Peroxisome Proliferator-activated Receptor α (PPARα) Signaling in the Gene Regulatory Control of Energy Metabolism in the Normal and Diseased Heart

Abstract 

B. N. Finck and D. P. Kelly. Peroxisome Proliferator-activated Receptor α (PPARα) Signaling in the Gene Regulatory Control of Energy Metabolism in the Normal and Diseased Heart. Journal of Molecular and Cellular Cardiology (2002) 34, 1249–1257. The tremendous energy demands of the post-natal mammalian heart are fulfilled via dynamic flux through mitochondrial oxidative pathways. The capacity for energy production via fatty acid (FA) β-oxidation pathway is determined, in part, by the regulated expression of genes encoding FA utilization enzymes and varies in accordance with diverse dietary and physiologic conditions. For example, fasting and diabetes activate the expression of cardiac FA oxidation (FAO). Peroxisome proliferator-activated receptor α (PPARα) is a ligand-activated transcription factor that is known to control the expression of many genes involved in cellular FA import and oxidation. Cardiac FA utilization rates are reduced in PPARα null mice due to diminished expression of genes encoding FAO enzymes. Recent work has shown that the PPARα regulatory pathway is deactivated in pathologic cardiac hypertrophy and hypoxia, two circumstances characterized by reduced FAO and increased dependence on glucose as a fuel source. Conversely, the activity of the PPARα gene regulatory pathway is increased in the diabetic heart, which relies primarily on FAO for energy production. In fact, evidence is emerging that excessive FA import and oxidation may be a cause of pathologic cardiac remodeling in the diabetic heart. This review summarizes the regulation of cardiac substrate utilization pathways via the PPARα complex in the normal and diseased heart.

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• f1 Please address all correspondence to: Daniel P. Kelly, MD, Center for Cardiovascular Research, Washington University School of Medicine, 660 South Euclid Avenue, Box 8086, St Louis, MO 63110, USA. Tel: 314-362-8908; Fax: 314-362-0186; E-mail:dkelly@imgate.wustl.edu