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HIF-driven SF3B1 induces KHK-C to enforce fructolysis and heart disease.

  • Mirtschink P Institute of Molecular Health Sciences, ETH Zurich, 8093 Zürich, Switzerland.
  • Krishnan J Institute of Molecular Health Sciences, ETH Zurich, 8093 Zürich, Switzerland.
  • Grimm F Institute of Molecular Health Sciences, ETH Zurich, 8093 Zürich, Switzerland.
  • Sarre A Department of Medicine, University of Lausanne, 1011 Lausanne, Switzerland.
  • Hörl M Institute of Molecular Systems Biology, ETH Zurich, 8093 Zürich, Switzerland.
  • Kayikci M MRC-Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK.
  • Fankhauser N Institute of Molecular Health Sciences, ETH Zurich, 8093 Zürich, Switzerland.
  • Christinat Y Institute of Molecular Health Sciences, ETH Zurich, 8093 Zürich, Switzerland.
  • Cortijo C Institute of Molecular Health Sciences, ETH Zurich, 8093 Zürich, Switzerland.
  • Feehan O Institute of Molecular Health Sciences, ETH Zurich, 8093 Zürich, Switzerland.
  • Vukolic A Institute of Molecular Health Sciences, ETH Zurich, 8093 Zürich, Switzerland.
  • Sossalla S Universitätsmedizin Göttingen, Klinik für Kardiologie und Pneumologie, D-37075 Göttingen, and DZHK (German Centre for Cardiovascular Research), Partner Site Göttingen, Germany.
  • Stehr SN Department of Anesthesiology and Critical Care Medicine, University Hospital Jena, 07747 Jena, Germany.
  • Ule J MRC-Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK.
  • Zamboni N Institute of Molecular Systems Biology, ETH Zurich, 8093 Zürich, Switzerland.
  • Pedrazzini T Department of Medicine, University of Lausanne, 1011 Lausanne, Switzerland.
  • Krek W Institute of Molecular Health Sciences, ETH Zurich, 8093 Zürich, Switzerland.
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  • 2015-06-18
Published in:
  • Nature. - 2015
Alternative Splicing
Animals
Cardiomyopathy, Hypertrophic
Disease Models, Animal
Fructokinases
Fructose
Humans
Hypoxia-Inducible Factor 1, alpha Subunit
Isoenzymes
Male
Metabolic Syndrome
Mice
Phosphoproteins
RNA Splicing Factors
Ribonucleoprotein, U2 Small Nuclear
English Fructose is a major component of dietary sugar and its overconsumption exacerbates key pathological features of metabolic syndrome. The central fructose-metabolising enzyme is ketohexokinase (KHK), which exists in two isoforms: KHK-A and KHK-C, generated through mutually exclusive alternative splicing of KHK pre-mRNAs. KHK-C displays superior affinity for fructose compared with KHK-A and is produced primarily in the liver, thus restricting fructose metabolism almost exclusively to this organ. Here we show that myocardial hypoxia actuates fructose metabolism in human and mouse models of pathological cardiac hypertrophy through hypoxia-inducible factor 1α (HIF1α) activation of SF3B1 and SF3B1-mediated splice switching of KHK-A to KHK-C. Heart-specific depletion of SF3B1 or genetic ablation of Khk, but not Khk-A alone, in mice, suppresses pathological stress-induced fructose metabolism, growth and contractile dysfunction, thus defining signalling components and molecular underpinnings of a fructose metabolism regulatory system crucial for pathological growth.
Language
  • English
Open access status
green
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Persistent URL
https://sonar.ch/global/documents/143655
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