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

Author

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  • Peter Mirtschink

    (Institute of Molecular Health Sciences, ETH Zurich)

  • Jaya Krishnan

    (Institute of Molecular Health Sciences, ETH Zurich
    † Present addresses: MRC Clinical Sciences Centre London, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 ONN, UK (J.K.); MRC National Institute for Medical Research, The Ridgeway, London NW7 1AA, UK (F.G.); MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK (M.K.); Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK (J.U.).)

  • Fiona Grimm

    (Institute of Molecular Health Sciences, ETH Zurich
    † Present addresses: MRC Clinical Sciences Centre London, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 ONN, UK (J.K.); MRC National Institute for Medical Research, The Ridgeway, London NW7 1AA, UK (F.G.); MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK (M.K.); Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK (J.U.).)

  • Alexandre Sarre

    (University of Lausanne)

  • Manuel Hörl

    (Institute of Molecular Systems Biology, ETH Zurich)

  • Melis Kayikci

    (MRC-Laboratory of Molecular Biology
    † Present addresses: MRC Clinical Sciences Centre London, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 ONN, UK (J.K.); MRC National Institute for Medical Research, The Ridgeway, London NW7 1AA, UK (F.G.); MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK (M.K.); Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK (J.U.).)

  • Niklaus Fankhauser

    (Institute of Molecular Health Sciences, ETH Zurich)

  • Yann Christinat

    (Institute of Molecular Health Sciences, ETH Zurich)

  • Cédric Cortijo

    (Institute of Molecular Health Sciences, ETH Zurich)

  • Owen Feehan

    (Institute of Molecular Health Sciences, ETH Zurich)

  • Ana Vukolic

    (Institute of Molecular Health Sciences, ETH Zurich)

  • Samuel Sossalla

    (Universitätsmedizin Göttingen, Klinik für Kardiologie und Pneumologie, D-37075 Göttingen, and DZHK (German Centre for Cardiovascular Research), Partner Site Göttingen)

  • Sebastian N. Stehr

    (University Hospital Jena)

  • Jernej Ule

    (MRC-Laboratory of Molecular Biology
    † Present addresses: MRC Clinical Sciences Centre London, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 ONN, UK (J.K.); MRC National Institute for Medical Research, The Ridgeway, London NW7 1AA, UK (F.G.); MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK (M.K.); Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK (J.U.).)

  • Nicola Zamboni

    (Institute of Molecular Systems Biology, ETH Zurich)

  • Thierry Pedrazzini

    (University of Lausanne)

  • Wilhelm Krek

    (Institute of Molecular Health Sciences, ETH Zurich)

Abstract

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.

Suggested Citation

  • Peter Mirtschink & Jaya Krishnan & Fiona Grimm & Alexandre Sarre & Manuel Hörl & Melis Kayikci & Niklaus Fankhauser & Yann Christinat & Cédric Cortijo & Owen Feehan & Ana Vukolic & Samuel Sossalla & S, 2015. "HIF-driven SF3B1 induces KHK-C to enforce fructolysis and heart disease," Nature, Nature, vol. 522(7557), pages 444-449, June.
    • Handle: RePEc:nat:nature:v:522:y:2015:i:7557:d:10.1038_nature14508
    DOI: 10.1038/nature14508
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