Activation of a HIF1alpha-PPARgamma 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)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.
Krishnan
Jaya
J
Institute of Cell Biology and Competence Center for Systems Physiology and Metabolic Diseases, ETH Zurich, Zurich, Switzerland.
Suter
Marianne
M
Windak
Renata
R
Krebs
Tatiana
T
Felley
Allison
A
Montessuit
Christophe
C
Tokarska-Schlattner
Malgorzata
M
Aasum
Ellen
E
Bogdanova
Anna
A
Perriard
Evelyne
E
Perriard
Jean-Claude
JC
Larsen
Terje
T
Pedrazzini
Thierry
T
Krek
Wilhelm
W
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
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