skeletal Muscles of Peroxisome Proliferator-activated Receptor (PPAR) alpha Knock-out Mice. EVIDENCE FOR COMPENSATORY REGULATION BY PPARdelta J. Biol. Chem., July 12, 2002; 277(29): 26089 - 26097. [Abstract] [Full Text] [PDF]
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Y. Kamijo, K. Hora, N. Tanaka, N. Usuda, K. Kiyosawa, T. Nakajima, F. J. Gonzalez, and T. Aoyama Identification of Functions of Peroxisome Proliferator-Activated Receptor {alpha} in Proximal Tubules J. Am. Soc. Nephrol., July 1, 2002; 13(7): 1691 - 1702. [Abstract] [Full Text] [PDF]
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C. J. Chou, M. Haluzik, C. Gregory, K. R. Dietz, C. Vinson, O. Gavrilova, and M. L. Reitman WY14,643, a Peroxisome Proliferator-activated Receptor alpha (PPARalpha ) Agonist, Improves Hepatic and Muscle Steatosis and Reverses Insulin Resistance in Lipoatrophic A-ZIP/F-1 Mice J. Biol. Chem., June 28, 2002; 277(27): 24484 - 24489. [Abstract] [Full Text] [PDF]
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 S. R. Master, J. L. Hartman, C. M. D'Cruz, S. E. Moody, E. A. Keiper, S. I. Ha, J. D. Cox, G. K. Belka, and L. A. Chodosh Functional Microarray Analysis of Mammary Organogenesis Reveals a Developmental Role in Adaptive Thermogenesis Mol. Endocrinol., June 1, 2002; 16(6): 1185 - 1203. [Abstract] [Full Text] [PDF]
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I. J. Waterman and V. A. Zammit Differential Effects of Fenofibrate or Simvastatin Treatment of Rats on Hepatic Microsomal Overt and Latent Diacylglycerol Acyltransferase Activities Diabetes, June 1, 2002; 51(6): 1708 - 1713. [Abstract] [Full Text] [PDF]
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O. Sato, C. Kuriki, Y. Fukui, and K. Motojima Dual Promoter Structure of Mouse and Human Fatty Acid Translocase/CD36 Genes and Unique Transcriptional Activation by Peroxisome Proliferator-activated Receptor alpha and gamma Ligands J. Biol. Chem., May 3, 2002; 277(18): 15703 - 15711. [Abstract] [Full Text] [PDF]
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H. Katagiri, T. Asano, T. Yamada, T. Aoyama, Y. Fukushima, M. Kikuchi, T. Kodama, and Y. Oka Acyl-Coenzyme A Dehydrogenases Are Localized on GLUT4-Containing Vesicles via Association with Insulin-Regulated Aminopeptidase in a Manner Dependent on Its Dileucine Motif Mol. Endocrinol., May 1, 2002; 16(5): 1049 - 1059. [Abstract] [Full Text] [PDF]
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O. Barbier, I. P. Torra, Y. Duguay, C. Blanquart, J.-C. Fruchart, C. Glineur, and B. Staels Pleiotropic Actions of Peroxisome Proliferator-Activated Receptors in Lipid Metabolism and Atherosclerosis Arterioscler. Thromb. Vasc. Biol., May 1, 2002; 22(5): 717 - 726. [Abstract] [Full Text] [PDF]
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T. E. Akiyama, C. T. Baumann, S. Sakai, G. L. Hager, and F. J. Gonzalez Selective Intranuclear Redistribution of PPAR Isoforms by RXR{alpha} Mol. Endocrinol., April 1, 2002; 16(4): 707 - 721. [Abstract] [Full Text] [PDF]
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R. B. Clark The role of PPARs in inflammation and immunity J. Leukoc. Biol., March 1, 2002; 71(3): 388 - 400. [Abstract] [Full Text] [PDF]
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F. M. Campbell, R. Kozak, A. Wagner, J. Y. Altarejos, J. R. B. Dyck, D. D. Belke, D. L. Severson, D. P. Kelly, and G. D. Lopaschuk A Role for Peroxisome Proliferator-activated Receptor alpha (PPARalpha ) in the Control of Cardiac Malonyl-CoA Levels. REDUCED FATTY ACID OXIDATION RATES AND INCREASED GLUCOSE OXIDATION RATES IN THE HEARTS OF MICE LACKING PPARalpha ARE ASSOCIATED WITH HIGHER CONCENTRATIONS OF MALONYL-CoA AND REDUCED EXPRESSION OF MALONYL-CoA DECARBOXYLASE J. Biol. Chem., February 1, 2002; 277(6): 4098 - 4103. [Abstract] [Full Text] [PDF]
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 B.N. FINCK, J.J. LEHMAN, P.M. BARGER, and D.P. KELLY Regulatory Networks Controlling Mitochondrial Energy Production in the Developing, Hypertrophied, and Diabetic Heart Cold Spring Harb Symp Quant Biol, January 1, 2002; 67(0): 371 - 382. [Abstract] [PDF]
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M. Guerre-Millo, C. Rouault, P. Poulain, J. Andre, V. Poitout, J. M. Peters, F. J. Gonzalez, J.-C. Fruchart, G. Reach, and B. Staels PPAR-{alpha}-Null Mice Are Protected From High-Fat Diet-Induced Insulin Resistance Diabetes, December 1, 2001; 50(12): 2809 - 2814. [Abstract] [Full Text] [PDF]
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S. Yu, W.-Q. Cao, P. Kashireddy, K. Meyer, Y. Jia, D. E. Hughes, Y. Tan, J. Feng, A. V. Yeldandi, M. S. Rao, et al. Human Peroxisome Proliferator-activated Receptor alpha (PPARalpha ) Supports the Induction of Peroxisome Proliferation in PPARalpha -deficient Mouse Liver J. Biol. Chem., November 2, 2001; 276(45): 42485 - 42491. [Abstract] [Full Text] [PDF]
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D. Linden, M. Alsterholm, H. Wennbo, and J. Oscarsson PPAR{alpha} deficiency increases secretion and serum levels of apolipoprotein B-containing lipoproteins J. Lipid Res., November 1, 2001; 42(11): 1831 - 1840. [Abstract] [Full Text] [PDF]
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T. E. Akiyama, C. J. Nicol, C. Fievet, B. Staels, J. M. Ward, J. Auwerx, S. S. T. Lee, F. J. Gonzalez, and J. M. Peters Peroxisome Proliferator-activated Receptor-alpha Regulates Lipid Homeostasis, but Is Not Associated with Obesity. STUDIES WITH CONGENIC MOUSE LINES J. Biol. Chem., October 12, 2001; 276(42): 39088 - 39093. [Abstract] [Full Text] [PDF]
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A. Flores-Morales, N. Stahlberg, P. Tollet-Egnell, J. Lundeberg, R. L. Malek, J. Quackenbush, N. H. Lee, and G. Norstedt Microarray Analysis of the in Vivo Effects of Hypophysectomy and Growth Hormone Treatment on Gene Expression in the Rat Endocrinology, July 1, 2001; 142(7): 3163 - 3176. [Abstract] [Full Text] [PDF]
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D. D. Patel, B. L. Knight, D. Wiggins, S. M. Humphreys, and G. F. Gibbons Disturbances in the normal regulation of SREBP-sensitive genes in PPAR{{alpha}}-deficient mice J. Lipid Res., March 1, 2001; 42(3): 328 - 337. [Abstract] [Full Text]
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M. E. YOUNG, S. PATIL, J. YING, C. DEPRE, H. S. AHUJA, G. L. SHIPLEY, S. M. STEPKOWSKI, P. J. A. DAVIES, and H. TAEGTMEYER Uncoupling protein 3 transcription is regulated by peroxisome proliferator-activated receptor {alpha} in the adult rodent heart FASEB J, March 1, 2001; 15(3): 833 - 845. [Abstract] [Full Text] [PDF]
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P. Tollet-Egnell, A. Flores-Morales, N. Ståhlberg, R. L. Malek, N. Lee, and G. Norstedt Gene Expression Profile of the Aging Process in Rat Liver: Normalizing Effects of Growth Hormone Replacement Mol. Endocrinol., February 1, 2001; 15(2): 308 - 318. [Abstract] [Full Text]
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G. Lazennec, L. Canaple, D. Saugy, and W. Wahli Activation of Peroxisome Proliferator-Activated Receptors (PPARs) by Their Ligands and Protein Kinase A Activators Mol. Endocrinol., December 1, 2000; 14(12): 1962 - 1975. [Abstract] [Full Text]
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R. A. Memon, L. H. Tecott, K. Nonogaki, A. Beigneux, A. H. Moser, C. Grunfeld, and K. R. Feingold Up-Regulation of Peroxisome Proliferator-Activated Receptors (PPAR-{alpha}) and PPAR-{gamma} Messenger Ribonucleic Acid Expression in the Liver in Murine Obesity: Troglitazone Induces Expression of PPAR-{gamma}-Responsive Adipose Tissue-Specific Genes in the Liver of Obese Diabetic Mice Endocrinology, November 1, 2000; 141(11): 4021 - 4031. [Abstract] [Full Text] [PDF]
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J. F. Horowitz, T. C. Leone, W. Feng, D. P. Kelly, and S. Klein Effect of endurance training on lipid metabolism in women: a potential role for PPARalpha in the metabolic response to training Am J Physiol Endocrinol Metab, August 1, 2000; 279(2): E348 - E355. [Abstract] [Full Text] [PDF]
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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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D. A. Pan, M. K. Mater, A. P. Thelen, J. M. Peters, F. J. Gonzalez, and D. B. Jump Evidence against the peroxisome proliferator-activated receptor {alpha} (PPAR{alpha}) as the mediator for polyunsaturated fatty acid suppression of hepatic L-pyruvate kinase gene transcription J. Lipid Res., May 1, 2000; 41(5): 742 - 751. [Abstract] [Full Text]
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M. C. Hunt, P. J. G. Lindquist, J. M. Peters, F. J. Gonzalez, U. Diczfalusy, and S. E. H. Alexson Involvement of the peroxisome proliferator-activated receptor {alpha} in regulating long-chain acyl-CoA thioesterases J. Lipid Res., May 1, 2000; 41(5): 814 - 823. [Abstract] [Full Text]
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T. Nakajima, Y. Kamijo, N. Usuda, Y. Liang, Y. Fukushima, K. Kametani, F. J. Gonzalez, and T. Aoyama Sex-dependent regulation of hepatic peroxisome proliferation in mice by trichloroethylene via peroxisome proliferator-activated receptor {alpha} (PPAR{alpha}) Carcinogenesis, April 1, 2000; 21(4): 677 - 682. [Abstract] [Full Text] [PDF]
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R. B. Vega, J. M. Huss, and D. P. Kelly The Coactivator PGC-1 Cooperates with Peroxisome Proliferator-Activated Receptor alpha in Transcriptional Control of Nuclear Genes Encoding Mitochondrial Fatty Acid Oxidation Enzymes Mol. Cell. Biol., March 1, 2000; 20(5): 1868 - 1876. [Abstract] [Full Text]
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P. N. Black, N. J. Færgeman, and C. C. DiRusso Long-Chain Acyl-CoA-Dependent Regulation of Gene Expression in Bacteria, Yeast and Mammals J. Nutr., February 1, 2000; 130(2): 305 - 305. [Abstract] [Full Text]
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S. Basu-Modak, O. Braissant, P. Escher, B. Desvergne, P. Honegger, and W. Wahli Peroxisome Proliferator-activated Receptor beta Regulates Acyl-CoA Synthetase 2 in Reaggregated Rat Brain Cell Cultures J. Biol. Chem., December 10, 1999; 274(50): 35881 - 35888. [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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 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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V. Giguère Orphan Nuclear Receptors: From Gene to Function Endocr. Rev., October 1, 1999; 20(5): 689 - 725. [Abstract] [Full Text]
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