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

TLDR

The study investigates how PPARα‑mediated metabolic derangements contribute to diabetic cardiomyopathy by characterizing insulin‑openic mice lacking PPARα or with cardiac‑restricted PPARα overexpression. Using these genetically modified mice, the authors examined myocardial metabolism and lipid accumulation to elucidate PPARα’s role. They found that PPARα deficiency protected against diabetes‑induced cardiac hypertrophy, whereas cardiac overexpression worsened cardiomyopathy with triglyceride buildup, was intensified by a high‑fat diet, mitigated by diet change, and linked to reactive oxygen species, supporting lipid‑lowering therapies for diabetic heart disease.

Abstract

To explore the role of peroxisome proliferator-activated receptor α (PPARα)-mediated derangements in myocardial metabolism in the pathogenesis of diabetic cardiomyopathy, insulinopenic mice with PPARα deficiency (PPARα −/− ) or cardiac-restricted overexpression [myosin heavy chain (MHC)-PPAR] were characterized. Whereas PPARα −/− 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 long-chain 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 PPARα gene regulatory pathway to cardiac dysfunction in the diabetic and provide a rationale for serum lipid-lowering strategies in the treatment of diabetic cardiomyopathy.