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

Détails

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Etat: Public
Version: de l'auteur
ID Serval
serval:BIB_B50534218442
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
HIF-driven SF3B1 induces KHK-C to enforce fructolysis and heart disease.
Périodique
Nature
Auteur(s)
Mirtschink P., Krishnan J., Grimm F., Sarre A., Hörl M., Kayikci M., Fankhauser N., Christinat Y., Cortijo C., Feehan O., Vukolic A., Sossalla S., Stehr S.N., Ule J., Zamboni N., Pedrazzini T., Krek W.
ISSN
1476-4687 (Electronic)
ISSN-L
0028-0836
Statut éditorial
Publié
Date de publication
2015
Peer-reviewed
Oui
Volume
522
Numéro
7557
Pages
444-449
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't Publication Status: ppublish
Résumé
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.
Pubmed
Web of science
Création de la notice
20/07/2015 10:10
Dernière modification de la notice
20/08/2019 15:23
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