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

Peter Mirtschink, Jaya Krishnan, Fiona Grimm, Alexandre Sarre, Manuel Hörl, Melis Kayikci, Niklaus Fankhauser, Yann Christinat, Cédric Cortijo, Owen Feehan, Ana Vukolic, Samuel Sossalla, Sebastian N. Stehr, Jernej Ule, Nicola Zamboni, Thierry Pedrazzini and Wilhelm Krek ()
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Peter Mirtschink: Institute of Molecular Health Sciences, ETH Zurich
Jaya Krishnan: Institute of Molecular Health Sciences, ETH Zurich
Fiona Grimm: Institute of Molecular Health Sciences, ETH Zurich
Alexandre Sarre: University of Lausanne
Manuel Hörl: Institute of Molecular Systems Biology, ETH Zurich
Melis Kayikci: MRC-Laboratory of Molecular Biology
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
Nicola Zamboni: Institute of Molecular Systems Biology, ETH Zurich
Thierry Pedrazzini: University of Lausanne
Wilhelm Krek: Institute of Molecular Health Sciences, ETH Zurich

Nature, 2015, vol. 522, issue 7557, 444-449

Abstract: 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.

Date: 2015
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DOI: 10.1038/nature14508

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