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Title

Activation of a HIF1alpha-PPARgamma axis underlies the integration of glycolytic and lipid anabolic pathways in pathologic cardiac hypertrophy

Authors
Krishnan, Jaya
Suter, Marianne
Windak, Renata
Krebs, Tatiana
Felley, Allison
Tokarska-Schlattner, Malgorzata
Aasum, Ellen
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Published in Cell Metabolism. 2009, vol. 9, no. 6, p. 512-524
Abstract 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)1alpha and PPARgamma, 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, HIF1alpha activates glycolytic genes and PPARgamma, 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 Hif1alpha in mice prevents hypertrophy-induced PPARgamma activation, the consequent metabolic reprogramming, and contractile dysfunction. We propose a model in which activation of the HIF1alpha-PPARgamma axis by pathologic stress underlies key changes in cell metabolism that are characteristic of and contribute to common forms of heart disease.
Keywords AnimalsApoptosisCardiomegaly/*metabolismFatty Acids/metabolism*GlycolysisHypoxia-Inducible Factor 1, alpha Subunit/genetics/*metabolism*Lipid MetabolismMiceMice, KnockoutMyocytes, Cardiac/metabolismPPAR gamma/genetics/*metabolismPhosphoric Monoester Hydrolases/metabolismUp-RegulationVon Hippel-Lindau Tumor Suppressor Protein/metabolism
Identifiers
PMID: 19490906
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Research group Biologie du myocarde (22)
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KRISHNAN, Jaya et al. Activation of a HIF1alpha-PPARgamma axis underlies the integration of glycolytic and lipid anabolic pathways in pathologic cardiac hypertrophy. In: Cell Metabolism, 2009, vol. 9, n° 6, p. 512-524. https://archive-ouverte.unige.ch/unige:19899

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Deposited on : 2012-04-23

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