title: Activation of a HIF1alpha-PPARgamma axis underlies the integration of glycolytic and lipid anabolic pathways in pathologic cardiac hypertrophy.
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.
authors.affiliation: Institute of Cell Biology and Competence Center for Systems Physiology and Metabolic Diseases, ETH Zurich, Zurich, Switzerland.
authors.forename: Jaya
authors.initials: J
authors.lastname: Krishnan
authors.forename: Marianne
authors.initials: M
authors.lastname: Suter
authors.forename: Renata
authors.initials: R
authors.lastname: Windak
authors.forename: Tatiana
authors.initials: T
authors.lastname: Krebs
authors.forename: Allison
authors.initials: A
authors.lastname: Felley
authors.forename: Christophe
authors.initials: C
authors.lastname: Montessuit
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Tokarska-Schlattner
authors.forename: Ellen
authors.initials: E
authors.lastname: Aasum
authors.forename: Anna
authors.initials: A
authors.lastname: Bogdanova
authors.forename: Evelyne
authors.initials: E
authors.lastname: Perriard
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Perriard
authors.forename: Terje
authors.initials: T
authors.lastname: Larsen
authors.forename: Thierry
authors.initials: T
authors.lastname: Pedrazzini
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Krek
mesh_terms: D000818:Animals; D017209:Apoptosis; D006332:Cardiomegaly / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism; D006019:Glycolysis; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D050356:Lipid Metabolism; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000378:metabolism; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D015854:Up-Regulation; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000378:metabolism
chemical_list: D005227:Fatty Acids; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D047495:PPAR gamma; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D010744:Phosphoric Monoester Hydrolases; C040842:glycerol-1-phosphatase; C494469:VHL protein, mouse