The cardiac phenotype induced by PPARα overexpression mimics that caused by diabetes mellitus

Abstract

Recent evidence has defined an important role for PPARα in the transcriptional control of cardiac energy metabolism. To investigate the role of PPARα in the genesis of the metabolic and functional derangements of diabetic cardiomyopathy, mice with cardiac-restricted overexpression of PPARα (MHC-PPAR) were produced and characterized. The expression of PPARα target genes involved in cardiac fatty acid uptake and oxidation pathways was increased in MHC-PPAR mice. Surprisingly, the expression of genes involved in glucose transport and utilization was reciprocally repressed in MHC-PPAR hearts. Consistent with the gene expression profile, myocardial fatty acid oxidation rates were increased and glucose uptake and oxidation decreased in MHC-PPAR mice, a metabolic phenotype strikingly similar to that of the diabetic heart. MHC-PPAR hearts exhibited signatures of diabetic cardiomyopathy including ventricular hypertrophy, activation of gene markers of pathologic hypertrophic growth, and transgene expression-dependent alteration in systolic ventricular dysfunction. These results demonstrate that (a) PPARα is a critical regulator of myocardial fatty acid uptake and utilization, (b) activation of cardiac PPARα regulatory pathways results in a reciprocal repression of glucose uptake and utilization pathways, and (c) derangements in myocardial energy metabolism typical of the diabetic heart can become maladaptive, leading to cardiomyopathy.

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.…”

“…Serum glucose levels were measured by tail blood glucometry (Bayer Corp., Mishawaka, IN, USA) 2 weeks after the first injection. Mice with random blood glucose levels >16.7 m m were considered diabetic and were recruited for the subsequent experiments (Finck et al., 2002). The DM were randomly divided into four groups: (i) DM; (ii) DM subcutaneously injected with exendin‐4 (Ex‐4) at 100 μg kg −1  day −1 ; (iii) DM orally treated with saxagliptin (Saxa) at 10 mg kg −1  day −1 ; (iv) DM treated with 1.5 U insulin.…”

“…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.…”

Lipid metabolism and its implications for type 1 diabetes-associated cardiomyopathy

“…Peroxisome proliferatoractivated receptor (PPAR)-alpha is a master regulator of many of these processes, modulating the expression of genes involved in FA uptake and modification, as well as lipid and glucose oxidation (Burkart et al 2007). Indeed, overexpression of Ppar-alpha in a cardiac-specific manner mimics much of the changes observed in the setting of diabetes including increased FA oxidation and decreased glucose oxidation, with concomitant cardiac hypertrophy and dysfunction (Finck et al 2002). In settings of both T1D and T2D, the heart becomes almost completely reliant upon FAs as a source of energy.…”