Activation of a HIF1α-PPARγ Axis Underlies the Integration of Glycolytic and Lipid Anabolic Pathways in Pathologic Cardiac Hypertrophy

Development of cardiac hypertrophy and progression to heart failure entails profound changes in myocardial metabolism, characterized by a switch from fatty acid utilization to glycolysis and lipid accumulation. We report that hypoxia-inducible factor (HIF)1 alpha and PPAR gamma, key mediators of glycolysis and lipid anabolism, respectively, are jointly upregulated in hypertrophic cardiomyopathy and cooperate to mediate key changes in cardiac metabolism. In response to pathologic stress, HIF1 alpha activates glycolytic genes and PPAR gamma, whose product, in turn, activates fatty acid uptake and glycerolipid biosynthesis genes. These changes result in increased glycolytic flux and glucose-to-lipid conversion via the glycerol-3-phosphate pathway, apoptosis, and contractile dysfunction. Ventricular deletion of Hif1 alpha in mice prevents hypertrophy-induced PPAR-gamma activation, the consequent metabolic reprogramming, and contractile dysfunction. We propose a model in which activation of the HIF1 alpha-PPAR gamma axis by pathologic stress underlies key changes in cell metabolism that are characteristic of and contribute to common forms of heart disease.