The role of the peroxisome proliferator-activated receptor alpha (PPAR alpha) 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 fo r pump function. Flux through the cardiac FAO pathway is tightly controlled in accordance with energy demands dictated by diverse physiologic and diet ary conditions. in this report, we demonstrate that the lipid-activated nuc lear receptor, peroxisome proliferator-activated receptor alpha (PPAR alpha ), regulates the expression of several key enzymes involved in cardiac mito chondrial FAO. In response to the metabolic stress imposed by pharmacologic inhibition of mitochondrial long-chain fatty acid import with etomoxir, PP ARa serves as a molecular 'lipostat' factor by inducing the expression of t arget genes involved in fatty acid utilization including enzymes involved i n mitochondrial and peroxisomal beta-oxidation pathways. In mice lacking PP AR alpha (PPAR alpha-/- mice), etomoxir precipitates a cardiac phenotype ch aracterized by myocyte lipid accumulation. Surprisingly, this metabolic reg ulatory response is influenced by gender as demonstrated by the observation that male PPAR alpha-/- mice are more susceptible to the metabolic stress compared to female animals. These results identify an important role for PP AR alpha in the control of cardiac lipid metabolism.