title: HIF-driven SF3B1 induces KHK-C to enforce fructolysis and heart disease.
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.
authors.affiliation: Institute of Molecular Health Sciences, ETH Zurich, 8093 Zürich, Switzerland.
authors.forename: Peter
authors.initials: P
authors.lastname: Mirtschink
authors.affiliation: Institute of Molecular Health Sciences, ETH Zurich, 8093 Zürich, Switzerland.
authors.forename: Jaya
authors.initials: J
authors.lastname: Krishnan
authors.affiliation: Institute of Molecular Health Sciences, ETH Zurich, 8093 Zürich, Switzerland.
authors.forename: Fiona
authors.initials: F
authors.lastname: Grimm
authors.affiliation: Department of Medicine, University of Lausanne, 1011 Lausanne, Switzerland.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Sarre
authors.affiliation: Institute of Molecular Systems Biology, ETH Zurich, 8093 Zürich, Switzerland.
authors.forename: Manuel
authors.initials: M
authors.lastname: Hörl
authors.affiliation: MRC-Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK.
authors.forename: Melis
authors.initials: M
authors.lastname: Kayikci
authors.affiliation: Institute of Molecular Health Sciences, ETH Zurich, 8093 Zürich, Switzerland.
authors.forename: Niklaus
authors.initials: N
authors.lastname: Fankhauser
authors.affiliation: Institute of Molecular Health Sciences, ETH Zurich, 8093 Zürich, Switzerland.
authors.forename: Yann
authors.initials: Y
authors.lastname: Christinat
authors.affiliation: Institute of Molecular Health Sciences, ETH Zurich, 8093 Zürich, Switzerland.
authors.forename: Cédric
authors.initials: C
authors.lastname: Cortijo
authors.affiliation: Institute of Molecular Health Sciences, ETH Zurich, 8093 Zürich, Switzerland.
authors.forename: Owen
authors.initials: O
authors.lastname: Feehan
authors.affiliation: Institute of Molecular Health Sciences, ETH Zurich, 8093 Zürich, Switzerland.
authors.forename: Ana
authors.initials: A
authors.lastname: Vukolic
authors.affiliation: Universitätsmedizin Göttingen, Klinik für Kardiologie und Pneumologie, D-37075 Göttingen, and DZHK (German Centre for Cardiovascular Research), Partner Site Göttingen, Germany.
authors.forename: Samuel
authors.initials: S
authors.lastname: Sossalla
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, University Hospital Jena, 07747 Jena, Germany.
authors.forename: Sebastian N
authors.initials: SN
authors.lastname: Stehr
authors.affiliation: MRC-Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK.
authors.forename: Jernej
authors.initials: J
authors.lastname: Ule
authors.affiliation: Institute of Molecular Systems Biology, ETH Zurich, 8093 Zürich, Switzerland.
authors.forename: Nicola
authors.initials: N
authors.lastname: Zamboni
authors.affiliation: Department of Medicine, University of Lausanne, 1011 Lausanne, Switzerland.
authors.forename: Thierry
authors.initials: T
authors.lastname: Pedrazzini
authors.affiliation: Institute of Molecular Health Sciences, ETH Zurich, 8093 Zürich, Switzerland.
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Krek
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D005631:Fructokinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D005632:Fructose / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007527:Isoenzymes / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D008297:Male; D024821:Metabolic Syndrome / Q000378:metabolism; D051379:Mice; D010750:Phosphoproteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000072260:RNA Splicing Factors; D017413:Ribonucleoprotein, U2 Small Nuclear / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: C497442:HIF1A protein, human; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007527:Isoenzymes; D010750:Phosphoproteins; D000072260:RNA Splicing Factors; D017413:Ribonucleoprotein, U2 Small Nuclear; C112491:SF3B1 protein, human; C491799:Sf3b1 protein, mouse; D005632:Fructose; D005631:Fructokinases; C021475:ketohexokinase