A critical role for PPARα-mediated lipotoxicity in the pathogenesis of diabetic cardiomyopathy: Modulation by dietary fat content

Abstract

To explore the role of peroxisome proliferator-activated receptor ␣ (PPAR␣)-mediated derangements in myocardial metabolism in the pathogenesis of diabetic cardiomyopathy, insulinopenic mice with PPAR␣ deficiency (PPAR␣ ؊/؊ ) or cardiac-restricted overexpression [myosin heavy chain (MHC)-PPAR] were characterized. Whereas PPAR␣ ؊/؊ mice were protected from the development of diabetes-induced cardiac hypertrophy, the combination of diabetes and the MHC-PPAR genotype resulted in a more severe cardiomyopathic phenotype than either did alone. Cardiomyopathy in diabetic MHC-PPAR mice was accompanied by myocardial longchain triglyceride accumulation. The cardiomyopathic phenotype was exacerbated in MHC-PPAR mice fed a diet enriched in triglyceride containing long-chain fatty acid, an effect that was reversed by discontinuing the high-fat diet and absent in mice given a medium-chain triglyceride-enriched diet. Reactive oxygen intermediates were identified as candidate mediators of cardiomyopathic effects in MHC-PPAR mice. These results link dysregulation of the PPAR␣ gene regulatory pathway to cardiac dysfunction in the diabetic and provide a rationale for serum lipid-lowering strategies in the treatment of diabetic cardiomyopathy. Results of epidemiologic studies indicate that diabetic individuals are at an extraordinarily high risk for the development of cardiovascular disease. The prevalence of risk factors including hyperlipidemia and hypertension certainly contribute to the high incidence of cardiovascular disease in the diabetic population. However, myocardial dysfunction (diabetic cardiomyopathy) is common in diabetic individuals independent of hypertension and coronary artery disease (1). In addition, morbidity and mortality after myocardial infarction is significantly greater in diabetic compared with nondiabetic patients (2). Although the pathogenesis of diabetic cardiomyopathy is poorly understood, recent evidence implicates perturbations in cardiac energy metabolism. Whereas mitochondrial fatty acid oxidation (FAO) is the chief energy source for the normal postnatal mammalian heart, the relative contribution of glucose utilization pathways is significant, allowing the plasticity necessary for steady ATP production in the context of diverse physiologic and dietary conditions (3). Because of the importance of insulin in the regulation of myocardial metabolism, chronic insulin deficiency or resistance results in a marked reduction in cardiac glucose utilization such that the heart relies almost exclusively on fatty acids to generate energy (4, 5). High rates of fatty acid utilization in the diabetic heart could lead to functional derangements related to accumulation of lipid intermediates, mitochondrial or peroxisomal generation of reactive oxygen species, or excessive oxygen consumption.Recently, we found that the diabetes-induced shift in cardiac fuel preference is associated with activation of the peroxisome proliferator-activated receptor (PPAR) ␣ gene regulatory system (6). PPAR␣ is a nuclear receptor that ...

Macrophages modulate cardiac function in lipotoxic cardiomyopathy

“…In many diabetic patients, this can occur in the absence of underlying coronary artery disease or hypertension, a phenomenon known as diabetic cardiomyopathy (1). The pathogenesis of diabetic cardiomyopathy is complex; however, myocardial lipid overload is a pathologic feature of this condition in humans and in animal models (6,7,12,25). The observation that cardiac myocyte lipid overload causes cardiomyopathy in genetic mouse models, without systemic abnormalities of insulin or glucose metabolism, supports the notion that excess lipids can be cardiotoxic (4,5,7,32).…”

Glucagon‐like peptide‐1 ameliorates cardiac lipotoxicity in diabetic cardiomyopathy via the PPARα pathway

“…It alone drives the pathologic changes and functional abnormalities in diabetic hearts (Finck et al., 2002, 2003). Therefore, the effects of GLP‐1 on PPARα expression in diabetes were explored.…”

“…PPARα may hasten the progress of DCM (Finck et al., 2002, 2003). In the present study, PPARα KO mice failed to develop DCM.…”

“…Cardiac‐restricted PPARα overexpression (MHC‐PPARα) in mice mimicked the DCM phenotype. These animals were relatively more susceptible to serious cardiomyopathy in response to high‐fat diets (HFD) or streptozotocin (STZ) stimulation and presented with significant increases in lipids accumulation (Finck et al., 2002, 2003; Yang et al., 2007). Therefore, PPARα activation‐induced metabolic abnormalities in diabetic hearts may be promising as therapeutic DCM targets.…”

Similar patterns of myocardial metabolism and perfusion in patients with type 2 diabetes and heart disease of ischaemic and non-ischaemic origin

“…The causal role of insulin resistance in nonischaemic heart failure (HF) is well defined. Animal models have repeatedly demonstrated the existence of an insulin-resistant cardiomyopathy [3], which is characterised by an inefficient energy metabolism [3,4] and can be reversed by improving energy (glucose) use [5]. In addition, clinical studies in humans strongly suggest a link between insulin resistance and non-ischaemic HF.…”