PPARs modulate cardiac metabolism and mitochondrial function in diabetes
© The Author(s). 2017
Received: 25 August 2016
Accepted: 5 December 2016
Published: 10 January 2017
Diabetic cardiomyopathy is a major complication of diabetes mellitus (DM). Currently, effective treatments for diabetic cardiomyopathy are limited. The pathophysiology of diabetic cardiomyopathy is complex, whereas mitochondrial dysfunction plays a vital role in the genesis of diabetic cardiomyopathy. Metabolic regulation targeting mitochondrial dysfunction is expected to be a reasonable strategy for treating diabetic cardiomyopathy. Peroxisome proliferator-activated receptors (PPARs) are master executors in regulating glucose and lipid homeostasis and also modulate mitochondrial function. However, synthetic PPAR agonists used for treating hyperlipidemia and DM have shown controversial effects on cardiovascular regulation. This article reviews our updated understanding of the beneficial and detrimental effects of PPARs on mitochondria in diabetic hearts.
KeywordsCardiomyopathy Diabetes mellitus Mitochondria Metabolism Peroxisome proliferator-activated receptors
Diabetes mellitus (DM) is one of the most common chronic diseases, and its prevalence continues to increase worldwide [1, 2]. Cardiovascular disease is the leading cause of morbidity and mortality in patients with DM. Diabetic cardiomyopathy is recognized as a distinct disease entity, since diabetic patients have an increased incidence of heart failure in the absence of hypertension, coronary artery disease, or valvular heart disease [3–5]. Diabetic cardiomyopathy is characterized by cardiac lipid accumulation, myocardial fibrosis, and increased myocardial cell death, all of which lead to left ventricular remodeling and hypertrophy, diastolic dysfunction, and ultimately systolic impairment . The pathophysiology of diabetic cardiomyopathy is complex and yet to be fully elucidated. Altered cardiac metabolism and mitochondrial dysfunction are proposed mechanisms underling diabetic cardiomyopathy .
Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors and major executors of modulating glucose and lipid homeostasis . There are three PPAR isoforms (PPAR-α, PPAR-β/PPAR-δ, and PPAP-γ), which differ in distribution, function, and ligand specificity. Accumulating evidence suggests that PPARs play crucial roles in cardiovascular disease . PPAR isoforms are differentially expressed in the atria and ventricles of diabetic hearts because of the increased inflammatory cytokines and oxidative stress . Moreover, we found increases in protein and messenger (m) RNA expressions of PPAR-γ, but decreases in protein and mRNA expressions of PPAR-α and PPAR-δ in hypertensive hearts. Diabetic spontaneously hypertensive rats were associated with greater reductions in cardiac PPAR-α and PPAR-δ, but higher increases in PPAR-γ mRNA and protein levels than were spontaneously hypertensive rats . Diabetic cardiomyopathy is associated with an increase in cardiac PPAR-γ and a decrease in PPAR-α, resulting in altered glucose transportation, increased cardiac lipid accumulation, and progressive diabetic cardiomyopathy [7, 10–12]. Calcitriol and histone deacetylase inhibitor improved diabetic cardiomyopathy by modulating cardiac PPAR expressions and regulating fatty acid metabolism [13, 14]. Mitochondria are the center of fatty acid and glucose metabolism and are thus likely to be impacted by metabolic derangements in DM. Proper mitochondrial function is critical for maintaining optimal cardiac performance. Several mouse models of mitochondrial defects are relevant to human cardiomyopathy . Patients with inherited mitochondrial disorders frequently manifest cardiac dysfunction, such as dilated or hypertrophic cardiomyopathy and conduction defects . This review elucidates our current understanding of different PPARs and their agonists on mitochondrial function in diabetic hearts.
Cardiac metabolism in normal and diabetic hearts
Altered cardiac metabolism in diabetes
Alteration of cardiac metabolism
Increases fatty acid β-oxidation
Decreases glucose oxidation
Reduces GLUT4 expression and translocation
High fatty acid oxidation suppresses PFK1 through accumulation of citrate in the cytosol
High fatty acid oxidation inhibits PDH through activation of PDK
Increases the expression of fatty acid transporters
PPAR-α activation promotes the expressions of genes that regulate fatty acid β-oxidation
Mitochondrial dysfunction in diabetic hearts
Mitochondria act as the powerhouse of cells because they generate most of the cell’s supply of ATP. Cardiomyocytes contain a relatively large amount of mitochondria (approximately 40% of the cardiomyocyte volume is comprised of mitochondria), because the heart has a high and continuous demand for ATP . In response to diverse physiological and nutritional conditions, it is critical to control the metabolic activity of mitochondria to meet cellular energy requirements.
A substantial body of evidence has demonstrated that there is significantly impaired mitochondrial function in diabetic cardiomyopathy. Excessive fatty acid uptake in diabetic hearts results in an altered mitochondrial architecture and reduced expressions of genes involved in mitochondrial oxidative phosphorylation . Moreover, PPAR-α activates genes involved in fatty acid uptake and β-oxidation, but does not increase expressions of genes associated with the tricarboxylic acid cycle or mitochondrial oxidative phosphorylation. Thus, the upregulated mitochondrial fatty acid uptake and β-oxidation may exceed the capacity of downstream mitochondrial respiration and lead to an accumulation of toxic lipid metabolites, which further worsens insulin resistance. In addition, increased fatty acid β-oxidation augments delivery of electrons to the mitochondrial electron transport chain and results in an elevated mitochondrial inner membrane potential, which stimulates reactive oxygen species (ROS) generation [19, 20]. ROS directly impair mitochondria and/or oxidize lipids to yield reactive lipid peroxidation, as a result of inducing oxidative damage to mitochondrial proteins that are associated with energy metabolism and oxidative phosphorylation. Moreover, ROS can activate mitochondrial uncoupling, and subsequently reduce cardiac efficiency [19–21, 23]. Excessive fatty acids lead to the generation of ceramide. Ceramide triggers apoptosis through nitric oxide- and peroxynitrite-mediated opening of mitochondrial permeability transition pores and release of cytochrome c. Ceramide also suppresses mitochondrial respiration through directly inhibiting the activity of mitochondrial electron transport chain complex III [19, 24]. Incomplete fat oxidation and accumulated toxic fatty acid intermediates lead to mitochondrial dysfunction through hyperpolarization of the mitochondrial inner membrane potential, mitochondrial uncoupling, and generation of ROS [21, 23, 25].
Upregulation of mitochondrial uncoupling proteins is another potential explanation for the reduced mitochondrial efficiency in diabetic hearts. Uncoupling proteins cause proton leaks across mitochondrial membranes from ATP synthesis, thereby decreasing the generation of mitochondrial superoxide. Increased mitochondrial uncoupling is presumably an adaptive mechanism; however, sustained activation of mitochondrial uncoupling may adversely affect cardiomyocyte ATP production and contractile function in DM [21, 25, 26]. Mitochondrial calcium handling was proposed to represent a mechanism for coordinating the ATP supply and demand for cardiomyocyte contractions . Mitochondrial calcium uptake may also act as a spatial buffering system, which regulates the activity of calcium-dependent processes and signaling . The mitochondrial transmembrane potential is not only required for ATP synthesis, but also plays a crucial role in driving calcium accumulation in mitochondria. Disruption of the mitochondrial membrane potential in the diabetic heart leads to altered mitochondrial calcium handling which contributes to the development of diabetic cardiomyopathy .
Mitochondrial DNA encodes proteins for the electron transport chain, which is localized in the mitochondrial inner membrane and drives ATP production through oxidative phosphorylation. The damage to mitochondrial DNA leads to impairment of mitochondrial respiration and ATP synthesis. Because dysfunctional mitochondria are a major source of ROS production, mitochondrial DNA is a vulnerable target of ROS damage [23, 29]. Several investigations have implied that cardiomyocyte apoptosis promotes the development of diabetic cardiomyopathy. Diabetic mice showed enhanced apoptotic signaling in the heart that was associated with changes in the mitochondrial membrane potential and the opening in mitochondrial permeability transition pores . Findings from mitochondrial proteomic studies in diabetic hearts supported the role of mitochondrial-induced apoptosis in diabetic cardiomyopathy . Furthermore, cardiac fibrosis is a major feature of diabetic cardiomyopathy. Apoptotic cardiomyocytes are replaced by fibrotic tissues. Myocardial fibrosis contributes to increased stiffness and decreased compliance of the ventricular wall, resulting in left ventricle dysfunction. Mitochondrial dysfunction augments ROS production, which is thought to be a crucial driving force for cardiac fibrosis [6, 32–34].
A number of studies provided evidence for mitochondrial alternations in hearts of patients with DM. Diastolic dysfunction in association with a reduction in myocardial energy metabolism was demonstrated using magnetic resonance techniques in asymptomatic normotensive patients with well—controlled DM . Mitochondria in atrial tissues of diabetic patients revealed a sharply decreased capacity for respiration and increased mitochondrial hydrogen peroxide emissions, suggesting an increase in oxidative stress . An association of worsened cardiac mitochondrial respiration with a reduced mitochondrial calcium retention capacity with decreased contractile performance in heart tissues of diabetic patients was shown before the onset of clinical cardiomyopathy .
PPARs regulate myocardial energy metabolism in diabetes
PPAR-δ is expressed in multiple tissues and shares certain similarities with PPAR-α in regulating cardiac lipid metabolism. Cardiac-specific deletion of PPAR-δ down regulates constitutive myocardial fatty acid oxidation, and induces myocardial lipid accumulation and cardiac hypertrophy in mice . Fatty acids and PPAR-δ-selective ligands increase fatty acid oxidation through transcriptional activation in both neonatal and adult cardiomyocytes [43, 44]. However, the PPAR-δ-selective ligand does not modify the expression of PPAR-α in cultured cardiomyocytes. PPAR-δ activation can partially restore the blunted expressions of genes encoding cardiac fatty acid oxidation enzymes in PPAR-α-knockout mice. These findings suggest that PPAR-δ-regulated cardiac fatty acid metabolism might not wholly interact with PPAR-α [44, 45]. Moreover, there was increasing myocardial glucose utilization without myocardial lipid accumulation or cardiac dysfunction in transgenic mice with cardiac-specific overexpression of PPAR-δ. Accordingly, PPAR-α and PPAR-δ may exert distinct cardiac metabolic regulatory actions .
PPAR-γ plays a crucial role in regulating lipid storage and adipogenesis. PPAR-γ is expressed at levels far below those of PPAR-α and PPAR-δ in the heart. PPAR-γ ligands do not affect the fatty acid oxidation rate or metabolic gene expression in cardiomyocytes . It was suggested that PPAR-γ modulates cardiac energy metabolism through its effects on extra cardiac tissues. Activation of PPAR-γ promotes glucose uptake and triglyceride synthesis in adipose tissues. Reductions in circulating glucose and fatty acid levels caused by PPAR-γ activation may directly modulate cardiac PPAR-α and PPAR-δ activities . Cardiac-specific PPAR-γ-overexpressing transgenic mice developed dilated cardiomyopathy with increased myocardial lipid and glycogen stores and upregulated cardiac expressions of genes associated with fatty acid utilization and glucose metabolism . The mechanism underlying cardiomyopathy in PPAR-γ-overexpressing transgenic mice was hypothesized to be combined lipid and glucose toxicity .
Adenosine monophosphate-activated protein kinase (AMPK) and PPAR-γ co-activator (PGC)-1α are two major signaling molecules that regulate mitochondrial biogenesis. AMPK upregulates mitochondrial biogenesis through activation of PGC-1α, which is a master metabolic regulator that coordinates gene expressions in association with mitochondrial biogenesis and respiratory function . Lee et al. showed that diabetic hearts have a lower ratio of phosphorylated AMPK2α to total AMPK2α and greater expression of PGC-1α compared to those of control rats [13, 14]. The up regulation of PGC-1α enables diabetic hearts to enhance their mitochondrial oxidative capacity . Therefore, up regulation of PPAR-α and PGC-1α may initially be adaptive responses in diabetic hearts [21, 25, 50]. However, sustained increases in fatty acid β-oxidation are detrimental to cardiac mitochondria and further promote the development of diabetic cardiomyopathy [21, 23, 25].
PPARs modulate mitochondrial function
Effects of PPAR-α on mitochondria
Transgenic mice with cardiac-specific overexpression of PPAR-α had disorganized mitochondria, altered mitochondrial cristae density and architecture, and decreased expressions of genes involved in mitochondrial metabolism, including the tricarboxylic acid cycle and oxidative phosphorylation . The cristae of mitochondria increased in number and density in cardiomyocytes of PPAR-α-null mice . These findings suggest that abnormal expression of PPAR-α is linked to an altered mitochondrial structure and metabolic function.
Effects of peroxisome proliferator-activated receptor (PPAR)-α agonists on mitochondria
Effects on mitochondria
Potential beneficial effects
Stimulates mitochondrial fatty acid β-oxidation
Improves mitochondrial oxidative capacity
Reduces mitochondrial membrane potential depolarization and apoptosis
Upregulates mitochondrial uncoupling protein 2
Reduces mitochondrial membrane potential depolarization and apoptosis
Modulates mitochondrial biogenesis and apoptosis
Upregulates mitochondrial uncoupling protein two
Induces mitochondrial CPT I expression
Stimulates mitochondrial fatty acid β-oxidation
Possible harmful effects
Inhibits mitochondrial respiratory chain complex I activity
Induces the mitochondrial permeability transition
Effects of PPAR-γ on mitochondria
Overexpression of cardiac PPAR-γ via the cardiac α-myosin heavy chain promoter produced a distorted architecture of the mitochondrial inner matrix and disrupted cristae in PPAR-γ transgenic mice . Transgenic mice overexpressing PPAR-γ2 had significantly increased expression of mitochondrial uncoupling protein one, elevated levels of PGC-1α, and reduced mitochondrial ATP concentrations in the subcutaneous fat . Cardiac expression of the gene encoding manganese superoxide dismutase as a mitochondrial antioxidant was suppressed in cardiac-specific PPAR-γ-knockout mice .
Effects of peroxisome proliferator-activated receptor (PPAR)-γ agonists on mitochondria
Effects on mitochondria
Potential beneficial effects
Upregulates expressions of mitochondrial respiratory complex I ~ IV genes
Increases the relative number of mitochondria
Maintains mitochondrial potential to promote cell survival
Regulates mitochondrial pyruvate import
Increases the mitochondrial DNA copy number
Increases mitochondrial biogenesis
Increase genes involved in the fatty acid oxidation
Regulates mitochondrial pyruvate import
Controls maximal mitochondrial respiratory rates
Possible harmful effects
Alters mitochondrial respiratory function
Changes membrane permeability
Damages the mitochondrial structure
Inhibits mitochondrial complex I activity and cell respiration
Substantial evidence has shown that TZDs exert direct and rapid PPAR-γ-independent effects on mitochondrial respiration, thereby leading to changes in glycolytic metabolism and fuel substrate specificity [71, 72]. It was shown that clinically relevant concentrations of TZDs acutely, specifically, and partially inhibit mitochondrial pyruvate carrier activity, thereby improving cellular glucose handling in human myocytes . Laboratory studies revealed that TZDs have a recognition site in the inner mitochondrial membrane that is comprised of a protein complex, which is involved in mitochondrial pyruvate importation . Pioglitazone was shown to specifically bind to a protein named mitoNEET, which is an iron-containing outer mitochondrial membrane protein, that is involved in controlling maximal mitochondrial respiratory rates . Therefore, these findings suggest that development of novel molecules designed to maintain this mitochondrial interaction while specifically avoiding significant interactions with PPAR-γ is very appropriate for clinical treatments.
Impaired mitochondrial biogenesis and function associated with derangement of cardiac metabolism play vital roles in the pathogenesis of diabetic cardiomyopathy. Therefore metabolic regulation targeting mitochondrial dysfunction may show therapeutic potential for treating diabetic cardiomyopathy. Synthetic PPAR-α and PPAR-γ agonists not only regulate expressions of genes involving lipid and glucose metabolism, but also modulate mitochondrial function and therefore appear to be promising treatments for diabetic cardiomyopathy. However, unfavorable effects of PPAR activation on cardiac mitochondria were also observed. Additional studies are required to develop optimal pharmacological approaches to improve mitochondrial function in diabetic hearts.
Adenosine monophosphate-activated protein kinase
Cluster of differentiation 36
Carnitine palmitoyltransferase 1
Glucose transporter type 4
Peroxisome proliferator-activated receptor
Reactive oxygen species
We gratefully acknowledge all of the funding sources.
This work was supported by grants from the Ministry of Science and Technology of Taiwan (MOST 104-2314-B-038-032 and 105-2314-B-038-019-MY2) and Taipei Medical University, Wan Fang Hospital (105-wf-phd-03 and 105-swf-09).
Availability of data and materials
“Not applicable” (The present paper is a review article that describes published data).
YHK, YJC, and KJB conceptualized, organized, and revised the content, and TWL, YHK, TFC, and TIL wrote the manuscript together. All authors read and approved the final manuscript.
The authors declare that they have no competing interests.
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Ethics approval and consent to participate
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