# The PPARα-PGC-1α Axis Controls Cardiac Energy Metabolism in Healthy and Diseased Myocardium

Authors: Jennifer G. Duncan; Brian N. Finck
Journal: PPAR Research
 (2008)

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## Abstract

The mammalian myocardium is an omnivorous organ that relies on multiple substrates in order to fulfill its tremendous energy demands. Cardiac energy metabolism preference is regulated at several critical points, including at the level of gene transcription. Emerging evidence indicates that the nuclear receptor PPARα and its cardiac-enriched coactivator protein, PGC-1α, play important roles in the transcriptional control of myocardial energy metabolism. The PPARα-PGC-1α complex controls the expression of genes encoding enzymes involved in cardiac fatty acid and glucose metabolism as well as mitochondrial biogenesis. Also, evidence has emerged that the activity of the PPARα-PGC-1α complex is perturbed in several pathophysiologic conditions and that altered activity of this pathway may play a role in cardiomyopathic remodeling. In this review, we detail the current understanding of the effects of the PPARα-PGC-1α axis in regulating mitochondrial energy metabolism and cardiac function in response to physiologic and pathophysiologic stimuli.


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## Body

## 1. Introduction

The
myocardium has an enormous and steady demand for energy that is met through
high-level mitochondrial oxidative metabolism.  Glucose, lactate,  and fatty
acids are all oxidized in the mitochondrion to produce reducing equivalents
required for ATP synthesis in the process of oxidative phosphorylation
(OXPHOS). Much of the mitochondrial-derived ATP is then transported to the
cytoplasm, making energy available for cellular work, which includes its
crucial role in cardiac myocyte contraction. Acute changes in flux through these
metabolic pathways are mediated by changes in substrate concentrations and
covalent or allosteric modification of enzymes catalyzing these reactions.
However, the capacity for mitochondrial oxidative metabolism is also mediated
at the level of gene transcription [1].Work in several
labs has demonstrated that the three PPAR isoforms (PPARα, β/δ, and γ) are
expressed, to varying degrees, in the myocardium and play important roles in
the transcriptional regulation of cardiac metabolism and function. The ability
to modulate PPAR activity with specific activating ligands as well as genetic
activation or deactivation in mice has enriched our understanding of the
importance of each of the various PPAR isoforms in determining cardiac
metabolism, structure, and function. However, given the limited space available
in this review, we will focus our attention on the PPARα isoform and its coactivator protein
PGC-1α.


## 2. PPARα and Myocardial Fatty Acid Metabolism

The PPARα
isoform is robustly expressed in the parenchymal cells of the adult heart and
plays an important role in regulating cardiac myocyte metabolism [2, 3].  In the myocardium, PPARα activation
induces the expression of genes encoding nearly every step in the cellular
fatty acid utilization pathway including (i) fatty acid transport proteins that
facilitate fatty acid entry into the cell, (ii) acyl-CoA synthetases that
esterify fatty acids to coenzyme A and prevent their efflux, (iii) fatty acid
binding proteins that shuttle fatty acids to various cellular compartments,
(iv) proteins that catalyze the import of fatty acids into the mitochondrion,
(v) every enzyme in the mitochondrial fatty acid β-oxidation spiral, and (vi) various
accessory components of fatty acid metabolism (e.g., uncoupling proteins).Administration of
PPARα ligand to
rodent models results in a robust activation of PPAR target genes in liver, but
the effects of in vivo ligand administration on cardiac gene expression is
minimal [4]. Indeed, PPARα agonist
administration to diabetic mice actually leads to diminished cardiac fatty acid
utilization [5, 6], possibly by reducing the
exposure of the heart to triglyceride-rich lipoproteins or endogenous fatty
acid ligands. It is unclear whether PPARα ligand administration targets the heart
directly in humans; and there are likely differences in the PPAR response
between the species. Due to the hepatic specific effects of PPARα ligands in
rodents, much of our knowledge regarding the target pathways of PPARα in
myocardium is based on studies with genetic alterations in PPARα activity.
Mice with constitutive deletion (in all tissues) of the gene encoding PPARα (PPARα null mice)
exhibit diminished rates of cardiac fatty acid oxidation (FAO) and increased
reliance on glucose utilization pathways [7–9]. This shift is mediated, at
least in part, by diminished expression of several genes involved in FAO [10] and a concomitant increase in
the expression of genes encoding proteins involved in glucose uptake and
utilization [7]. At the other end of the
metabolic spectrum, we have characterized transgenic mice overexpressing PPARα in a
cardiac-restricted manner (MHC-PPARα mice) [8, 11–16]. The expression of many genes
involved in fatty acid uptake and utilization is upregulated in MHC-PPARα mice, while
the expression of glucose transporter and glycolytic enzymes is strikingly
suppressed [11]. Consistent with this pattern
of metabolic gene expression, MHC-PPARα mice rely almost exclusively on FAO and
use very little glucose [8, 9, 11]. In summary, the opposing
metabolic phenotypes of these transgenic models with activation or deactivation
of PPARα
support an important role for PPARα in regulating cardiac energy
metabolism.


## 3. The PGC-1α Transcriptional Coactivator and the Control of Cardiac Energy Metabolism

Transcriptional coactivators are a group of proteins that control gene
expression via protein-protein interactions with DNA-bound transcription
factors, including PPARα (Figure 1). Although several
transcriptional coactivators are known to interact with PPARα, in the
heart, the physical and functional interaction with PPARγ coactivator 1α (PGC-1α) has been best described. PGC-1α was
originally discovered in a yeast two-hybrid screen for proteins that interacted
with the PPARγ
isoform and that were enriched in a brown adipocyte library [17]. Based on sequence homology
in some highly conserved regions, two additional PGC-1 family members have now
been identified (PGC-1β
and PGC-related coactivator (PRC)) [18, 19].Mechanisms of PPARα activation and PGC-1α coactivator
activity.
Depiction of a potential
PPARα target gene
and nuclear receptor response element (NRRE) within the promoter region in the
nonactivated state (top). PPARα activation by fatty acid (FA) ligand  leads to binding to the NRRE with its
heterodimeric partner RXRα; and its coactivator PGC-1α. PGC-1α recruits
additional coactivators with histone acetyltransferase (HAT) activity, which promotes
chromatin unwinding and increases RNA polymerase II (POL II) access to the
target gene promoter (middle). PGC-1α also interacts with the TRAP/DRIP
complex and with ménage-à-trois 1 (MAT1) which phosphorylates POL II to
increase the probability of gene transcription. In addition, PGC-1α plays a role
in RNA splicing via an RNA processing domain in its C-terminus
(bottom).
(a)(b)(c)Coactivators are
broadly categorized into two classes. Class I coactivators regulate gene
transcription through enzymatic modification of chromatin (e.g., acetylation and
methylation), which facilitates DNA unwinding and enhances the probability that
a gene will be transcribed by the RNA polymerase II complex. Class II coactivators
work by interacting with the RNA polymerase machinery (e.g., RNA polymerase II
or the TRAP/DRIP complex) [20, 21]. PGC-1α functions as a Class II coactivator
since it does not possess intrinsic chromatin modifying activity and interacts
directly with the TRAP/DRIP complex to link with RNA polymerase II  (Figure 1) [20].  PGC-1α also recruits Class I coactivators with histone acetyltransferase activity
to chromatin in the target gene promoter [20, 22] and docks with a protein
called ménage-à-trois 1, which phosphorylates RNA
polymerase II to modulate its activity (Figure 1) [23]. Finally, PGC-1α possesses an
RNA processing domain that may also contribute to its transcriptional
regulatory function [24].PGC-1
interacts with and coactivates a broad array of transcription factors to
transduce developmental, nutritional, and physiological stimuli to the control
of diverse cellular energy metabolic pathways
[25, 26]. In heart, PGC-1α has thus far been
linked with 3 families of transcription factors: (i) the PPAR family, (ii)
the estrogen-related receptor (ERR) family, and (iii) nuclear respiratory
factor 1 (NRF-1). The interaction between PGC-1α and PPARα serves to control the expression of
enzymes involved in fatty acid uptake and oxidation [27] and possibly proteins
involved in the process of mitochondrial biogenesis [15]. The ERR family (ERRα, β, γ) of orphan
nuclear receptors is also an important cardiac PGC-1α target that drives increased expression
of genes encoding FAO and OXPHOS enzymes [28–31]. Finally, NRF-1 is a
nuclear-encoded transcription factor that is coactivated by PGC-1α to regulate
transcription of genes involved in mitochondrial OXPHOS, mtDNA transcription
and replication, and mitochondrial biogenesis [32–35]. Additional details regarding
PGC-1-mediated control of energy metabolism through ERRα and NRF-1 can be found in other recent
reviews [26, 35–37].Several
genetically-engineered mouse models have been used to probe the role of PGC-1α in
regulating cardiac metabolism.  Mice that
constitutively overexpress PGC-1α in the myocardium exhibit profound
mitochondrial proliferation, cardiomyopathy, and early death secondary to heart
failure [33].  The severity of the cardiomyopathy in this
model precluded a full investigation of the pathologic mechanisms that
contribute to cardiac dysfunction. To address this issue, a second model
evaluated overexpression of PGC-1α in the heart using a
tetracycline-inducible system [38]. This model revealed dramatic
mitochondrial proliferation when PGC-1α was overexpressed in the neonatal
phase, without overt effects on cardiac function. In contrast, overexpression
of PGC-1α
in adult mice provoked only modest mitochondrial proliferation, but led to
abnormal mitochondrial and myofibril architecture and severe cardiac
dysfunction [38]. Interestingly,
cardiomyopathy in these mice was completely reversible by discontinuing PGC-1α
overexpression [38]. These gain-of-function
strategies indicate that PGC-1α plays important roles in regulating
multiple aspects of myocardial metabolism and is a strong stimulus for the
process of mitochondrial biogenesis.The cardiac
phenotype of two separate lines of mice with constitutive PGC-1α deficiency
also support an important role for PGC-1α in cardiac metabolism and function [39–41]. Both lines of PGC-1α-deficient
mice exhibit impaired mitochondrial OXPHOS function and decreased expression of
many genes encoding enzymes in mitochondrial metabolic pathways. PGC-1α deficiency
also leads to cardiac dysfunction, especially in the context of
pathophysiologic stimuli like pressure overload-induced cardiac hypertrophy [40, 41]. Interestingly, the severity
of the cardiac functional phenotype varies between the two lines of knockout mice.
One line exhibits age-associated cardiac dysfunction that is manifested by 7-8 months old as
left ventricular chamber dilatation, diminished fractional shortening, and an
activation of gene markers of cardiomyopathy [41]. Conversely, the other line
of knockout mice exhibits no signs of cardiac dysfunction, but displays
diminished chronotropic capacity in response to a β-adrenergic stimulus [39]. The mechanistic basis for
this disparity in the two mouse mouse models
is unknown. Collectively, these gain- and loss-of-function studies demonstrate
that PGC-1α
has a critical role in control of cardiac energy metabolism.


## 4. PPARα-PGC-1α-Mediated Control of Metabolism in Response to Developmental or Physiologic Cues

Myocardial energy substrate preference is remarkably
pliant and the heart can rapidly modulate fuel utilization depending upon the
developmental stage, nutritional context, or disease state [42]. The PPARα-PGC-1α complex
plays an important role in catalyzing these changes. For example, the fetal
heart utilizes predominantly anaerobic glucose metabolism to fulfill its energy
needs. However, almost immediately after birth, a rapid and profound
developmental shift occurs. The workload of the heart is increased and the
availability of fatty acids and oxygen for fuel becomes much greater (Figure 2). In response to these changes, the myocardium increases its reliance on
mitochondrially derived ATP as an energy source
through a coordinated induction of mitochondrially and nuclear-encoded
genes involved in mitochondrial metabolism, structure, and function [43–45]. This developmental shift is
accompanied by a robust activation of the PPARα-PGC-1α system [33, 43]; and it is likely that these
two factors play a crucial role in this developmental switch.Figure 2
Dynamic regulation of
PPARα-PGC-1α complex
activity in developing, failing, and diabetic heart. Physiological cardiac growth resulting from postnatal maturation is
associated with increased PPARα and PGC-1α expression and marked expansion of mitochondrial
volume density and oxidative capacity. Conversely, pathologic hypertrophy is
linked to decreased PPARα-PGC-1α expression and/or activity and diminished reliance
on oxidative mitochondrial metabolism often leading to intramyocellular lipid
accumulation. Finally, in the diabetic heart, PPARα-PGC-1α complex activity is increased along with the
cardiac reliance on FAO. Despite of high-level FAO, the cardiac lipid
accumulation is a hallmark of the diabetic heart and lipotoxicity may play a
key role in the development of diabetic cardiomyopathy.Fasting
is another physiologic context associated with a marked increase in PPARα-PGC-1α activity. To
“spare” glucose for other organs that lack the capacity to catabolize fatty
acids, the heart markedly increases its use of fatty acids under conditions of
food deprivation [42]. Although the expression of
the gene encoding PPARα
is unaltered, the expression of PGC-1α is strongly induced [33]. Together with heightened
availability of fatty acids that act as endogenous ligands for PPARα, this serves
to rapidly amplify PPARα transcriptional activity. In fact, the
expression of the broad program of myocardial FAO enzymes is markedly induced
by food deprivation and this response is significantly blunted in mice lacking
PPARα [10]. In sum, the PPARα-PGC-1α complex
serves to regulate the capacity for FAO in response to physiologic cues that
signal an increased need for mitochondrial fatty acid utilization.


## 5. Altered PPARα-PGC-1α Signaling in the Failing Heart

Cardiac
energy substrate metabolism is perturbed in the hypertrophied and failing
heart, reverting to a program of energy substrate metabolism similar to the
“fetal” profile (Figure2). Specifically, the myocardium shifts from
dependence on FAO towards glucose utilization; primarily anaerobic glycolysis [46–49]. Importantly, this switch in
energy substrate preference detected in various experimental models is also
observed in humans with idiopathic dilated cardiomyopathy [50]. These changes in energy
substrate preference are mediated, at least in part, by a downregulation of the
genes encoding enzymes involved in FAO, OXPHOS, and the PPARα-PGC-1α complex [3, 48, 51–60].
The expression of the genes encoding PPARα and PGC-1α is known to be diminished in several
rodent models of pressure overload or hypertensive heart disease [3, 40, 61], pacing-induced heart failure
[62, 63], hypoxia [52], ischemic heart disease [55, 58, 59, 64], as well as genetically  engineered models of heart failure [65–67]. The molecular mechanisms
whereby pathologic stimuli lead to a transcriptional downregulation of PPARα and PGC-1α are not well
understood, but may involve reactive oxygen species generation [64]. In addition, under
pathologic conditions, PPARα activity is inhibited
post-translationally through lower levels of the obligate heterodimeric partner
of PPARα,
retinoid X receptor (RXR) [57], and direct phosphorylation
by the extracellular signal-related kinase and mitogen-activated protein kinase
(ERK-MAPK) pathway [3]. These findings suggest that
deactivation of the cardiac PPARα-PGC-1α axis in failing heart is a key
component of the observed shift in energy metabolism. In support of this,
reactivation of PPARα
or PGC-1α
prevents the downregulation of oxidative gene expression that occurs in cardiac
myocytes challenged with pathologic stimuli [61, 63–65, 68, 69]. Experimental models have
found altered metabolism and gene expression in both the hypertrophied and the
overtly failing heart, but longitudinal evaluation of progressive changes in
the PPARα-PGC-1α axis has not
been done. Studies to evaluate the sequence of events will be crucial to
understanding the role of altered metabolic regulation in disease progression.One
point that remains to be addressed is whether deactivation of oxidative
metabolism and the PPARα-PGC-1α complex in the hypertrophied and
failing heart is adaptive or maladaptive. The shift towards glycolysis allows
continued ATP production with less oxygen consumption, and thus would appear to
be an adaptive response.  Indeed,
overexpression of the GLUT1 glucose transporter prevented cardiac dysfunction
in response to pressure overload [70]. Partial inhibitors of FAO
also produce positive inotropic effects in patients with ischemic and
nonischemic heart disease [71–76]. Ligand-mediated activation
of PPARα
in models of pressure overload [61] or ischemia [64] exacerbated ventricular
dysfunction and pathologic remodeling. However, other reports show no ill
effects of PPARα
agonism or increased FAO in pathologic conditions [68, 69, 77]. Moreover, there is abundant evidence that chronic shifts towards
glycolysis are maladaptive. Most reports suggest that PPARα agonists are
beneficial in the response to ischemia [78–80] and various models of heart
failure [63, 81–83]. Similarly, PGC-1α
overexpression rescued the cardiac myocyte dysfunction and apoptosis in a mouse
model of cardiomyopathy [65]. Mice with chronic reliance
on glucose metabolism due to loss of cardiac lipoprotein lipase develop cardiac
dysfunction with age and demonstrate significant mortality associated with the
stress of aortic banding [84].  Finally, PPARα deficient animals that shift metabolism
predominantly towards glucose oxidation exhibit age-associated cardiac fibrosis
[85] and were unable to respond to
increased workload and developed energy depletion [86].The concept that
the myocardium must maintain metabolic flexibility and a balance of substrate
utilization during pathologic remodeling has recently pushed to the forefront.
However, the biologic basis for this concept is unclear.  It may be that chronic reliance on glucose as
the predominant substrate is insufficient for ATP production in failing heart.
Compared to FAO, glycolysis produces much less ATP per mole of substrate and
there is evidence that long-term reliance on glycolysis leads to ATP deficiency
in failing heart. Indeed, the phospho-creatine/ATP ratio is reduced in failing
heart [49, 87–89] and a decline in this ratio
is predictive of impending mortality in human heart failure patients [90]. The idea that energy
starvation plays a significant role in the development of heart failure is also
supported by severe cardiomyopathies in animal models with deletions in FAO
enzymes [91, 92] or enzymes involved in
mitochondrial ATP production [93–95]. Moreover, humans with inborn
errors in these pathways often present with cardiomyopathy [96]. It is also possible that
impairments in rates of FAO in failing heart are maladaptive because they lead
to myocardial lipid accumulation (lipotoxicity) [97], which is linked to cardiac
dysfunction [98–100]. Alternatively, or in
addition, the inability to switch energy substrate preference in the context of
changes in substrate availability could also contribute to pathologic
remodeling.


## 6. PPARα and PGC-1α in the Diabetic Heart

Cardiovascular disease is
exceptionally prevalent in patients with diabetes. Although the prevalence of
dyslipidemias
and hypertension certainly contributes to cardiovascular risk in diabetic
subjects, cardiomyopathy is highly prevalent independent of these risk factors.
Cardiomyopathy in diabetic subjects that occurs in the absence of known risk
factors is often termed “diabetic cardiomyopathy” [101–104]. Unfortunately, the etiology
of diabetic cardiomyopathy is poorly understood.Evidence has emerged that abnormalities
in myocardial energy metabolism play a significant role in the pathogenesis of
diabetic cardiomyopathy. Indeed, in experimental models of uncontrolled
diabetes (type 1 or 2), cardiac energy substrate flexibility becomes
constrained and the diabetic heart relies almost exclusively on mitochondrial
FAO for its ATP requirements [105–108]. Recently, these metabolic
observations from animal models have also been confirmed in human subjects with
type 1 diabetes [109]. The expression of PPARα, PGC-1α, and many
target genes involved in FAO are increased in the murine insulin-resistant [15] and diabetic heart (type 1
and type 2) [11, 110, 111] and may play a key role in
the observed metabolic switch to FAO. PPARα deficiency in the setting of insulin
resistance [15] or diabetes [110] blunts activation of FAO gene
expression, suggesting that activation of the PPARα-PGC-1α regulatory network is critical for the
increased FAO rates and lipid uptake seen in the diabetic heart. Consistent
with this, transgenic mice that overexpress PPARα exclusively in the heart (MHC-PPARα mice) have a
cardiac metabolic phenotype similar to that observed in diabetic heart,
including accelerated rates of FAO, a striking diminution in glucose uptake and
utilization, and a mitochondrial biogenic response [11, 15]. We have also observed that
high-level fatty acid utilization in hearts of MHC-PPARα mice leads to the development of
cardiac hypertrophy and dysfunction [11, 12]. We believe that sustained
activation of the PPARα-PGC-1α complex in
the insulin-resistant and diabetic heart promotes a state of metabolic
inflexibility that leads to cardiomyopathic remodeling.Despite high rates of FAO,
myocardial lipid accumulation is a hallmark of the diabetic heart [112–116]. Prolonged accumulation of
fats in the myocardium is believed to be highly toxic and is linked to the
development of insulin resistance and cardiac dysfunction [12, 98–100, 114]. Our data suggest that PPARα drives this
lipotoxic response in diabetic heart. The cardiomyopathic phenotype is
relatively mild in unchallenged MHC-PPARα mice, but when the transgenic mice were
given a high-fat diet, the cardiomyopathic phenotype was strikingly exacerbated;
and mice exhibited clinical signs of heart failure, including depressed
fractional shortening and ventricular chamber dilatation [12]. Pathologic remodeling in
MHC-PPARα
mice was accompanied by marked cardiac lipid accumulation. Moreover, genetic
ablation of the fatty acid transporter CD36 in the context of PPARα
overexpression prevents high-fat diet-induced cardiac lipid accumulation and
dysfunction [16]. Finally, ligand-mediated
activation of PPARα
also drives lipid accumulation and an adverse outcome following ischemic insult
[64]. These findings suggest that
PPARα-driven
lipotoxicity could be an important mechanism in cardiomyopathic remodeling of
the diabetic heart.Other components of the metabolic
derangements in diabetic heart are abnormalities in mitochondrial
ultrastructure and function [15, 111, 117–120]. Mitochondria isolated from
diabetic rodents exhibit depressed rates of OXPHOS [117, 118] and diminished efficiency in
ATP synthesis [120, 121], likely due to increased
uncoupled respiration [121]. Mitochondrial proliferation
is common in hearts of diabetic rodents [15, 119, 121, 122]. However, mitochondria from
both type 1 and type 2 diabetic hearts often exhibit ultrastructural
abnormalities, including degenerative cristae [15, 119]. The literature regarding the
effects of insulin resistance and diabetes on mitochondrial gene expression is
mixed with some reports showing an activation [15, 119] and others showing
deactivation [123, 124]. We recently found that
mitochondrial biogenesis and OXPHOS gene expression are increased in a mouse
model of obesity-related insulin resistance [15]. These effects of insulin
resistance were blunted in PPARα null mice and recapitulated in MHC-PPARα mice,
suggesting that PPARα
is involved in mitochondrial biogenesis in the myocardium in the context of
insulin resistance, which was previously not well-appreciated.


## 7. Conclusions

In summary, the heart requires a
continuous and abundant source of substrate to meet it high-energy demands. In
situations where energy needs change, such as heart failure, the heart must
adapt and will utilize the most efficient source of substrate (glucose) to meet
its needs. Similarly, when glucose availability becomes limited, as it does in
fasting or diabetes, the heart will adapt and use fatty acid to meet its ATP
requirements. PPARα
and PGC-1α
play a central role in this metabolic flexibility by driving robust changes in
gene expression of key components of mitochondrial biogenesis and metabolism.
However, it is still not entirely clear whether long-term PPARα-PGC-1α-mediated
alterations in energy metabolism are adaptive versus maladaptive changes for both heart failure and diabetic
cardiomyopathy.



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