The role of the peroxisome proliferator-activated receptor α (PPARα) in the control of cardiac lipid metabolism

The postnatal mammalian heart uses mitochondrial fatty acid oxidation (FAO) as the chief source of energy to meet the high energy demands necessary for pump function. Flux through the cardiac FAO pathway is tightly controlled in accordance with energy demands dictated by diverse physiologic and dietary conditions. In this report, we demonstrate that the lipid-activated nuclear receptor, peroxisome proliferator-activated receptor α (PPARα), regulates the expression of several key enzymes involved in cardiac mitochondrial FAO. In response to the metabolic stress imposed by pharmacologic inhibition of mitochondria long-chain fatty acid import with etomoxir, PPARa serves as a molecular 'lipostat' factor by inducing the expression of target genes involved in fatty acid utilization including enzymes involved in mitochondrial and peroxisomal β-oxidation pathways. In mice lacking PPARα (PPARα-/- mice), etomoxir precipitates a cardiac phenotype characterized by myocyte lipid accumulation. Surprisingly, this metabolic regulatory response is influenced by gender as demonstrated by the observation that male PPARα-/- mice are more susceptible to the metabolic stress compared to female animals. These results identify an important role for PPARα in the control of cardiac lipid metabolism.