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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Alternative Splicing
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Animals
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Cardiomyopathy, Hypertrophic / genetics
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Cardiomyopathy, Hypertrophic / metabolism*
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Cardiomyopathy, Hypertrophic / pathology
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Cardiomyopathy, Hypertrophic / physiopathology
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Disease Models, Animal
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Fructokinases / deficiency
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Fructokinases / genetics
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Fructokinases / metabolism*
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Fructose / metabolism*
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Humans
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Hypoxia-Inducible Factor 1, alpha Subunit / genetics
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Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
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Isoenzymes / deficiency
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Isoenzymes / genetics
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Isoenzymes / metabolism
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Male
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Metabolic Syndrome / metabolism
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Mice
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Phosphoproteins / deficiency
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Phosphoproteins / genetics
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Phosphoproteins / metabolism*
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RNA Splicing Factors
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Ribonucleoprotein, U2 Small Nuclear / deficiency
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Ribonucleoprotein, U2 Small Nuclear / genetics
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Ribonucleoprotein, U2 Small Nuclear / metabolism*
Substances
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HIF1A protein, human
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Hif1a protein, mouse
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Hypoxia-Inducible Factor 1, alpha Subunit
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Isoenzymes
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Phosphoproteins
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RNA Splicing Factors
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Ribonucleoprotein, U2 Small Nuclear
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SF3B1 protein, human
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Sf3b1 protein, mouse
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Fructose
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Fructokinases
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ketohexokinase