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INVITED REVIEW
effects on the heart and other vascular tissues
1Canadian Institutes of Health Research Group on Molecular and Cell Biology of Lipids and Departments of Medicine and Biochemistry, University of Alberta, Edmonton, Alberta, Canada T6G 2S2; and 2Institut de Génétique et Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Université Louis Pasteur, 67404 Illkirch, France
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ABSTRACT |
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 TOP ABSTRACT CLINICAL USE OF PPAR-{alpha}...PPAR-{alpha} EFFECTS ON TG,...PPAR-{alpha} AND THE HEARTPPAR-{alpha} AND THE VESSEL...LESSONS FROM PPAR-{alpha}...REFERENCES |
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is a member of a
large nuclear receptor superfamily whose main role is to activate genes
involved in fatty acid oxidation in the liver, heart, kidney, and skeletal
muscle. While currently used mainly as hypolipidemic agents, the cardiac
effects and anti-inflammatory actions of PPAR- agonists in arterial
wall cells suggest other potential cardioprotective and antiatherosclerotic
effects of these agents. This review summarizes current knowledge regarding
the effects of PPAR- agonists on lipid and lipoprotein metabolism, the
heart, and the vessel wall and introduces some of the insights gained in these
areas from studying PPAR--deficient mice. The introduction of new and
more potent PPAR- agonists will provide important insights into the
overall benefits of activating PPAR- clinically for the treatment of
dyslipidemia and prevention of vascular disease.
atherosclerosis; fatty acid oxidation; lipoproteins; cholesterol; nuclear receptors; peroxisome proliferator-activated receptor-; ATP-binding cassette transporter A1; fibrate; high-density lipoprotein
is 1 of 48 members of the nuclear receptor superfamily
presently identified in the human genome
(70). PPAR- is one of
the primary "metabolic" nuclear receptors that act as sensors of
fatty acid and other metabolites to enable the organism to adapt quickly to
environmental changes by inducing or inhibiting appropriate metabolic genes
and pathways (27).
PPAR- was identified as the nuclear receptor for clofibrate, a member
of the fibrate amphipathic carboxylic acid family originally found to induce
proliferation of the cell organelle peroxisomes in addition to activating
genes involved in fatty acid oxidation (FAO) and lowering lipid levels in
rodents (37,
88). The receptor activated by
clofibrate and several other "peroxisome-proliferating" agents was
subsequently cloned and given the name PPAR-
(41). Although these same
agents enhance FAO in humans, neither they nor the other members of the PPAR
family, PPAR-
/
and PPAR-
, actually induce peroxisome
proliferation in humans, but the name PPAR has stuck
(23,
32,
75).
PPARs all bind as heterodimers with another nuclear receptor partner, the
retinoid X receptor (RXR), to peroxisome proliferator response elements (PPRE)
consisting of a direct repeat of the hormone receptor response element
half-site spaced by one nucleotide in target genes
(58). Activation of
PPAR- by ligand binding and/or phosphorylation induces a conformational
change in the receptor, resulting in recruitment of coactivator complexes that
facilitate target gene transcription. Coregulator recruitment is thus an
integral part of nuclear receptor signaling pathways.
PPAR- is expressed in metabolically active tissues including the
liver, heart, kidney, skeletal muscle, and brown fat
(3,
9). It is also present in the
artery wall in monocyte/macrophages, vascular smooth muscle cells, and
endothelial cells (15,
40,
82). Fatty acids are the
primary natural ligands of PPAR-, which then activates genes for fatty
acid uptake and oxidative catabolism
(26,
42,
44,
46). High-fat diets,
particularly those rich in very-long-chain fatty acids and polyunsaturated
fatty acids (e.g., doxosahexaenoic acid and eicosapentaenoic acid), induce
fatty acid -oxidation via PPAR--dependent gene regulation.
Eicosanoids, derived from arachidonic acid via either the lipoxygenase or
cyclooxygenase pathways, also act as PPAR- ligands
(31). Synthetic ligands for
PPAR- include the fibrate drugs, phthalate ester plasticizers,
herbicides, food flavors, and leukotriene D4 receptor antagonists
(31,
67). Glucocorticoids induce
PPAR- transcription according to diurnal variations in glucocorticoid
levels and in response to stress
(54). This indicates that
situations of stress can enhance the impact of nutritional factors on
metabolic processes. PPAR- activity is also enhanced by protein kinase
A-dependent phosphorylation
(51).
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CLINICAL USE OF PPAR- AGONISTS
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agonists in the form of fibric acid derivatives or fibrates
(clofibrate, gemfibrozil, fenofibrate, bezafibrate, and ciprofibrate) have
been in use for over 40 yr for the treatment of dyslipidemia, mainly due to
their actions of lowering triglyceride (TG) levels, raising high-density
lipoprotein (HDL), and the more recently recognized effect of decreasing
levels of small, dense low-density lipoprotein (LDL) particles
(24,
81). The Helsinki Heart Study
was the first large clinical trial to show benefits from the use of a fibrate,
demonstrating a 34% reduction in the overall cardiac event rate in men with
dyslipidemia treated for 5 yr with gemfibrozil
(30). The more recent Veterans
Affairs HDL Cholesterol Intervention Trial demonstrated a 22% reduction in
coronary events and mortality in men with low HDL as their primary lipid
abnormality and treated for over 5 yr with gemfibrozil
(72). Although attributed
mainly to the hypolipidemic and HDL-raising actions of fibrate drugs, other
actions of these PPAR- agonists on blood vessels, thrombotic factors,
and possibly the heart itself may also have contributed to the benefits seen
in these trials.
The success of these trials has provided an increased recognition of the
importance of nuclear receptors, including PPAR-, as master regulators
of genes involved in metabolic control at several levels. This awareness has
resulted in an intensive search for novel activators of these receptors that
might be used in preventive and therapeutic strategies to combat common
diseases such as atherosclerosis, diabetes, obesity, and possibly some forms
of heart disease. The following sections review the current understanding of
the effects of PPAR- agonists in various tissues and the potential
benefits and drawbacks associated with broader use of these agents to treat
and prevent cardiovascular disease. The major actions of PPAR- on lipid
homeostasis and the cardiovascular system are summarized in
Fig. 1.
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PPAR- EFFECTS ON TG, LDL, AND HDL METABOLISM
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TOPABSTRACTCLINICAL USE OF PPAR-{alpha}...PPAR-{alpha} EFFECTS ON TG,...PPAR-{alpha} AND THE HEARTPPAR-{alpha} AND THE VESSEL...LESSONS FROM PPAR-{alpha}...REFERENCES |
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agonists are those at the
hepatic and extrahepatic levels on lipoprotein metabolism. PPAR- is the
primary PPAR subtype expressed in the liver and is a major regulator of the
hepatic metabolism of fats, synthesis and catabolism of lipoproteins, and some
steps in the HDL synthetic and reverse cholesterol transport pathways. Binding
to PPAR- by fatty acid, eicosanoid, and fibrate drug ligands leads to
activation of numerous genes involved in -oxidative catabolism of fatty
acids (26,
42,
44). In addition to inducing
all the genes encoding enzymes of the classical fatty acid -oxidation
pathway [e.g., acyl-CoA oxidase, very-long-chain and medium-chain acyl-CoA
dehydrogenase, and 3-keto-acyl-CoA thiolase
(66)], PPAR- also
activates the genes necessary for cellular uptake of fatty acids (fatty acid
transport protein) and their initial derivatization for entry into the
-oxidation cycle (acyl-CoA synthetase) (for a review, see Ref.
76). PPAR- also
stimulates FAO by these enzymes in the other tissues in which it is expressed,
including the heart, skeletal muscle, and kidney
(5,
78). Increased diversion of
fatty acids into -oxidation decreases the availability of fatty-acyl CoA
substrates for TG synthesis and therefore decreases very-low-density
lipoprotein (VLDL) secretion by the liver. The relative importance of hepatic
peroxisomal FAO induced by PPAR- agonists in humans, which have an
order of magnitude less PPAR- mRNA in the liver compared with rodents,
is not yet clear. Hepatic mitochondrial, rather than peroxisomal,
-oxidation of fatty acids is likely the major site of PPAR-
action in the human liver, as seen in the heart
(94). The lower expression of
PPAR- in the liver and the lack of a peroxisome proliferative response
in humans may be the major reason the fibrates have not been associated with
hepatocarcinogenesis in humans as they have in rodents
(36).
In addition to limiting substrate availability for TG and VLDL synthesis,
PPAR- has been reported to inhibit expression of apolipoprotein (apo)
C-III (34,
84), a protein that inhibits
both the TG-hydrolyzing action of lipoprotein lipase (LPL) and the uptake of
TG-rich lipoprotein remnants
(80,
99). Inhibition of apo C-III
expression would therefore enhance TG-rich particle hydrolysis and improve the
uptake of their remnants by the liver, thereby decreasing plasma TG levels
further. Although active in inhibiting apo C-III in rodents, the ability of
PPAR- agonists to lower apo C-III in humans remains controversial
(38,
50). PPAR- agonists may
also decrease TG levels by increasing the expression of LPL in the liver
(77) and in macrophages
(2,
60). How much of the
hypotriglyceridemic effect of PPAR- ligands can be ascribed to direct
versus indirect effects (via decreased apo C-III) on LPL is not yet known.
The fibrate drug class of PPAR- agonists also decreases TG content
of LDL particles, converting them from the more atherogenic small, dense
phenotype to larger, less atherogenic LDL
(55,
101). This effect is likely
due to the combined effects of lower VLDL and TG and increased VLDL remnant
clearance and therefore lower TG levels available for transfer to LDL.
In addition to beneficial effects on fatty acid and TG metabolism,
PPAR- also enhances components of the HDL synthetic pathway. Synthesis
of apo A-I and apo A-II, the two major proteins of HDL, by the liver and
intestine is the first step in HDL particle formation. PPAR- activation
by fibrates activates human apo A-I and apo A-II genes in the liver, leading
to increased synthesis of these proteins
(95–98).
A recent study (36) using
rabbits expressing the human apo A-I transgene along with its PPRE showed an
increase in human apo A-I mRNA and mass in response to fenofibrate treatment
in the absence of any peroxisome-proliferative effect of the fibrate.
The second mechanism for increasing HDL-cholesterol concentrations in
plasma is the delivery of redundant surface phospholipid and apolipoprotein
components of VLDL and chylomicrons onto HDL during hydrolysis of TG-rich
particles by LPL (35).
Enhancement of TG hydrolysis, by PPAR--induced reduction in apo C-III
synthesis and an increase in LPL synthesis and activity, decreases TG levels,
increasing the transfer of other surface components of TG-rich particles to
HDL (6,
35). HDL synthesis is also
enhanced by the actions of the phospholipid transport protein (PLTP), which
may explain a portion of the HDL-raising effect of fibrates because they
increase expression of PLTP by PPAR-
(8).
The third and rate-limiting mechanism of HDL formation is the removal of
cellular phospholipids and cholesterol by lipid-free or lipid-poor HDL
apolipoproteins (63). The
importance of this pathway was highlighted by the discovery that, despite
normal synthesis of HDL apolipoproteins
(43,
57), cultured cells isolated
from patients with the low HDL syndrome Tangier disease failed to release both
phospholipids and cholesterol to apo A-I
(28,
68). The gene defect
responsible for Tangier disease was identified in 1999 by several groups in
the ATP-binding cassette transporter AI (ABCA1) (for a review, see Ref.
62). Regulation of this
membrane transporter, currently thought to mediate the delivery of either
phospholipid alone or both phospholipid and cholesterol to apo A-I, is in a
large part by nuclear receptors including the liver X receptor (LXR) and the
PPAR-s (18,
69,
79,
93). Some studies suggest both
PPAR- and PPAR- activate ABCA1 expression indirectly by
enhancing the transcription of LXR-, the promoter of which contains a
PPRE (13,
16,
49,
90). A recent study, however,
found no change in liver ABCA1 mRNA levels in PPAR- knockout mice
(48). While additional studies
are required, these findings lend further support for the use of synthetic
PPAR as well as LXR or RXR agonists in the prevention or treatment of
atherosclerosis.
The final uptake of cholesterol carried on HDL by the liver is mediated
through the concerted actions of scavenger receptor B-I and hepatic lipase.
These players in reverse cholesterol transport are also affected by nuclear
receptors. We (83) have
previously shown that fenofibrate may also raise HDL-cholesterol levels by a
PPAR--induced decrease in hepatic lipase activity. Although the role of
scavenger receptor B-I in mediating cholesterol efflux to HDL from peripheral
cells remains controversial, some evidence suggests that scavenger receptor
B-I is expressed in atherosclerotic tissue macrophages and is increased in
cultured macrophages in response to both PPAR- and PPAR- ligands
(14). Stimulation of the
phospholipid transporter MDR2 could be a final point where PPAR-
agonists affect reverse cholesterol transport, by favoring the excretion of
phospholipids and associated cholesterol from the liver into bile
(48)
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PPAR- AND THE HEART
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TOPABSTRACTCLINICAL USE OF PPAR-{alpha}...PPAR-{alpha} EFFECTS ON TG,...PPAR-{alpha} AND THE HEARTPPAR-{alpha} AND THE VESSEL...LESSONS FROM PPAR-{alpha}...REFERENCES |
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agonists on
lipoprotein metabolism, the net effects of PPAR- activation on cardiac
metabolism and function in normal and disease states are less well defined.
The main activity of PPAR- in the heart is to provide energy to the
myocardium by activating genes regulating mitochondrial fatty acid uptake and
oxidation (94). The fetal
heart relies primarily on glucose and lactate as energy sources. After birth,
the capacity for PPAR--dependent FAO increases markedly. This results
in the heart using FAO as the preferred substrate for ATP production while
retaining the ability to switch to glucose and lactate utilization to meet its
energy demands with varying dietary and physiological conditions
(74,
94). Studies using cultured
neonatal cardiomyocytes have demonstrated the direct effects of fatty acids
and PPAR- agonists in activating PPAR--dependent enzymes of
fatty acid uptake and FAO in the heart
(10,
91,
92). In vivo studies in adult
rats showed that expression of myocardial uncoupling protein 3, a
PPAR--dependent enzyme, was increased on a high-fat diet and decreased
on a low-fat diet (103).
These results suggest that the circulating levels of TGs and fatty acids are
important determinants of substrate availability for myocardial PPAR-
and FAO.
A major controversy regarding changes in PPAR- activity in cardiac
disease states is whether these are adaptive or causally related to myocardial
pathology. In conditions of pressure-induced cardiac hypertrophy, PPAR-
is downregulated, resulting in reversion of the heart to the fetal pattern of
glucose and lactate substrate utilization
(4,
74). Diminished cardiac FAO
and increased utilization of glucose has been found in studies of both murine
(73) and human
(19) cardiac hypertrophy. This
switch reduces the oxygen requirement of the heart to produce ATP, which is
higher per mole of fatty acid substrate oxidized than for glucose
(94). In this sense, the shift
from PPAR--dependent FAO to glucose utilization can be considered an
adaptive response (29). In the
long term, however, this switch becomes detrimental as less ATP is generated
per mole of glucose oxidized, and lipid accumulation and lipotoxicity of the
myocardium may develop (5).
Whether this switch of energy substrates by deactivation of PPAR- is
actually an adaptive response to pressure overload or a mediator of the
development of heart failure in pressure-induced cardiac hypertrophy, due to
decreased ATP production and lipid accumulation, is not yet known
(53). In a murine model of
pressure-overload cardiac hypertrophy, reactivation of PPAR- by
agonists prevented substrate switching to glucose and resulted in severe
depression of cardiac power and efficiency in the hypertrophied heart
(102). The conclusion from
this study was that PPAR- downregulation is essential for the
maintenance of contractile function of the hypertrophied heart. The
significance of these findings to human cardiac hypertrophy is not yet known.
To date, there are no reports of worsening of cardiac function in human
cardiac hypertrophy with the use of PPAR- agonist fibrates. The lack of
such reports suggests any detrimental direct effects of PPAR- agonists
on cardiac function in cardiac hypertrophy may be offset by the beneficial
effects of decreasing TG and free fatty acid substrate availability to the
ailing myocardium, thereby decreasing lipid accumulation in hearts undergoing
a switch to increased glucose utilization.
In contrast to the alterations in substrate use by the hypertrophied
myocardium, the heart in uncontrolled diabetes is constrained from switching
to glucose oxidation due to lack of insulin or insulin resistance, resulting
in impaired glucose utilization and an almost exclusive use of FAO to provide
the ATP needs of the myocardium
(71,
85). Increased myocardial
fatty acid uptake and reliance on FAO for energy production results in
increased myocardial oxygen consumption due to excessively high mitochondrial
oxidative flux. High circulating levels and uptake of TG and free fatty acids
by the diabetic heart leads to excess myocardial lipid accumulation, which
further predisposes to contractile dysfunction and myocyte death
(17,
104). Whether this is the
fault of PPAR- induction of FAO, or simply a reflection of the altered
substrate availability in the diabetic heart, is unknown. If, however, excess
fatty acid substrates are the culprit, a reduction of circulating TG and free
fatty acid levels induced by PPAR- agonists such as fibrates would
likely have a net beneficial effect on the diabetic myocardium. Aasum et al.
(1) found that treatment of
diabetic db/db mice with a PPAR- agonist normalized
circulating free fatty acid, TG, and glucose levels, actually reduced
myocardial FAO by 50%, and increased myocardial glucose utilization. They also
found that FAO enzymes were not upregulated by the PPAR- agonist in
these mouse hearts. These results suggested that the extra-cardiac effects of
the PPAR- agonist, by decreasing circulating free fatty acid levels and
increasing insulin sensitivity, have greater effects on cardiac energy
utilization by decreasing the activation of PPAR- and the substrate
availability of FAO enzymes rather than directly inducing their expression in
the heart. This conclusion is consistent with the requirement of fatty acid
substrates to activate PPAR--dependent fatty acid uptake and FAO by
cultured neonatal cardiomyocytes
(10,
91,
92) and the direct correlation
between UCP-3 expression in adult rat hearts and dietary fat intake by these
animals (103). Although the
Aasum et al. study (1) also
showed a 46% decrease in myocardial TG content after a 4- to 5-wk treatment
with a PPAR- agonist, they did not show improvements in contractile
function of the myocardium. In contrast to this study, which started agonist
treatment at 8 wk of age, Zhou et al.
(104) found decreased
myocardial TG content and improved myocardial function in Zucker diabetic
fatty rats treated with a PPAR- agonist for 6 or 13 wk beginning at
6–7 wk of age. The ability of PPAR- agonists to prevent or
reverse structural changes in the diabetic myocardium may therefore depend on
earlier or more prolonged treatment with the agonist. Further studies are
required to answer this question.
In contrast to these findings suggesting that substrate availability is the
key determinant of the activity of PPAR-activated FAO genes in the myocardium,
Finck et al. (25) showed that
cardiac-specific overexpression of PPAR- increased FAO, decreased
glucose utilization, and induced a diabetic-type cardiomyopathy in otherwise
normal mice. The fact that these changes occurred even on a normal chow diet
in non-diabetic animals may argue against substrate availability being a key
determinant of PPAR- function in the heart. The constitutive
overexpression of PPAR- in the hearts of these animals, however, and
their inability to utilize glucose as an energy source means they cannot be
compared with diabetic mice capable of increasing glucose utilization in
response to improved insulin sensitivity, as seen with the use of a
PPAR- agonist in the Aasum et al. study
(1). Final conclusions about
the overall importance of direct versus indirect (noncardiac) effects of
PPAR- agonists on the heart await further studies.
The net effects of PPAR- agonists on the ischemic heart are also
still unclear. Whereas some studies demonstrated the beneficial effects of
pretreatment with PPAR- agonists on the degree of ischemic injury,
others emphasized the importance of the energy switch away from
PPAR--induced FAO in the postischemic heart to decrease the oxygen cost
of energy production from fatty acids. Tabernero et al.
(87) showed that pretreatment
of control mice with fenofibrate for 10 days reduced infarct size and improved
postischemic contractile dysfunction using an ischemia-reperfusion injury
model, whereas PPAR--null mice were more susceptible to the ischemic
injury and refractory to protection by fenofibrate. Wayman et al.
(100) also found that
pretreatment with both PPAR- and PPAR- agonists for just 30 min
before ischemic injury resulted in a substantially decreased postischemic
myocardial infarct size in rats. Explanations for these findings include
improvements in the metabolic milieu (decreased free fatty acid and TG levels)
before ischemia, improved ATP stores before ischemia, and decreased expression
of the proinflammatory markers nuclear factor (NF)-
B and activator
protein (AP)-1 (see PPAR- EFFECTS AND THE VESSEL
WALL) after ischemia. Agents that diminish FAO and increase glucose
utilization after the ischemic insult have been found to improve myocardial
recovery postischemia (56).
The rationale in this case is that glucose utilization requires less oxygen
consumption for energy generation than does FAO and does not worsen acidosis
in the damaged myocardium the way FAO can. Severe ischemia itself turns off
PPAR--regulated gene expression as a source of ATP production from
fatty acids (39,
65). Glucose transporter
GLUT4-deficient mice develop profound myocardial dysfunction during ischemia
(89), suggesting the ability
to switch to glucose utilization after ischemia is critical
(56). Overall, it appears that
treatment with PPAR- agonists preischemia may limit ischemic damage to
the myocardium but that postischemia the physiological or treatment-induced
[using agents such as trimetazidine or dichloroacetate
(56)] switch from FAO to
glucose utilization improves cardiac efficiency and aids in recovery of the
damaged myocardium.
The heart also expresses LPL, which has been found to be upregulated in the
liver and macrophages in response to PPAR- agonists
(60,
77). Although likely a key
player in myocardial TG hydrolysis and fatty acid uptake, cardiac LPL activity
has been found to be inhibited by PPAR- agonists in cultured rat
cardiomyocytes (12). These
results suggest that PPAR- activation by fatty acids or agonists could
actually inhibit LPL as a protective mechanism against a potentially toxic
oversupply of fatty acids to the myocardium
(12).
In summary, it appears that PPAR- is vital as an activator of FAO
and energy production by the heart but that PPAR- agonists might
decrease net FAO in the heart due to decreasing circulating TG and free fatty
acid levels, i.e., by limiting substrate availability for
PPAR--activated FAO enzymes (Fig.
1). Pretreatment with PPAR- agonists may improve the
outcome of cardiac ischemic events; however, it seems likely these agents
would be contraindicated in the immediate postischemic period if they reverse
the switch to glucose utilization during recovery of the damaged myocardium.
Further studies are required to more clearly define the role of PPAR-
in the pathogenesis of cardiac hypertrophy, myocardial substrate utilization,
and protecting against postischemic injury.
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PPAR- AND THE VESSEL WALL
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agonists have been found to have numerous potentially
beneficial actions in cultured artery wall cells, suggesting further
antiatherosclerotic activities of these agents in addition to their beneficial
effects on lipids and lipoproteins
(7,
94). Nonlipid-related effects
on atherosclerosis were also suggested by studies in cholesterol-fed rabbits
where fibrates decreased atherosclerosis without appreciable effects on
circulating lipid levels (for a review, see Ref.
94). PPAR- is expressed
in human aortic smooth muscle cells and mediates inhibition of interleukin
(IL)-6 and prostaglandin production and expression of cyclooxygenase 2
(82). The latter effect is due
to PPAR- repression of NF-B signaling. This effect also inhibits
IL-6 secretion by activated endothelial cells
(20), which also express
PPAR-, thereby decreasing IL-6-dependent induction of monocyte
chemotactic protein 1 expression. Clinically, fibrate treatment reduces
circulating IL-6 levels as well as the prothrombotic factor fibrinogen and the
marker of inflammation C-reactive protein
(82). Tumor necrosis
factor--induced expression of vascular cell adhesion molecule 1 by
endothelial cells, an effect also mediated through NF-B signaling, is
also inhibited by PPAR- agonists
(59). Tissue factor expression
by monocytes, a major component of thrombus formation in acute coronary
events, is also inhibited by PPAR- agonists
(61). This effect is thought
to be mediated by inhibition of NF-B and AP-1
(59,
61). PPAR--dependent
inhibition of AP-1 is likewise thought to mediate the inhibition of expression
of endothelin 1, a potent inducer of cell adhesion molecules expression after
endothelial injury (21).
Macrophage production of scavenger receptor A, a mediator of uptake of
oxidized LDL and therefore of foam cell formation, and of matrix
metalloproteinase 9, a mediator of cell invasion from the vessel wall into the
intima, are also inhibited by PPAR- agonists
(94). In addition, fibrates
have been shown to reduce plasma levels of fibrinogen, which in vivo would
reduce the likelihood of thrombogenesis
(47). Clearly, PPAR-
agonists are likely to have numerous beneficial antiatherosclerotic actions in
addition to their defined benefits on lipid and lipoprotein metabolism. |
LESSONS FROM PPAR- KNOCKOUT MICE
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TOPABSTRACTCLINICAL USE OF PPAR-{alpha}...PPAR-{alpha} EFFECTS ON TG,...PPAR-{alpha} AND THE HEARTPPAR-{alpha} AND THE VESSEL...LESSONS FROM PPAR-{alpha}...REFERENCES |
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-null mice has helped to confirm several of
the proposed actions of this nuclear receptor as well as identifying new
actions. These mice are viable, fertile, and exhibit no gross phenotypic
defects (52). They do,
however, exhibit profound metabolic abnormalities in the liver and heart.
These mice fail to exhibit peroxisome proliferation or activation of FAO
target genes when exposed to PPAR- agonists
(52,
64,
87). They accumulate increased
hepatic TG in response to feeding and during fasting
(64,
86). PPAR--null mice
develop severe hypoglycemia when fasted
(45), due to impaired FAO and
increased reliance on glucose as an energy source. This also likely explains
their resistance to high-fat diet-induced insulin resistance
(33). These mice also develop
massive accumulation of myocardial lipids under conditions that increase fatty
acid flux, confirming the importance of PPAR- in mediating FAO and
preventing the toxic accumulation of fat in the heart
(22). Campbell et al.
(11) showed that the marked
increase in malonyl-CoA, a potent inhibitor of FAO, in the hearts of
PPAR--null mice is due to decreased expression of malonyl-CoA
carboxylase. These results demonstrate yet another mechanism of regulation of
FAO by PPAR-.
In conclusion, it is now well established that PPAR- agonists have
beneficial effects clinically in lipid metabolism and in decreasing coronary
vascular events and mortality. In vitro and animal studies now also suggest
numerous direct anti-inflammatory and antiatherosclerotic effects of
PPAR- agonists in the artery wall. Less certain are the overall effects
of PPAR- on the development of pressure-induced and diabetic
cardiomyopathy and the role of PPAR- agonists in preventing
postischemic myocardial injury. Drugs under development with enhanced
PPAR- agonist or combined PPAR-/PPAR- activity will
further help in identifying the benefits of activating this receptor
clinically, but will need to be assessed critically for potentially
detrimental effects in situations such as cardiac ischemia.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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REFERENCES |
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,-, and - in the adult rat.
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354-366, 1995.
ligands
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Circ Physiol 281:
H888-H894, 2001.-oxidation pathway by a novel family of nuclear hormone
receptors. Cell 68:
879-887, 1992.[ISI][Medline]
and PPAR activators direct a tissue-specific
transcriptional response via a PPRE in the lipoprotein lipase gene.
EMBO J 15:
5336-5348, 1996.[ISI][Medline]
