Impact of peroxisome proliferator-activated receptor-α on diabetic cardiomyopathy

Abstract

The prevalence of cardiomyopathy is higher in diabetic patients than those without diabetes. Diabetic cardiomyopathy (DCM) is defined as a clinical condition of abnormal myocardial structure and performance in diabetic patients without other cardiac risk factors, such as coronary artery disease, hypertension, and significant valvular disease. Multiple molecular events contribute to the development of DCM, which include the alterations in energy metabolism (fatty acid, glucose, ketone and branched chain amino acids) and the abnormalities of subcellular components in the heart, such as impaired insulin signaling, increased oxidative stress, calcium mishandling and inflammation. There are no specific drugs in treating DCM despite of decades of basic and clinical investigations. This is, in part, due to the lack of our understanding as to how heart failure initiates and develops, especially in diabetic patients without an underlying ischemic cause. Some of the traditional anti-diabetic or lipid-lowering agents aimed at shifting the balance of cardiac metabolism from utilizing fat to glucose have been shown inadequately targeting multiple aspects of the conditions. Peroxisome proliferator-activated receptor α (PPARα), a transcription factor, plays an important role in mediating DCM-related molecular events. Pharmacological targeting of PPARα activation has been demonstrated to be one of the important strategies for patients with diabetes, metabolic syndrome, and atherosclerotic cardiovascular diseases. The aim of this review is to provide a contemporary view of PPARα in association with the underlying pathophysiological changes in DCM. We discuss the PPARα-related drugs in clinical applications and facts related to the drugs that may be considered as risky (such as fenofibrate, bezafibrate, clofibrate) or safe (pemafibrate, metformin and glucagon-like peptide 1-receptor agonists) or having the potential (sodium-glucose co-transporter 2 inhibitor) in treating DCM.

Keywords: Diabetic cardiomyopathy; Glucagon-like peptide 1-receptor agonists; Metformin; PPARα modulator; Sodium–glucose co-transporter type 2 inhibitors.

Fig. 1

Alteration of cardiac metabolism under diabetic condition. Although circulating levels of branched chain amino acids (BCAA), ketones, glucose and fatty acids are increased under diabetic condition, their oxidation rates are not increased accordingly. Reduced BCAA and glucose oxidation, while increased ketone and fatty acid oxidation are evident in diabetic subject. Thus, reduced ATP production contributes to cardiac dysfunction

Fig. 2

Metabolism of branched chain amino acids (BCAAs) and ketones. a BCAAs consist of valine, leucine and isoleucine. The metabolic homeostasis of BCAAs is controlled by a series of BCAA catabolic including branched chain aminotransferase (BCAT) and branched chain α-keto acid dehydrogenase (BCKDH). As the rate-limiting enzyme of BCAA degradation, activity of BCKDH is regulated by phosphorylation/inactivation via BCKDH-kinase (BCKD), while dephosphorylated and activated by a mitochondrion-localized protein phosphatase-2C. BCAAs are converted to acetyl CoA, which enters the tricarboxylic acid cycle (TCA) and electron transport chain (ETC) to generate ATP. b Ketone bodies are produced predominantly in the liver through ketogenesis, as the form of acetone, β-hydroxybutyrate and acetoacetate. The later two are the the main ketones circulating in the blood and transported to heart for oxidation. Once ketones enter the cardiomyocytes and be transported to the mitochondrial matrix, β-hydroxybutyrate and acetoacetate is oxidized into acetyl-CoA by β-hydroxybutyrate-dehydrogenase (BDH) and succinyl-CoA:3-oxoacid-CoA-transferase (SCOT). Acetyl CoA enters TCA and ETC to generate ATP

Fig. 3

PPARα, pemafibrate, metformin and cellular abnormalities in diabetic cardiomyopathy (DCM). In diabetes, enhanced hepatic lipids, glucose and BCAA output are enhanced, resulting in lipids accumulation, increased O-GlcNAcylation and mTORC1 activation in heart. Along with the altered mitochondrial energy metabolism, these intracellular abnormalities contribute to the formation of cardiac hypertrophy and cardiac dysfunction. Pemafibrate, a novel selective PPARα modulator, is highly effective in activating PPARα than the conventional fibrates and having a better triglyceride-lowering activity through up-regulating not only hepatic fibroblast growth factor 21 (FGF21), but also lipoprotein lipase (LPL) in mice. Metformin is used in treating DCM due to its effect on reduces hepatic gluconeogenesis by inhibiting phosphoenolpyruvate carboxykinase (PEPCK). In addition, an effect of metformin in reducing circulating branched chain amino acids (BCAA) is observed in insulin-resistant mice. Further studies need to clarify if metformin may reduce cardiac hypertrophy through down-regulating BCAA-mediated mTORC1 pathway